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Gene Regulation and
Therapeutics for Cancer
Editors
Surinder K. Batra, Ph.D
and
Moorthy P. Ponnusamy, Ph.D
Department of Biochemistry and Molecular Biology
University of Nebraska Medical Center, Omaha, NE, USA
p,
A SCIENCE PUBLISHERS BOOK
Cover illustration reproduced by kind courtesy of the editors.
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Version Date: 20200723
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Library of Congress Cataloging-in-Publication Data
Names: Batra, Surinder K., editor. | Ponnusamy, Moorthy P., editor.

Title: Gene regulation and therapeutics for cancer / editors, Surinder K.
Batra and Moorthy P. Ponnusamy.
Description: First edition. | Boca Raton, FL : CRC Press, [2020] | Includes
bibliographical references.
Identifiers: LCCN 2020013566 | ISBN 9781138712423 (hardcover)
Subjects: MESH: Neoplasms--therapy | Molecular Targeted Therapy |
Neoplasms--genetics | Gene Expression Regulation, Neoplastic--drug
effects
Classification: LCC RC270.8 | NLM QZ 266 | DDC 616.99/406--dc23
able at https://lccn.loc.gov/2016028261
LC record available at https://lccn.loc.gov/2020013566
Visit the Taylor & Francis Web site at

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Preface
Physicians and research scientists have been working “hand in hand” to find
every possible way to prevent and treat patients from the deadly disease
“cancer” since the early 1900. The fact that “cancer is a complex disease
involving several drivers and passenger mutations in multiple “oncogene
and tumor suppressor” genes makes it more challenging to identify an
appropriate drug to manage numerous signalling”. One among five thousand
pre-clinically investigated drugs will take a journey time of around 10-12
years to travel from lab bench to pharmacy shelf with 2.5 bn investment.
Hence, it is necessary to understand the root cause of its molecular mechanism
controlled by the genes and their product proteins to better manage and to
design targeted therapies.
In the first edition of this book, we focused on discussing the genes that
regulate several cancers, and available and optimized targeted therapies
along with first-line treatment options to treat such cancers. These chapters
comprehensively cover 13 different topics reviewing different cancers such
as head and neck, lung, pancreatic, prostate, breast cancers, and paediatric
Medulloblastoma. Several research scientists and physicians who are experts
in pre-clinical drug testing in mouse models and translating its benefits to
cancer centres discussed these chapters. We extensively discuss the role
of transcriptional dysregulations in cancer. The authors provide a strong
rationale to target such a transcriptional effector and the re-programming
process driving the cancer. Most targeted therapeutics developed to date
have been focused on targeting proteins encoding cell surface or cytoplasmic
kinases that function in intracellular signalling cascades while leaving a sub-
group of cell-surface proteins such as mucins. One of the chapters addresses
the regulation of mucins and targeted therapy in pancreatic cancer.
Furthermore, the authors also discuss the role and biomarker potential
of few secretory factors such as MUC5AC and exosomes in cancers. This
chapter deals with the recent development and early detection strategies
using liquid biopsies in pancreatic cancer. Because early detection is one of
the significant challenges in pancreatic cancer, it can also be used to predict
treatment response. In particular, summarized studies on the development
and contributions of PD-1-mediated immunomodulatory effects in pancreatic
cancer. One of the chapters summarizes the targeting approach of subgroup-
specific cancer epitopes for effective treatment of paediatric Medulloblastoma.
iv Gene Regulation and Therapeutics for Cancer
Furthermore, two individual chapters focus on prostate cancer biology, and

contemporary updates on clinically developed therapeutics for castration-
resistant prostate cancer were also discussed. In the final section of this
book, the applications of cancer stem cells as a promising target in cancer
therapy to abrogate aggressiveness, drug-resistance, and recurrence nature,
as observed in most solid tumors are highlighted.
We strongly believe this edition, with all the recent information, will be
very knowledgeable for students, scientists, and physicians who are working
in the field of gene regulation and targeted therapy for different cancers.
We sincerely hope that the discussed inhibitors, chemotherapy, or targeted
therapy agents will serve as a platform to design future clinical trials and aid
in curing cancer patients.
Surinder K. Batra
Moorthy P. Ponnusamy
Contents
Preface iii
1. Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory

Effects in Pancreatic Cancer 1
Ashu Shah, Catherine Orzechowski and Maneesh Jain
2. Nuclear Factor Kappa-B: Bridging Inflammation and Cancer 23
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair,
Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad and
Ajay Pratap Singh
3. The S100A7/8/9 Proteins: Novel Biomarker and Therapeutic
Targets for Solid Tumor Stroma 50
Sanjay Mishra, Dinesh Ahirwar, Mohd W. Nasser and
Ramesh K. Ganju
4. Nuclear Receptor Coactivators: Mechanism and Therapeutic
Targeting in Cancer 73
Andrew Cannon, Christopher Thomson, Rakesh Bhatia and Sushil Kumar
5. Liquid Biopsies for Pancreatic Cancer: A Step Towards Early
Detection 108
Joseph Carmicheal, Rahat Jahan, Koelina Ganguly, Ashu Shah and
Sukhwinder Kaur
6. Targeting Subgroup-specific Cancer Epitopes for Effective
Treatment of Pediatric Medulloblastoma 132
Sidharth Mahapatra and Naveen Kumar Perumal
7. Aberrant Methylation of UC Promoters in Human Pancreatic
Ductal Carcinomas 151
Michiyo Higashi and Seiya Yokoyama
8. Receptor Tyrosine Kinase Signaling Pathways as a Goldmine
for Targeted Therapy in Head and Neck Cancers 163
Muzafar A. Macha, Satyanarayana Rachagani, Sanjib Chaudhary,
Zafar Sayed, Dwight T. Jones and Surinder K. Batra
vi Gene Regulation and Therapeutics for Cancer
9. Molecular Drivers in Lung Adenocarcinoma: Therapeutic

Implications 185
Imayavaramban Lakshmanan and Apar Kishor Ganti
10. Molecular Mediator of Prostate Cancer Progression and
Its Implication in Therapy 207
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam
and Kaustubh Datta
11. Therapeutic Options for Prostate Cancer: A Contemporary
Update 234
Sakthivel Muniyan, Jawed A. Siddiqui and Surinder K. Batra
12. Regulation and Targeting of MUCINS in Pancreatic Cancer 264
Shailendra K. Gautam, Abhijit Aithal, Grish C. Varshney and
Parthasarathy Seshacharyulu
13. Targeted Therapy for Cancer Stem Cells 291
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik,
Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu and
Moorthy P. Ponnusamy
Index 321
CHAPTER
1
Programmed Death 1 Receptor (PD-1)-
mediated Immunomodulatory Effects
in Pancreatic Cancer
Ashu Shah1, Catherine Orzechowski1 and Maneesh Jain1,2*

1 Department of Biochemistry and Molecular Biology, University of Nebraska
Medical Center, Omaha, NE, USA
2 Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center,
Omaha, NE, USA
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal, treatment
refractory malignancies that has emerged as the third leading cause of cancer
related deaths in the United States. The overall five-year survival rate for
PDAC patients is dismally low at 8% with an estimated 55,440 new cases
and 44,330 deaths in the year 2018 [1]. Existing therapies for PDAC include
chemotherapy, radiotherapy, and radical surgery. However, the failure to
diagnose PDAC at an early stage makes the treatment options ineffective in
almost 80% of the patients. Even after surgery, recurrence occurs in 80% of
the patients. Till now, only five FDA approved drugs and one combination
therapy exists for PDAC patients [2]. Chemotherapy combined with
radiation has not shown much success in the patients. The reasons attributed
to inadequacy of treatment options is complex molecular landscape of
pancreatic tumors [2].
Pancreatic cancer is driven by an accumulation of several activating
mutations in the oncogene KRAS and inactivating mutations in tumor
suppressor genes TP53, CDKN2A (p16), and SMAD4 in the normal pancreatic
duct epithelium. Activating KRAS mutations are present in approximately
95% of PDAC cases and is responsible for activation of PI3K-Akt, notch
pathway, hedgehog signaling, and STAT3 pathways which are potent drivers
of tumor initiation and maintenance. In addition, shortened telomerase,
genomic instability and epigenetic alterations play significant roles in the
*Corresponding author: mjain@unmc.edu

2 Gene Regulation and Therapeutics for Cancer
progression of pancreatic cancer [3]. The disease is believed to originate

from a spectrum of precursor lesions including pancreatic intraepithelial
neoplasms (PanINs), intraductal papillary neoplasm (IPMN), and mucinous
cystic neoplasm (MCN) which over several years develop into aggressive
PDAC that invades surrounding tissues and metastasize to different organs.
PDAC is characterized by dense stroma (desmoplasia) comprising
pancreatic stellate cells, fibroblasts, vascular, glial, smooth muscle cells, fat
cells, epithelial cells, and immune cells along with extracellular matrix (ECM)
and extracellular molecules surrounding epithelial cells. PDAC progression
is driven by a complex interplay between tumor cells and the surrounding
cells of stroma [4].
Immune System in Pancreatic Cancer

PDAC is characterized by infiltration of both innate and adaptive immune cells
including monocytes, macrophages (M1, M2), dendritic cells, B cells (B1, B2,
Breg), T cell subtypes (Teff, Treg), NK cells and myeloid derived suppressor cells
(MDSC). Although the proportion of these immune cells may vary but their
number, location, and stage of maturation in the tumor microenvironment,
and their ultimate functional differentiation may impact tumor growth and
progression [5, 6]. Intricate cross-talk of infiltrating immune cells, with tumor
cells and other stromal cells, result in the establishment of a microenvironment
rich in immunosuppressive myeloid and lymphoid subtypes [7, 8]. PDAC is
enriched in M2 macrophages, neutrophils, CD4+ T cells, Treg and relatively
less number of CD8+ T cells [9, 10]. Therefore, PDAC has generally been
considered as a poorly immunogenic cancer [11]. However, studies in KPC
and other pancreatic cancer mouse models have highlighted the sensitivity
of pancreatic cancer to CD8+ T cell mediated cytotoxicity [12, 13]. Also, recent
studies have clustered PDAC patients into three subtypes on the basis of
genetic and transcriptional signatures and these subtypes display differences
in their immune cytolytic activity suggesting the importance of immune
activity in PDAC [14]. Conversely, multiple studies indicate that PDAC is
characterized by lesser immune cell infiltration compared to other cancers
such as melanoma, NSCLC, and HNSC where immunotherapy has been
successful [15-17].
Checkpoint Blockade Receptor Programmed Death-1

Receptor (PD-1) in Pancreatic Cancer
Tumor cells exploit intrinsic mechanisms of immune evasion which include
reduced antigen presentation, increased expression of immunosuppressive
molecules such as PD-L1 and accumulation of antigen specific Tregs in
the tumor microenvironment resulting in immunosuppression [18]. The
immune system is characterized by its ability to distinguish between normal
cells in the body and tumor cells through the expression of costimulatory
Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory… 3
and coinhibitory molecules on immune cells called immune checkpoints.

These immune checkpoint molecules play a key role in immunoregulation
and immune homeostasis through on-off switch mechanisms and protect
the host against autoimmunity. However, tumor cells use these checkpoint
molecules to protect themselves from an attack by the immune system. One
such checkpoint protein, PD-1, is a coinhibitory receptor which is present
on conventional T cells in conjunction with other costimulatory and co-
inhibitory molecules and is an important regulator of T cell activation. PD-1
operates as off switch to limit T cell activation by interacting with its ligand,
PD-L1, present on normal cells. Under inflammatory conditions like cancer,
receptor PD-1 overexpression on T cells is congruent with upregulation of
its ligand PD-L1 on antigen presenting cells (APC) and tumor cells [19]. The
interaction between PD-1 receptor and its ligand PD-L1 leads to suppressed
T cell activation and proliferation which promotes an immunosuppressed
condition in the inflammatory microenvironment.
Extensive research over the last two decades on dense desmoplastic
stroma in PDAC has elucidated the role of the inflammatory milieu in
preventing specific and significant immune response within the tumor. Many
immunosuppressive mechanisms operate simultaneously in the PDAC
microenvironment, thus making PDAC inaccessible to immunotherapy.
Nomi et al. investigated, for the first time, the expression of PD-L1 on
human pancreatic cancer cells [20] and showed an association of PD-L1
with poor survival outcomes in PDAC patients. This was associated with
lesser number of CD8+ T cells in tumor infiltrating lymphocytes of patients
with increased PD-L1 expression. Higher PD-L1 levels in 51 human PDAC
samples have been correlated with tumor growth rather than progression
in contrast to other cancers where PD-L1 expression has been shown to be
associated with advanced stage of disease [21, 22]. However, these findings
need to be validated in studies with a larger cohort of PDAC patients. The
importance of PD-1/PD-L1 axis in pancreatic cancer was further evaluated
by testing anti-PD-L1 antibody in the Panc02 subcutaneous mouse model.
Treatment with anti-PD-L1 antibody after two weeks of tumor development
resulted in a significant reduction of tumor growth along with an increase in
tumor reactive CD8+ T cells infiltration and IFNγ, Granazyme B and perforin
secretion in the tumor. Furthermore, combination of anti-PD-L1 antibody
with the FDA approved chemotherapeutic drug Gemcitabine resulted in a
substantial decrease in tumor growth as compared to gemcitabine treatment
alone [23]. Similar results were obtained with anti-PD-L1 and anti-PD-L2
antibodies in a mouse model, with orthotopically implanted Panc02 cells
where antibody treatment resulted in significant tumor suppression along
with enhanced intratumoral infiltration of IFNγ-producing CD8+ T cells and
reduced FoxP3+ Treg cells [24]. However, these preclinical observations were
not recapitulated in subsequent clinical studies where PDAC patients were
found to be refractory to anti-PD-1 therapy [25]. A possible explanation for
this can be the difference in heterogeneity of murine and human tumors;
while murine Panc02 tumors are hypermutated, human pancreatic tumors

have low mutational load [26]. Another study evaluated the efficacy of anti-
PD-1 antibodies in KPC mouse model of PDAC which closely recapitulates
the immune environment of human disease. In both KPC mouse and human
PDAC, expression of PD-L1 is independent of the presence of tumor-specific
CD8+ T cells [23]. In spite of very high expression of immune checkpoint
molecules PD-1, CTLA4 in the tumor microenvironment and upregulation
of PD-L1 in tumor associated dendritic cells and macrophages, anti-PD-1
antibodies did not show any effect on tumor growth. The contrasting
results with anti-PD-1 antibody in two different models of PDAC represent
the difference in tumor biology and malignancy. Interestingly, anti-PD-1
antibodies in combination with anti-CD40 agonist showed significant tumor
cell killing by activated CD8+ T cells and enhanced survival of tumor-bearing
KPC mice by 80%. Nevertheless, these studies demonstrated the relevance
of immune checkpoint receptor, PD-1 in PDAC and the induction of tumor
immune response combined with checkpoint blockade might provide a
curative treatment for PDAC.
PD-1 Regulation in Pancreatic Cancer

PD-1 and its ligand PD-L1 are expressed on infiltrating immune cells and
tumor cells, respectively, and are regulated through intrinsic immune
resistance and adaptive resistance mechanisms. Oncogenes activating Akt and
STAT3 pathways have been shown to regulate constitutive PD-L1 expression
in triple negative breast cancer and NSCLC [27, 28]. This phenomenon is
referred to as intrinsic immune resistance. In contrast, IFN- secreted by CD8+
T cells stimulates the upregulation of PD-L1 on tumor cells, as shown in
melanoma, HNSCC, and other solid tumors [19, 29, 30], resulting in adaptive
immune resistance. These resistance mechanisms have been acquired by
tumors for immune evasion. As a result, anti-PD-1 immunotherapy has
shown an effect in PD-L1 induced immunosuppressed patients. Surprisingly,
in PDAC no correlation was observed between IFNγ and PD-L1 expression
on tumor cells, although intratumoral dendritic cells and macrophages
exhibited slightly elevated PD-L1 in tumors with high IFNγ secretion [23].
Possibly, this difference in expression levels of PD-L1 on tumor cells could
be another determinant for unresponsiveness to anti-PD-1/PD-L1 antibody
efficacy in PDAC unlike other cancers. In contrast, one recent study showed
uniform and higher expression of PD-L1 on mouse tumor cells Panc02 and
UN-KC-6141, both in vitro and in vivo orthotopic tumors, human pancreatic
tumor cell lines, and 60-90% of human PDAC tumor samples coupled with
a corresponding increase in PD-1 on tumor infiltrating CD8+ T cells [31-33].
This discrepancy in levels of PD-L1 in pancreatic tumors might be attributed
to different anti-PD-L1 antibodies being used for detection. Furthermore,
the role of epigenetic mechanisms in regulating PD-L1 expression in PDAC
is just beginning to be unravelled. In contrast to the normal pancreas, PD-
L1 (CD274) promoter region in both human and mouse pancreatic tumor
cells exhibited enhanced H3K4 methylation by histone methylase MLL1

suggesting its transcriptional activation in PDAC. This observation also
opens a new avenue of epigenetic targeting for improved therapeutic efficacy
of immune checkpoint inhibitors in nonresponding PDAC patients. In fact,
inhibition of MLL1 activity resulted in enhanced efficacy of anti-PD-1/PD-
L1 immunotherapy in pancreatic cancer but, the combination of epigenetic
and immune checkpoint inhibitor did not show a synergistic effect which
may need further optimization in terms of dose and timing of treatments
[30]. Very recently, the role of microbiome in mediating PDAC progression
through modulating tumor microenvironment and induction of immune
suppression has been deciphered in the mouse model [32]. The same study
showed upregulation of PD-1 in intratumoral CD4+ and CD8+ T cells after
microbiome ablation which became more evident when the reduction in
tumor growth was observed by combination therapy of oral antibiotic
(microbiome ablation) and anti-PD-1 antibody.
Immune Cells Mediated PD-1 Regulation in

Pancreatic Cancer
PDAC immune suppressive tumor microenvironment has been proposed
as a major hallmark of cancer pathogenesis [34, 35]. How the multifaceted
interactions between tumor and tumor infiltrating myeloid and lymphoid
cells help cancer cells to evade immune surveillance, are not fully understood
which might explain the reason for not much success gained with current
immunotherapeutic strategies. Here, we discuss in detail how these
interactions induce immunosuppression through PD-1/PD-L1 axis.
Myeloid Cells in Mediating PD-1/PD-L1 Activation

in PDAC Microenvironment
The initial observation that myeloid derived cells suppress T cell activation
was made two decades ago and has been well established in various cancers.
Immature myeloid cells have the potential to differentiate between various
subsets such as macrophages, dendritic cells, endothelial cells, neutrophils,
and myeloid derived suppressor cells (MDSC) in tumors. Of importance,
these different myeloid subsets function through multiple mechanisms
such as nitric oxide production, STAT5 signaling inhibition, T cell function
suppression by nitrosylation of essential amino acids, switching CD4+ T
cell differentiation to Treg and induction of immunosuppression in tumor
microenvironment [4, 36-38]. High numbers of tumor infiltrating myeloid cells
have been shown to be associated with relapse and poor survival of PDAC
patients [9, 39, 40]. Different signaling pathways such as JAK-STAT, CSF1-
CSF1R, and MAPK form a crosslink between the immune system and non-
immune cells and inhibit the immune cell activation along with promoting the
factors for immunosuppression (Fig. 1) [31, 41]. Several attempts have been
Fig. 1: Signaling axes implicated in the regulation of PD-1/PD-L1 expression and

downstream events in pancreatic tumor microenvironment. IFNγ secreted from
activated CD8+ T cells increases the expression of PD-L1 on tumor cells which in
turn binds to PD-1 on T cells and result in their functional exhaustion. EGFR-MAPK,
JAK-STAT and CSF1-CSF1R signaling axes augment PD-L1 expression on myeloid
derived suppressor cells (MDSC), dendritic cells and macrophages respectively,
leading to PD-1/PD-L1 mediated exhaustion of CD8+ T cells. IL-18 Secreted from
tumor cells induce PD-L1 expression on Breg cells by binding to IL-18R.
made to target these signaling pathways using pharmacological inhibitors in

haematological malignancies [42]. Role of these signaling axes in regulating
PD-1/PD-L1 expression on myeloid cells have been dissected and blocking
these pathways have increased the efficacy of anti-PD-1/PD-L1 antibodies
in tumor regression in vitro and in vivo mouse models [31, 42]. For example,
inhibition of the CSF1-CSF1R signaling resulted in elevated expression of
PD-L1 and CTLA-4 in the tumors, and the treatment increased the efficacy of
the anti-PD-1 antibody in the mouse model of PDAC [43]. This was attributed
to the selective depletion of the CD206Hi population of tumor infiltrating
macrophages and the reprograming of remaining TAMs for reduced
immunosuppression and decreased PD-1 expression with CSF1R inhibition.
Recently, selective inhibition of IFNγ-STAT1 signaling in JAK-STAT pathway
resulted in an increase in CTL infiltration and induction of T cell response
in an orthotropic mouse model of PDAC. This was possibly linked to the
reduction of IFNγ induced PD-L1 expression on pancreatic tumors and thus
diminished PD-1-PD-L1 interaction in the tumor microenvironment [31].
STAT3, another arm of JAK-STAT pathway and a key molecule for Kras
driven PDAC progression, upon activation augments immunosuppressive
conditions in the tumor microenvironment and inhibits T cell activation thus
enhancing PD-1/PD-L1 mediated immune suppression in the pancreatic
tumor microenvironment [44]. Reg3g through HMOX1 (heme-oxygenase),
dendritic cell maturation inhibiting enzyme, activation and induction of
JAK2/STAT3 signaling pathway, promoted the upregulation of PD-1 and

PD-L1 on DCs and T cells respectively in orthotopic pancreatic tumor mice
and thereby abolished cross priming and cytotoxic activities of T cells [45].
Previous studies have demonstrated the role of Reg3g activated HMOX1 in
regulating immune suppression by causing dendritic cell impairment [46].
The role of EGFR-MAPK signaling in the upregulation of PD-L1 expression
on various myeloid cell populations including macrophages, MDSCs, stromal
cells and to some extent on pancreatic tumor cells has also been described
[47]. Confirmation of the role of EGFR ligand in PD-L1 regulation has been
deciphered using MEK inhibitors which resulted in the reduction of PD-L1
expression. Interestingly, MEK inhibitors increased the efficacy of anti-PD-1
antibody, reducing the tumor burden in a mouse model.
Taken together, these findings suggest the importance of combining
signaling inhibitors with checkpoint inhibitor for the regression of well-
established PDAC tumors.
Regulatory B- and T-cells Mediated PD-1 Regulation

in Pancreatic Cancer
Regulatory B (Breg) and T (Treg) cells play an important role in maintaining
immune tolerance by suppressing the proinflammatory response of B and
T cells. The role of B cells became more evident when their transfer into
mammary tumor-bearing B cell deficient mice (BCDM) led to Treg proliferation
and depletion of CD8+ T cells and NK cells in the tumor microenvironment
and thereby enhanced tumor growth [48]. Similarly, in another study,
adoptive transfer of WT B cells in oxaliplatin treated BCDM mice interfered
with oxaliplatin-mediated tumor reduction while PD-L1 or IL10 deficient B
cells enhanced the efficacy of oxalplatin in tumor regression, thus suggesting
an independent role of IL-10 and PD-L1 in Breg mediated immunosuppression
[49, 50]. Several studies have shown Breg mediated conversion of CD4+ T
cells to Tregs which subsequently attenuates the immune response in various
cancers [51, 52]. Accumulating evidence now suggests that infiltration of
Bregs in the tumor microenvironment of several solid cancers leads to an
immunosuppressive phenotype. Bregs exhibit immunosuppression through
PD-L1, lymphotoxin, IL-10, TGFβ secretion and interaction with other
immune cells. In PDAC patients, a significantly higher number of Bregs in
peripheral blood than healthy controls has been correlated with tumor node
metastasis (TNM) stage [53]. In addition, IL10+ Bregs displayed higher IL-18R
expression which on binding to IL-18 secreted from pancreatic tumor cells,
induced PD-L1 expression on Bregs. Tregs participate in the negative regulation
of immune response by suppressing effector T cell proliferation and activation.
Presence of Tregs has been associated with disease progression in PDAC and
correlates with poor prognosis [54]. Indeed, the level of tumor infiltrating
Tregs was higher in PD-L1 positive pancreatic tumors than PD-L1 negative
ones [55], suggesting a plausible role of PD-L1 in immune downregulation
8
Table 1: Active clinical trials investigating PD-1-PD-L1 axis targeting alone or in combination immunotherapy
approaches for pancreatic cancer
Type of therapy Name Target population Clinical trial Phase (status)

number
Single agent checkpoint Pembrolizumab Resectable or Borderline NCT02305186 PI
inhibitor PD-1/PD-L1 resectable pancreatic cancer
Advanced or metastatic cancers NCT01295827 PI
(1 Pancreatic cancer patient)
MDX-11-5 Pancreatic cancer NCT00729664 PI completed, no objective
(anti-PD-L1) responses in patients with
colorectal or pancreatic
cancer, efficacy in 50% of
pancreatic cancer patients
observed (7/14)
Durvalumab Resected PDA patients NCT03038477 PI, suspended
(anti-PD-L1)
PD-1 combination Pembrolizumab+ CXCR4 Metastatic PDAC NCT02826486 PII
with other checkpoint antagonist
molecules/small molecule (BL-8040)
drugs Nivolumab + Advanced pancreatic cancer NCT02526017 PI
Cabiralizumab
Durvalumab + Metastatic pancreatic cancer NCT02734160 PI
Galunisertib
Durvalumab + Metastatic PDAC NCT02558894 PII
Tremelimumab
Gene Regulation and Therapeutics for Cancer
Pembrolizumab+ GI cancers (including NCT02268825 PI
mFOLFOX pancreatic cancers)
Ulocuplumab + Pancreatic cancer NCT02472977 PI, lack of efficacy so
Nivolumab terminated
Durvalumab + TGF Metastatic NCT02734160 PI
beta receptor inhibitor pancreatic cancer
Galunisertib (LY2157299)
Nivolumab + Advanced pancreatic cancer NCT02423954 PII, Terminated,
Chemotherapy Investigator no longer at
(NivoPlus) site to enroll patients or
write up data
Gemcitabine and CT-011 Pancreatic Neoplasms NCT01313416 PII, suspended , drug
clinical issue
Nivolumab With Pancreatic Neoplasms NCT02309177 PI
Nab-Paclitaxel +/-
Gemcitabine
Combination with Pembrolizumab+ Stage IV pancreatic cancer NCT03331562 PII
chemotherapy Paricalcitol patients
ACP-196 in combination Advanced or Metastatic NCT02362048 PII
with Pembrolizumab pancreatic cancer patients
BL-8040 + Metastatic pancreatic cancer NCT02826486 PII
Pembrolizumab patients
IDO-1 Inhibitor Advanced pancreatic NCT03432676 PII, withdrawn
Epacadostat in cancer with chromosomal
Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory…
combination Instability/Homologous
with Pembrolizumab Recombination Repair
Deficiency (HRD)
(Contd.)
9
Table 1: (Contd.)
10
Type of therapy Name Target population Clinical trial Phase (status)

number
Combination with Radiation with Metastatic PDAC NCT02866383 PII
radiotherapy Nivolumab with or
without Ipilimumab
Anti-PD-1 in combination Pancreatic cancer NCT03374293 PII
with radiotherapy
Pemrolizumab+ Resectable or Borderline NCT02305186 PI
neoadjuvant resectable pancreatic cancer
chemoradiation
Combination with Durvalumab + “Booster” Metastatic NCT02885727 PII withdrawn (funding
vaccines RT Adenocarcinoma pancreas issue)
cancer
CT-011+p53 genetic Advanced pancreatic cancer NCT01386502 withdrawn
vaccine
Multiple combinations Cyclophosphamide+ Pancreatic cancer NCT02648282 PII
Pembrolizumab+
GVAX+SBRT
Cyclophosphamide+ Borderline resectable NCT03161379 PII
Nivolumab+GVAX+ pancreatic cancer
SBRT
Losartan Localized pancreatic cancer NCT03563248 PII
and Nivolumab in
combination with
Folfirinox and SBRT
Gene Regulation and Therapeutics for Cancer
Cabiralizumab in Advanced pancreatic cancer NCT03336216 PII
combination with
nivolumab, with or
without chemotherapy
MEDI4736 in combination Metastatic PDAC NCT02583477 P1b/II
with nab-paclitaxel and
gemcitabine
Cyclophosphamide Previously treated Metastatic NCT02243371 PII
(CY)+Nivolumab + Adenocarcinoma of the
GVAX pancreas
Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory…
11
through Tregs. Despite extensive Teffector cell infiltration in the PDAC

microenvironment, there remains a bias towards immune suppression due
to an increase in the numbers of tumor infiltrating CD4+ Tregs in comparison
to those present in peripheral blood and also, a concomitant increase in PD-1
overexpressing CD4+ and CD8+ T cells suggests PD-1 mediated regulation
and T cell exhaustion [56]. However, another study showed that blockade of
PD-L2, another ligand for PD-1, enhanced anti-tumor response by reducing
Treg infiltration in tumors and decreased IL-10 mRNA levels as compared
to anti-PD-L1 antibody which predominantly affected IFNγ expression.
These observations suggest that PD-1-PD-L2 and PD-1-PD-L1 axes exert Treg
mediated immunosuppression in PDAC by distinct mechanisms [24]. Of
interest, the depletion of Tregs in animal model of Panc02 tumor has shown
enhanced tumor regression [57].
Pathobiological Significance of PD-1 Expression in

Pancreatic Cancer
Expression of PD-1 and PD-L1 has been extensively examined in PDAC
tissues. PD-1, present on the T cells, has been identified as the receptor for
ligand PD-L1 (B7-H1) which is upregulated under inflammatory conditions
on antigen presenting cells such as dendritic cells, macrophages, and cancer
cells [20, 58] . PD-1/PD-L1 interaction leads to cancer antigen-specific T cell
exhaustion and attenuation of CD4+ and CD8+ T cell activation thus leading
to immunosuppression in the tumor microenvironment and immune evasion
of the tumor. Higher expression of PD-L1 in poorly differentiated human
pancreatic tumors than well differentiated tumors has been correlated with
tumor progression through increased IL-10 secretion and the inhibition of
Th1 cytokines inducing immunosuppression [59]. Many other mechanisms
for PD-L1-mediated tumor progression in PDAC have been suggested.
For example, PD-L1 was reported to directly promote pancreatic tumor
cell proliferation via enhanced JNK signaling and cyclin D1 upregulation
[60, 61]. High levels of PD-L1 expression on tumors were correlated with
enhanced infiltration of Tregs and significantly shorter postoperative survival
in PDAC patients [55]. Surgically resected PDAC patients with high PD-L1
were associated with a higher pathological stage and lower two-year survival
rate (32%) as compared to PD-L1 negative patients (65%). Several studies
revealed the correlation of PD-L1 expression with the pathological stage
of PDAC and implicate its role in PDAC prognosis and survival analysis
[20, 62, 63]. However, PD-L1 in combination with B7-1 served as better
postoperative prognosis marker than PD-L1 alone. One study examined the
levels of CD8+ TILs, FoxP3+Tregs, PD-1, and PD-L1 expression in conjunction
with stromal density and activity and examined their correlation with four
clinical endpoints [overall survival-OS; progression free survival PFS; local
progression-free survival-LPFS; distant metastases free-survival-DMFS], in
a cohort of 145 patients following surgical resection. In univariate analysis,
patients with high infiltration of CD8+ T cells or PD-1+ TILs had better
prognosis (for all four clinical endpoints) compared to patients with low
intratumoral CD8+ T cells or PD-1+ TILs while the expression of FoxP3 and
PD-L1 did not correlate with clinical outcome [64]. However, prognostic
value of PD-1+ TILs or CD8+ T cells varied with respect to their location in
intratumoral compartments. High stromal infiltrating PD-1+CD8+ TILs served
as better prognostic marker than intraepithelial and peripheral compartment
TILs which had high PD-1 expression but lacked CD8+ T cells. Furthermore,
patients with higher PD-1+CD8+ TILs infiltration in lymphoid aggregates
were associated with better OS, LPFS and DMFS in comparison to patients
with low PD-1 and CD8 expression. In line with this, another study using a
cohort of 94 Chinese PDAC patients demonstrated correlation between high
PD-L1 expression and lymph node metastasis, while low PD-L1 patients with
high number of PD-1+ T cells exhibited an improved overall survival [65].
In addition, the patients with high PD-1 and dense stroma had much more
favorable prognosis (median OS > 24 months) as compared to those with
low PD-1 and moderate stroma (median OS = 7 months). The presence of a
very low number of PD-L1+ cells with tumoral CD8+ T cells overexpressing
other inhibitory receptors in PDAC may account for the failure of PD-1/
PD-L1 blockade therapies. Nonetheless, disparities exist in results obtained
with PD-L1 expression levels predicting response to anti-PD-1 therapy in
PDAC [66]. Qualitative analysis of PDAC tumors suggested the presence of
PD-1+ CD8 T cells with minimal clonality in a subset of patients. In addition,
they observed that tertiary lymphoid structures (TLS) of tumor stroma were
enriched in PD-1+/PD-L1+ T cells which are usually associated with positive
prognosis. Lesser clonality of PDAC tumors might explain their resistance to
anti-PD-1 therapy in comparison to other high clonal tumors like colorectal
cancer and melanoma which respond to anti-PD-1 therapy.
The observed variability in the association between the expressions of
PD-1/PD-L1 with various clinicopathological characteristics across these
studies can be attributed to several factors including small size of patient
population or analysis being restricted to tissue microarray or small sections
which may not represent the heterogeneity present in complex desmoplastic
tumor microenvironment. This warrants further studies on larger cohorts
and accounting for heterogeneity in the tumor microenvironment. Overall,
the correlation of PD-1 and PD-L1 with clinical outcomes has been variable
across studies. Further clarity on their role in prognosis and survival will
help dictate the effectiveness of anti-PD-1/PD-L1 antibodies in immune
therapy in PDAC.
Resistance to Anti-PD-1 Based Immunotherapy in

Pancreatic Cancer
It is becoming increasingly evident that PDAC is a poorly immunogenic
malignancy which stands out as the dominant reason for the failure of
checkpoint inhibitor immunotherapies. Given that a majority of checkpoint

blockade trials have targeted the PD-1/PD-L1 axis, it is important to
understand the underlying mechanism of the single agent anti-PD-1/PD-
L1 immunotherapy failure in PDAC. The response to checkpoint inhibitor-
based immunotherapy is dependent on immunological characteristic of
the tumor, based on which, there exist two categories: immune active and
immune quiescent tumors [67]. Immune active tumors are characterized
by rich immune CD8+ T cell infiltration and are, therefore, sensitive to
checkpoint inhibitors while immune quiescent ones have poor effector T
cell infiltration and thereby do not respond to immune checkpoint blockade
therapies. PDAC being a relatively quiescent tumor might provide limited
targets for anti-PD-1/PD-L1 or other checkpoint blockade antibodies.
Several hypotheses have been proposed for the limited success with anti-
PD-1/PD-L1 therapies in PDAC. According to the immunoediting theory
by Pardoll, tumor antigens, also called neoantigens, are acquired by a series
of genetic mutations and other events. Thus, tumor antigens become very
different from normal cellular antigens and are recognized by host immune
system for elimination [68]. However, T cell exhaustion by multiple co-
inhibitory receptors and ligands such as PD-1, CTLA-4, PD-L1, IDO, IL-
10, TIM3, and TGFβ lead to an ineffective anti-tumor immune response.
Therefore, antibodies against these molecules would allow activation of a
patient’s own immune system and restore anti-cancer immune response.
Nevertheless, despite the presence of multiple inhibitory and co-inhibitory
receptors on exhausted T cells, single agent checkpoint blockade agents
showed limited success in PDAC [25, 69]. Rather, combining immune
activation strategies with anti-PD-1 antibodies may provide better efficacy
against pancreatic cancer patients and show promise in the clinic. Loss of
tumor antigens due to mutations or epigenetic silencing can also contribute
to the failure of T-cells in immunotherapy [70]. Additionally, PDAC, being
a relatively quiescent tumor, is characterized by poor T cell infiltration and
therefore might provide limited target inaccessibility for anti-PD-1/PD-L1
or other checkpoint blockade antibodies [67]. PDAC frequently metastasizes
to liver which is relatively more tolerogenic and may present an altogether
different immune milieu from the pancreas, thereby a varying degree of
PD-1 expression might influence its efficacy in those patients [71]. Several
efforts have been made to understand PDAC in the context of immune
microenvironment. Of note, genomic and transcriptional stratification of
134 PDAC patients was done on the basis of cytolytic T cell activity and
delineated a new link between genomic alterations and immune activation.
Also, in contrast to other tumors, no direct correlation was found between
neoepitope load and T cell cytolytic activity which might explain the lack
of clinical response to anti-PD-1 therapies in PDAC [14]. Feng et al. have
thoroughly discussed the relation of immune profile with PD-1/PD-L1
blockade therapies according to which PDAC patients with immune desert
and immune excluded phenotype do not respond to anti-PD-1 therapy due
to low number of CD8+T and that too functionally exhausted [72]. Sharma
et al. have described in detail how cancer cells exploit intrinsic and extrinsic
mechanism of resistance, which include lack of antigenic proteins or their
presentation, genetic T cells exclusion or their inaccessibility, inhibitory
immune checkpoints and immunosuppressive cells, and limit the success of
anti-PD-1 or PD-L1 antibody therapies [73]. A very recent study stratified a
cohort of 110 PDAC patients, using next generation sequencing and tissue
microarray staining, in to three subtypes as immune escape, immune rich
and immune exhausted, for prognosis and indicated that immune exhausted
subtype displayed high PD-L1 expression along with higher frequency of
PIK3CA mutations and higher rate of PTEN loss in one subpopulation.
This stratification might be useful in designing novel approaches for the
use of immunotherapy and overcome immunosuppression in PDAC
microenvironment [74]. Besides genetic and immunological factors for
determining resistance to anti-PD-1 therapies, transcriptional mechanisms
regulating PD-1 expression have also been implicated in resistance to
checkpoint blockade therapies in several other metastatic tumors. However,
transcriptional profiling also poses serious technical challenges in terms
of instability and fragmentation of RNA. PD-1/PD-L1 based therapeutic
strategies seem to be highly challenging for immune-quiescent pancreatic
cancer and require further understanding of immune resistance to overcome
obstacles associated with checkpoint blockade.
Current Progress in Anti-PD-1 Therapy in

Pancreatic Cancer
Pembrolizumab (Keytruda) and Nivolumab (Opdivo) were the first two anti-
PD-1 antibodies approved by FDA for the treatment of metastatic melanoma
patients in the year 2014, announced as a breakthrough therapy and have
been tested in several clinical trials of solid cancers, including PDAC to
evaluate therapeutic potential [25, 75, 76]. Pembrolizumab eventually
stood out with a significantly higher response rate and prolonged patient
survival than Ipilimumab, the anti-CTLA4 (inhibitory receptor on T cells)
mAb. The results of clinical trials evaluating anti-PD-1/PD-L1 therapy
in 50 MMR deficient cases (NCT01876511 and NCT02465060) including
PDAC patients are awaited [77]. Anti-PD-1/PD-L1 immunotherapy reduces
immunosuppression but combining it with other checkpoint blockade
antibodies or immune activation mechanism might offer an additional
advantage to PDAC patients in terms of improving clinical responses. We
searched ongoing clinical trials in pancreatic cancer for anti-PD-1 antibodies
alone and/or in combination with chemotherapy, radiotherapy, vaccine or
multiple combinations and those are enlisted in Table 1.
Induction of endogenous anti-tumor T cell response by the use of
therapeutic vaccines and/or neoadjuvant treatment has resulted in specific
treatment with minimal toxicity in PDAC patients and genetically engineered
mouse model of pancreatic cancer [56, 78]. GVAX (granulocyte-macrophage
colony-stimulating factor (GM-CSF) secreting, allogeneic PDAC vaccine),

a vaccine-based immunotherapy, when administered to PDAC patients
demonstrated for the first time that immune therapies can convert immune
quiescent tumors to immunogenic tumors, amenable to checkpoint blockade
therapies [11, 79]. This was the first study to show that vaccination induced
the formation of intratumoral lymphoid aggregates and gene signature
analysis of the isolated aggregates was indicative of diminished Tregs
activity, augmented Th17 pathway, and upregulation of PD-1 and PD-L1
axis. In another preclinical study, GVAX treatment showed upregulation of
PD-L1 on pancreatic tumor cells and treatment with anti-PD-1 antibodies
resulted in IFNγ secretion from infiltrated effector T cells [80] which is in
line with observations made by Lutz et al. in human subjects. An alternative
approach for developing neo-antigen based vaccine, based on neoepitopes,
accumulated as a result of genetic mutations, for PDAC could also lead to
optimal anti-tumor response by combination with immune checkpoint
blockade molecules [67, 81].
Conclusions
While considerable research efforts have suggested that PD-1/PD-L1 axis
is a potential target for combating immunosuppression in PDAC, this
optimism has been tempered by the limited success of clinical studies
involving anti-PD-1/PD-L1 antibodies. The inadequate clinical efficacy of
anti-PD-1 antibodies in PDAC patients can be due to immune quiescent
nature of tumor and inappropriate patient selection criteria in clinical trials.
PDAC is immunologically cold due to the limited repertoire of neoantigens,
immunosuppressive driver mutations, and stromal obstruction to immune
cell infiltration. However, recent studies demonstrating the utility of anti-
stromal agents in enhancing the immune cell trafficking have raised the
possibility of combination therapy involving such agents with anti-PD-1/
PD-L1 therapies [82]. Further, the recent findings also suggest that the focus
for immunotherapy development should be more on neoantigen quality
rather than quantity [83]. Another challenge that remains to be addressed
is the variability observed in various studies examining correlation between
PD-1/PD-L1 expression and clinicopathological outcomes in PDAC patients.
While this can be attributed to the differences in immunostaining methods
for the detection of PD-1/PD-L1 expression, some of the variability can
be due to the inherent heterogeneity of tumors in terms of tumor grade
stage and histology. Furthermore, there is no uniformity across studies in
defining the PD-1/PD-L1 expression in specific cellular compartment: while
some studies have defined PD-L1 expression on tumor cells, other studies
have examined PD-L1 expression of fibroblasts and other stromal cells
like macrophages. There is also variability in the sensitivity of detection of
expression across various studies due to differences in staining methods and
reagents. One recent study reported enhanced detection of PD-L1 expression
using a sensitive nanoparticle based immunodetection method but these

studies need validation in larger sample set [84]. Recent advancements in
understanding intrinsic and extrinsic mechanisms of immune resistance
along with PDAC patient stratification into different immune subtypes
suggest upregulation of other checkpoint molecules [73, 74]. Given the non-
redundant nature of immune checkpoints, it will be of merit to examine
anti-PD-1/PD-L1 immunotherapies in combination with other immune
checkpoint blockade agents. Much work also needs to be done to define how
various therapeutic modalities like chemotherapy and radiation therapy
impact PD-1/PD-L1 expression. Tissue samples from the completed and
ongoing immunotherapy trials can help address these questions and may
lead to more effective combination immunotherapies against PDAC.
Acknowledgement
These authors are supported, in part, by the following grants from the National
Institute of Health: U01 CA213862, R01 CA195586 and U01 CA200466.
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Another random document with
no related content on Scribd:
BELSIZE HOUSE
Belsize House was a large Elizabethan mansion, modified in the

time of Charles II. Pepys, who visited it in 1668 (17 August) when it
was the residence of Lord Wotton, describes its gardens as
“wonderful fine: too good for the house the gardens are, being,
indeed, the most noble that ever I saw, and brave orange and lemon
trees.”[202]
The house was a private residence until 1720, when it was
converted into a place of public amusement, under the management
of a Welshman named Howell. At this time it was a somewhat
imposing structure, with wings, and a tower in the centre. The
entrance was by a door placed between the wings, and also by an
external staircase at one wing.
The inaugural entertainment took place about April, 1720, and
consisted of an “uncommon solemnity of music and dancing.” The
place was usually open from 6 a.m. till 8 p.m., without charge for
admission. The Park, Wilderness and Garden, about a mile in
circumference, were advertised (about 1721?), as being wonderfully
improved and filled with a variety of birds, “which compose a most
melodious and delightful harmony.” Those who wished for an early
stroll in the park could “breakfast on tea or coffee as cheap as at
their own chambers.” As the journey from London was not
unattended with risks, twelve stout fellows (afterwards increased to
thirty), completely armed, were announced as “always at hand to
patrol timid females or other.”
BELSIZE HOUSE AND PARK.
Belsize became a fashionable rendezvous. In July 1721 the
Prince and Princess of Wales, attended by several persons of rank,
dined at the house, and were entertained with hunting and other
diversions. In June, 1722, on the occasion of a wild deer hunt, three
or four hundred coaches brought down the “Nobility and Gentry”
from town. Athletic sports were introduced, and the proprietor gave a
plate of several guineas to be run for by eleven footmen (1721).
Gambling and intrigue were the less wholesome results of this influx
of the nobility and gentry. In May 1722 the Justices took steps to
prevent the unlawful gaming, while in the same year “A serious
Person of Quality” published a satire called Belsize House, in which
he undertook to expose “the Fops and Beaux who daily frequent that
Academy,” and also the “characters of the women who make this an
exchange for assignations.”
This house, which is a nuisance to the land
Doth near a park and handsome garden stand
Fronting the road, betwixt a range of trees
Which is perfumed with a Hampstead breeze.
The Welsh Ambassador has many ways
Fool’s pence, while summer season holds, to raise.
For ’tis not only chocolate and tea,
With ratafia, bring him company.
Nor is it claret, Rhenish wine or sack
The fond and rampant Lords and Ladies lack
Or ven’son pasty for a certain dish
With several varieties of fish;
But hither they and other chubs resort
To see the Welsh Ambassador make sport,
Who in the art of hunting has the luck
To kill in fatal corner tired buck,
The which he roasts and stews and sometimes bakes,
Whereby His Excellency profit makes.
He also on another element
Does give his choused customers content
With net or angling rod, to catch a dish
Of trouts or carp or other sorts of fish.
The Welsh Ambassador was the nickname of the proprietor,

James Howell, an enterprising though not very reputable person,
who had once been imprisoned for some offence in Newgate.
Races[203] and similar amusements continued for several years to
be provided, and music was performed every day during the season.
In the spring of 1733 (31 May) a race was advertised for ponies
twelve hands six inches high. The length of the race was six times
round the course; “Mr. Treacle’s black pony,” which distinguished
itself by winning the plate at Hampstead Heath in the previous year,
being excluded.
In 1736 a fat doe was advertised to be hunted to death by small
beagles, beginning at nine in the morning, and sportsmen were
invited to bring their own dogs, if “not too large.” In the same year
(16 September) a boys’ race was run, beginning at three o’clock, six
times round the course: a prize of one guinea was given to the
winner, and half a guinea to the second runner. “Each person to pay
sixpence coming in, and all persons sitting on the wall or getting over
will be prosecuted.”
For an afternoon in August 1737, there was announced a running
match six times round the park, between “the Cobler’s Boy and John
Wise the Mile-End Drover,” for twenty guineas. In 1745 there were
foot-races in the park, and this is the last notice we have of Belsize
as a place of amusement.
The mansion falling into a ruinous state[204] was pulled down at
the close of the eighteenth century (before 1798), and a large,
plainly-built house was erected in its stead. From 1798–1807 this
new Belsize House was tenanted by the Right Hon. Spencer
Perceval and others. In the autumn of 1853 the house was pulled
down (cp. The Illustrated London News for 9th September, 1854, p.
239), and the buildings of the Belsize Estate were subsequently
erected on the site of the Park.
The present Belsize Avenue (on the west side of Haverstock Hill)
is the representative of a beautiful avenue of elms, which originally
led up to the old Belsize House, the site of which was near the
present St. Peter’s Church.
[Palmer’s St. Pancras, 227, ff.; Baines’s Hampstead; Walford v.
494, ff.; Howitt’s Northern Heights; Lambert’s London, 1806, iv. 256;
Thorne’s Environs of London, s.v. “Hampstead”; Park’s Hampstead;
newspaper advertisements, W. Coll.]
VIEWS.
1. Old Belsize House. A view on a Belsize House advertisement,
circ. 1721? and a view by Maurer, 1750; cp. Howitt’s Northern Heights
and C. Knight’s Old England, ii. fig. 2404.
2. Belsize House in 1800 (Walford, v. 492).
KILBURN WELLS
The spring known as Kilburn Wells was situated in the Abbey

Field near the site of the old Kilburn Priory, and in the rear of the Bell
Tavern. It attracted public notice about the middle of the last century;
[205] and some endeavours were made, probably by the proprietor of
the Bell, to bring Kilburn Wells into vogue: at any rate, in 1752 it is
referred to as a place in some respects akin to Sadler’s Wells:—
Shall you prolong the midnight ball
With costly supper at Vaux Hall,
And yet prohibit earlier suppers
At Kilburn, Sadler’s Wells or Kupers?[206]
About 1773 Kilburn Wells began to be more widely known, and

the proprietor’s advertisement of 17 July in that year announced that
the water was then in the utmost perfection, the gardens enlarged
and greatly improved, and the house and offices “repainted and
beautified in the most elegant manner.” The Great Room was
described as specially adapted for “the use and amusement of the
politest companies” who might require it for music, dancing, or
entertainments. “This happy spot is equally celebrated for its rural
situation, extensive prospects, and the acknowledged efficacy of its
waters; is most delightfully situated on the site of the once famous
Abbey of Kilburn on the Edgware Road, at an easy distance, being
but a morning’s walk from the metropolis, two miles from Oxford
Street; the footway from Marybone across the fields still nearer. A
plentiful larder is always provided, together with the best of wines
and other liquors. Breakfasting and hot loaves.”
An account of the medicinal water drawn up by the usual “eminent
physician” was given away to visitors, and in one of the rooms was a
long list of the diseases said to have been cured. Tn 1792 Godfrey
Schmeisser made a careful analysis of the water. It was a mild
purgative, milky in appearance, and had a bitterish saline taste. The
use of the water for curative purposes appears to have ceased in the
early part of the present century (before 1814), but the Old Bell, or
Kilburn Wells as the place was generally denominated, enjoyed
popularity as a tea-garden as late as 1829.[207]
About 1863 the Old Bell was pulled down, and the present Bell
public-house erected on the spot. A brick reservoir long enclosed the
spring, but some years ago it was demolished and built over. It stood
immediately behind the Bank at the corner of Belsize Road.
[Thorne’s Environs of London; Lambert’s London, iv. 288; Howitt’s
Northern Heights; Baines’s Hampstead; Park’s Hampstead; Walford,
v. 245, ff.]
VIEWS.
1. The Bell Inn, Kilburn, 1750 (Walford, v. 246).
2. The Bell Inn, Kilburn, from a mezzotint, 1789, reproduced in
Baines’s Hampstead.
3. View of the Old Bell Inn at Kilburn on the Edgware Road.
Rathbone del. Prestal sculp. 1789. Crace, Cat. p. 670, No. 76.
4. An engraved handbill, describing the waters, at the top of which
is a print of the Long Room, by F. Vivares; mentioned in Park’s
Hampstead, p. xxxi*, additions.
V
CHELSEA GROUP
RANELAGH HOUSE AND GARDENS
§ 1. Origin of Ranelagh
About the year 1690 Richard, Viscount (afterwards Earl of)
Ranelagh, Paymaster-General of the Forces, built for himself on the
east side of Chelsea Hospital a private residence known as
Ranelagh House, and laid out a garden. In 1691[208] the house is
described as “very fine within, all the rooms being wainscotted with
Norway oak,” and the garden plats and walks were “curiously kept
and elegantly designed.” Bowack in 1705 says that the gardens were
“esteemed to be the best in England, the size considered.” Here
Lord Ranelagh lived till his death in 1712.
In 1733 the property was sold, and at that time Lacy, patentee of
Drury Lane Theatre, made arrangements for forming Ranelagh into a
place of public amusement. Nothing decisive was done till 1741,
when a large circular building, the famous Rotunda (at first generally
called the Amphitheatre), was erected in the Ranelagh grounds by
William Jones, architect to the East India Company.[209]
The capital for the undertaking was furnished by a few
shareholders, and was divided into thirty-six shares of £1,000 each.
The principal shareholder and manager was Sir Thomas Robinson,
Bart., M.P., whose gigantic form was for many years familiar to all
frequenters of the Rotunda: a writer of 1774 calls him its Maypole
and Garland of Delights.[210]
The Rotunda and Gardens were first opened on 5 April, 1742,
with a public breakfast, and a visit to Ranelagh became the vogue.
Of the early fortunes of the place the best chronicler is Horace
Walpole. On April 22, 1742, he writes to Mann:—“I have been
breakfasting this morning at Ranelagh Garden: they have built an
immense amphitheatre, with balconies full of little ale-houses: it is in
rivalry to Vauxhall and costs above twelve thousand pounds.”[211]
On May 26[212] he again describes the “vast amphitheatre, finely
gilt, painted and illuminated; into which everybody that loves eating,
drinking, staring, or crowding, is admitted for twelvepence.” In 1744,
[213] Mr. Walpole goes “every night constantly” to Ranelagh, “which
has totally beat Vauxhall.” “Nobody goes anywhere else; everybody
goes there. My Lord Chesterfield is so fond of it, that he says he has
ordered all his letters to be directed thither.” “The floor is all of beaten
princes”; “you can’t set your foot without treading on a Prince or
Duke of Cumberland.” In 1748,[214] “Ranelagh is so crowded, that
going there t’other night in a string of coaches, we had a stop of six
and thirty minutes.”
In 1745 Mr. Thomas Gray had written to a friend[215] that he had
no intention of following the stream to Ranelagh, and he touched a
weak spot in the delights of the London Pleasure Gardens—the
uncertainty of the London weather. “I have never been at Ranelagh
Gardens since they were opened.... They do not succeed: people
see it once, or twice, and so they go to Vauxhall. Well, but is it not a
very great design, very new, finely lighted? Well, yes, aye, very fine
truly, so they yawn and go to Vauxhall, and then it’s too hot, and then
it’s too cold, and here’s a wind and there’s a damp.” But in August
1746 we find Gray declaring[216] that his evenings lately have been
chiefly spent at Ranelagh and Vauxhall.
Other literary people, at least as interesting, as Walpole’s Dukes
and Princes, frequented Ranelagh. The learned Mrs. Carter was
there in 1748, and found the gardens very pleasant on a June
evening, though she did not relish such “tumultary torchlight
entertainments.” Goldsmith and Reynolds used to go there together
about 1771, and Dr. Johnson “often went to Ranelagh,” which he
deemed, as the Rev. Dr. Maxwell apologetically observes, “a place of
innocent recreation.”
§ 2. The Rotunda
The guide-books abound with architectural details of the
Ranelagh Rotunda.[217] A sufficient idea of its general appearance
may be gained by glancing at some of the contemporary prints and
by noticing a few salient features. Writers of the time compare it to
“the Pantheon at Rome”: the Londoner of to-day will think rather of
the British Museum Reading Room which it resembled in size and, to
some extent, in general appearance. The circumference was 555
feet and the internal diameter 150 feet. It was entered by four Doric
porticoes opposite one another, and the interior architecture
corresponded with the exterior.
On the exterior was an arcade encircling the building, and above
this arcade was a gallery reached by steps placed at the porticoes.
In the interior was a circle of fifty-two[218] boxes, separated by
wainscotting. Each box had its “droll painting” and its bell-lamp with
candles; and in each seven or eight people could be accommodated
with refreshments. Benches covered with red baize were dispersed
about the area, and the plaster floor was covered with matting.
Above the circle of boxes was a gallery containing a similar range
of boxes which were entered by folding-doors from the gallery
outside the building. The Rotunda was lighted by sixty windows, and
the chief material used in its construction was wood.
The ceiling was painted an olive colour, with a rainbow round the
extremity, and there hung from it numerous chandeliers, each
ornamented with a gilt crown and containing crystal bell-lamps of
candles. When all the candles were lighted, the sight, we are told,
was “very glorious.”
In the centre of the building was a remarkable square erection
supporting the roof, and made up of pillars and arches elaborately
decorated. This “grand and elegant structure” was nothing more or
less than a fireplace containing a chimney and an open fire. On cold
days in February and March the best place was “one of the hot
blazing red-cloth benches” by the fire. This fireplace structure had
originally contained the orchestra, but after a few years the orchestra
was, for acoustic reasons, moved to the side of the Rotunda. Behind
the orchestra was an organ by Byfield, set up in 1746.[219]
The Inside View of the Rotunda in Renelagh Gardens with the
Company at Breakfast.
Vue de la Compagnie à Dejeuner dans la Rotonde au Mellieux des
Jardines de Renelagh.
THE ROTUNDA AT RENELAGH, circ. 1751.
Johnson declared that “the coup d’œil” of Ranelagh was “the
finest thing he had ever seen.”[220] When Johnson first entered
Ranelagh and its brilliant circle, it gave, as he told Boswell,[221] “an
expansion and gay sensation” to his mind, such as he had never
experienced anywhere else. Miss Lydia Melford, in Humphry Clinker,
wrote about Ranelagh to her ‘dear Willis’ with an enthusiasm less
restrained, and without Dr. Johnson’s moralising comment:—“Alas,
Sir, these are only struggles for happiness.” “Ranelagh (she writes)
looks like the enchanted palace of a genio, adorned with the most
exquisite performances of painting, carving, and gilding, enlightened
with a thousand golden lamps that emulate the noonday sun;
crowded with the great, the rich, the gay, the happy and the fair;
glittering with cloth of gold and silver, lace, embroidery, and precious
stones. While these exulting sons and daughters of felicity tread this
round of pleasure, or regale in different parties, and separate lodges,
with fine imperial tea and other delicious refreshments, their ears are
entertained with the most ravishing delights of music, both
instrumental and vocal.”
§ 3. The entertainments and the company.

The usual charge for admission was half a crown,[222] which
always included the ‘regale’ of tea, coffee and bread and butter.
Foote called Ranelagh the Bread and Butter Manufactory, and,
except on ball nights, no other refreshments seem to have been
procurable.
The place was usually open on three days in the week, Mondays,
Wednesdays and Fridays.[223] The regular season for the evening
concerts and garden-promenade began at Easter, but the Rotunda
was often open in February, or earlier, for the dances. In the early
days of Ranelagh the public breakfastings and the morning concerts
at twelve were a constant feature. About 1754 the proprietors of
Ranelagh were refused a license for music, and the breakfasting
took place that year without concerts: these breakfasts and morning
concerts do not appear to have been subsequently renewed.
The evening concerts (from May 1742, onwards) generally began,
at 6.30 or 7. Between the Acts the company walked in the gardens to
the music of horns and clarinets, and a garden-orchestra was
erected about 1764. The gardens were illuminated, but fireworks did
not become a prominent feature till about 1767.
The gardens themselves were somewhat formally laid out. There
were several gravel walks, shaded by elms and yews; a flower-
garden, and “a beautiful octagon grass plat.” The principal walk led
from the south end of Ranelagh House to the bottom of the gardens,
where there was a circular Temple of Pan. At night the walks were
prettily lit with lamps attached to the trees. There was also a canal
with a Temple indifferently described as the Chinese House and the
Venetian Temple.
The Chinese House, the Rotunda, & the Company in Masquerade in

Renelagh Gardens
In its earliest as well as in its latest days masquerades attracted
many to the Rotunda and the gardens, but the chief diversion was
the promenade in the Rotunda. A guide-book of 1793 states that
“walking round the Rotundo” was “one of the pleasures of the place.”
We hear much at all periods of “the circular labour” of the company
and “the ring of folly.”[224] Matthew Bramble found one half of the
company “following one another’s tails in an eternal circle like asses
in an olive mill while the other half are drinking hot water under the
denomination of tea.” Mr. Bramble exacted much from places of
amusement, but it is to be suspected from other testimonies that
there was an atmosphere of dulness, a note of ennui, about the
ordinary diversions of this fashionable rendezvous. “There’s your
famous Ranelagh (says ‘Evelina’) that you make such a fuss about;
why what a dull place is that!” A Frenchman describing Ranelagh
about 1800—foreigners were always expected to visit it—calls it “le
plus insipide lieu d’amusement que l’on ait pu imaginer,” and even
hints at Dante’s Purgatory. Another Frenchman writing much earlier,
circ. 1749, briefly comments “on s’ennuie avec de la mauvaise
musique, du thé et du beurre.”
Samuel Rogers (Table Talk), who must have known Ranelagh
from about 1786 till its close, was struck by the solemnity of the
whole thing: “all was so orderly and still that you could hear the
whishing sound of the ladies’ trains as the immense assembly
walked round and round the room.” An “affray” of the kind familiar at
Vauxhall and not infrequent at Marylebone was practically unknown
at Ranelagh. On May 6th, 1752, Dr. John Hill was caned in the
Rotunda by an angry gentleman, and the newspapers and
caricaturists were momentarily excited, chiefly because Hill’s injuries
were supposed to be a sham. One almost welcomes a scene at
Ranelagh. On the 12th of May, 1764, four footmen were charged
before Sir John Fielding with riotous behaviour at Ranelagh House,
“hissing several of the nobility, relative to their not giving or suffering
vails to be taken, pelting several gentlemen with brick-bats and
breaking the windows.”[225]
Throughout its career of more than a hundred and sixty years,
Ranelagh fairly maintained its position as a fashionable resort, but at
all periods the company was a good deal mixed. Philomides, “a
gentleman of sprightly wit, and very solid judgment,” has
described[226] the frequenters of the place four or five years after it
was first opened. My Lord (he says) was sure to meet his tailor
there, and Statira would see her toyman “cursing himself for letting
this Statira have a service of very fine Dresden china, which she
assured him her Lord would pay for immediately.” The ubiquitous
Templar was easily recognised—a pert young fellow in a fustian
frock, and a broad-brimmed hat “in an affected impudent cock.”
There was an Oxford scholar, a political pamphleteer and a spruce
military spark smelling of lavender water. A coxcomb just returned
from his travels was more absurd. He had set up as virtuoso, and
brought home a headless Helen and a genuine ‘Otho’ coined at
Rome two years ago. He might now be heard talking Italian in a loud
voice and “pronouncing the word Gothic fifty times an hour.”
In 1760 a fashionable lady complains that there were too many
tradesmen’s wives at Ranelagh. But compared with Vauxhall it was
fashionable, at least according to a lady’s maid in “High Life Below
Stairs” (circ. 1759, Act I. sc. 2):—
Lady Charlotte’s Maid: Well, I say it again, I love Vauxhall.
Lady Bab’s Maid: Oh, my stars! Why, there is nobody there but
filthy citizens—Runelow for my money.
THE ATTACK ON DR. JOHN HILL AT RANELAGH, 6 MAY, 1752.
From about 1774 it was considered fashionable to arrive at the
Rotunda about 11 p.m., one hour after the concert was over. In 1777,
according to Walpole, the company did not arrive till twelve. “The
people of the true ton,” says the satirical “Harlequin in
Ranelagh,”[227] (1774), “come in about eleven, stare about them for
half an hour, laugh at the other fools who are drenching and scalding
themselves with coffee and tea ... despise all they have seen, and
then they trail home again to sup.” The citizens, on the other hand,
came to stare at the great, at the Duke of Gloucester or Lady
Almeria Carpenter, or whoever it might be. They came to see how
the great folks were dressed, how they walked and how they talked.
Some worthy men were compelled by their wives to wear swords,
and in the circling promenade found it hard “to adjust the spit to the
humour of those behind and before” them. The ‘Harlequin’ enlarges
on some unpleasant characters who haunted Ranelagh, Baron H
——g (for instance), who trails about like a wounded worm, and Lord
C——y who “runs his nose under every bonnet.” It is not to be
denied that Ranelagh, though on the whole decorous, had a
tolerable reputation as a place of assignation.
§ 4. Annals of Ranelagh 1742–1769.

From this general sketch of Ranelagh and its frequenters, we may
pass on to some details of its amusements year by year.
The principal performer at the concerts in the earliest days (1742–
circ. 1760) was the well-known actor and vocalist Beard, who was
considered by Dibdin to be, “taken altogether, the best English
singer.” Giulia Frasi, young and interesting, with her “sweet clear
voice,” was heard in 1751 and 1752. Michael Festing at first led the
band, and was succeeded (about 1752) by Abram Brown, a
performer who (according to Burney) had “a clear, sprightly and loud
tone, with a strong hand,” but who was deficient in musical
knowledge and feeling. Parry, the Welsh harper (1746), and
Caporale, the violoncello player, were also among the earlier
performers.[228]
At first, choruses from oratorios (this was still the case in 1763)
were a feature of the concerts, but the performances soon came to
differ little from those of Vauxhall and Marylebone. In 1754 an
entertainment of recitation, with a procession, was given under the
name of Comus’s Court. In 1757 “Acis and Galatea” was performed
for the benefit of the Marine Society. On 10 June, 1763[229] Bonnell
Thornton’s ‘Burlesque Ode on St. Cecilia’s Day’ was performed,
“adapted (by Burney) to the antient British music, viz.: the salt-box,
the Jew’s-harp, the marrow-bones and cleavers, the hum-strum or
hurdy-gurdy, etc., etc.” The performers sang the recitative, airs and
choruses in masquerade dresses, and the salt-box song was
especially successful. The fun must have been rather forced, though
Johnson, who read the Ode when printed, “praised its humour,”
seemed much diverted with it, and repeated the lines:—
In strains more exalted the salt-box shall join,
And clattering and battering and clapping combine;
With a rap and a tap while the hollow side sounds,
Up and down leaps the flap, and with rattling rebounds.
In 1762–1764 the principal singer was the Italian Tenducci,[230]

whose voice, according to Miss Lydia Melford, was “neither man’s
nor woman’s; but it is more melodious than either, and it warbled so
divinely, that while I listened I really thought myself in Paradise.”
On 29 June, 1764, Mozart, then eight years old, performed on the
harpsichord and organ several of his own compositions. On 12 May,
1767,[231] Catches and Glees were rendered with instrumental parts
by Arne, an addition considered necessary on account of the size of
the Rotunda. This was stated to be the first public performance of
the kind in England.
In 1769 Dibdin was a singer of ballads, and on 12 May of this year
there was a Jubilee Ridotto, an event at which we may pause to
recall some of the earlier masquerades and balls which, from time to
time, enlivened the routine of Ranelagh.
The most famous of these entertainments was the “Grand Jubilee
Masquerade, in the Venetian taste,” that took place on Wednesday,
26 April, 1749, to celebrate the proclamation of the peace of Aix-la-
Chapelle. The Masquerade (says Horace Walpole[232]) “had nothing
Venetian in it, but was by far the best understood and prettiest
spectacle I ever saw; nothing in a fairy tale ever surpassed it.... It
began at three o’clock; at about five, people of fashion began to go;
when you entered, you found the whole garden filled with masks and
spread with tents, which remained all night very commodely. In one
quarter was a Maypole dressed with garlands, and people dancing
round it to a tabor and pipe, and rustic music, all masked, as were all
the various bands of music that were disposed in different parts of
the garden; some like huntsmen with French-horns, some like
peasants, and a troop of harlequins and scaramouches in the little
open temple on the mount. On the canal was a sort of gondola,
adorned with flags and streamers, and filled with music, rowing
about. All round the outside of the amphitheatre were shops, filled
with Dresden china, Japan, &c., and all the shopkeepers in mask.
The amphitheatre was illuminated, and in the middle was a circular
bower, composed of all kinds of firs in tubs, from twenty to thirty feet
high; under them, orange trees, with small lamps in each orange,
and below them all sorts of the finest auriculas in pots; and festoons
of natural flowers hanging from tree to tree. Between the arches, too,
were firs, and smaller ones in the balconies above. There were
booths for tea and wine, gaming-tables, and dancing, and about two
thousand persons. In short, it pleased me more than the finest thing I
ever saw.”
Later masquerades, though attended by fashionable people, were
less select, as appears, for example, from an advertisement which a
gentleman inserted in the Public Advertiser of 8 March, 1753[233]:
—“This is to inform the Lady that was in a wite mask, red Beard and
Ey’s at the last Masquereade but one, in a brown and silver flora
Pethecoat and head-dress, remarkable gentle, very finely maid, who
lost her company and walked with several masks, perticuler with
one, who in raptorous heared her declare a dislike to gameing and
the intention of Maskquerdes ... on which he asked, wathere single
or ingaged, and under whos care that Night? the lady pointing to a
tall gentleman in black and a bag wigg, said his, my Brother.” His
intentions were honourable, and he begged to see her face. In reply,
“she repetted Part out of the Orphin ‘Trust not a man’; said he had
taken notice enough of her to know her again; bid him look sharp at
the next Makquered, at wich and all other Places he as been
dispionted of seeing her; he therefore hops (if not ingaged) will get
her Brother or some Friend to call on him” as he feels assured he
could be happy for life with her.
On the occasion of the Jubilee Ridotto on 12 May, 1769, the
gardens and the Chinese House were illuminated. “A large sea-
horse stuck full of small lamps floated on the Canal, and had a very
agreeable aspect.” A favourite Ranelagh ‘serenata,’ Dibdin’s
‘Ephesian Matron,’ was performed at ten, and the Rotunda and
gardens were gradually filled by a brilliant company. The Dukes of
York and Cumberland were there, and one of the prettiest characters
was “a rural nymph in rose-coloured sattin, trimmed with silver.” The
tickets, which cost a guinea, included the supper. Unfortunately, the
wine and sweetmeats were not immediately forthcoming, and some
gentlemen broke open the wine cellar and helped themselves. Sir
Thomas Robinson, to make things pleasant, thereupon sent a
general invitation to the company to sup with him. The dancing
began at twelve, and was continued till four, a comparatively early
hour at Ranelagh masquerades.
§ 5. Later history of Ranelagh, 1770–1805.

A “Gentleman in Town,” writing in The Town and Country
Magazine for April 1770 (p. 195) to his friend in the country, enlarges
on the fashionable assemblages to be then seen at Ranelagh three
times a week. And we may note that about this time the tradesmen
advertised their silver Ranelagh silks and Ranelagh waistcoats in
gold, silver and colours. The sweet voice of “the lovely Mrs.
Baddeley” was then to be heard in the Rotunda, and she sang (in the
autumn, 1770) in “The Recruiting Sergeant,” together with Mrs.
Thompson, Dibdin, and Bannister.[234]
The garden concerts, and the fireworks, and transparent pictures
in a building in the grounds had by this time become prominent
features of the place.[235]
The event of 1775 was the Ranelagh Regatta and Ball,[236] which
took place on June 23rd. Early in the afternoon of that day the whole
river from London Bridge to Millbank was covered with pleasure
boats, and scaffold erections were to be seen on the banks, and
even on the top of Westminster Hall. Gambling tables lined the
approaches to Westminster Bridge: men went about selling
indifferent liquor, Regatta songs and Regatta cards. The river banks
now resembled a great fair, and the Thames itself a floating town.
Wild calculations fixed the number of the spectators at 200,000, or
“at least” three millions. At 7.30 a cannon signalled the start of the
racing-boats, and about 8.30, when the prizes had been awarded,
the whole procession began to move “in a picturesque irregularity
towards Ranelagh.” The Directors’ barge, with its band playing and
gold Regatta ensign flying, led the way, and the fortunate persons
who had ball-tickets landed at Ranelagh Stairs at nine o’clock.
Dancing took place in the Temple of Neptune, a temporary
octagon erection in the grounds. Mrs. Cornelys had been given
seven hundred guineas (it is said) to supply the supper, and it is
lamentable to reflect that the supper was “indifferent, and the wine
very scarce.” However, there was a great company: the Duke of
Gloucester, the Duke of Northumberland, Lord North, the Duchess of
Devonshire, Sir Joshua Reynolds, Garrick, Colman, Samuel Foote.
A band of two hundred and forty instrumentalists, under Giardini,
performed in the Rotunda, and there was singing by Vernon and
Reinhold, including the cheering ballad:—
Ye lords and ye ladies who form this gay throng,
Be silent a moment, attend to our song,
And while you suspend your fantastical round,
Come, bless your sweet stars that you’re none of you drowned.
ADMISSION TICKET, BY CIPRIANI AND BARTOLOZZI.
From this time (1775) till about 1790 the concerts continued as
usual, but Ranelagh seems during the period to have suffered a
certain eclipse. In May 1788 the shares are said to have fallen from
their par value (£1,000) to £900. Ranelagh was “voted a bore with
the fashionable circles,” and its distance from town began to be
considered an obstacle.
About 1791, however, its fortunes revived, and numerous
masquerades, sometimes lasting till six or eight in the morning, and
firework displays (chiefly by Caillot and by Rossi and Tessier)
remained a feature of Ranelagh till its close.
Henry Angelo (Reminiscences, ii. p. 3 f.), speaking of its later
days, declares that it was frequented by “the élite of fashion.” The
gentlemen wore powder, frills and ruffles, and had gold-headed
canes. “Cropped heads, trousers or shoe-strings” were not to be
seen there. The men used to buy in the ante-room myrtles, hyacinths
and roses, not to wear themselves, but for presentation to the ladies.
A masquerade of 1792 (14 February) was attended by Mrs.
Jordan, “supported” (as the newspapers said) “between the friendly
arms of the Prince of Wales and the Duke of Clarence.” Mr. Petit was
good as a man walking in his sleep with a candle, and amid the
usual crowd of harlequins, sailors and flower-girls, “a monkey of the
largest size was offensively dexterous.”[237] At another masquerade
this year (16 May) a Guy Faux, a ‘Bath Maccarony,’ an African
Princess, and three or four Romps attracted attention.
On May 7th, 1792, the exhibition called Mount Etna was
introduced and remained popular at Ranelagh for several years. A
special building with a scene designed by G. Marinari, ‘painter to the
Opera,’ was prepared for it in the gardens. The idea was evidently
borrowed from Torré’s Forge of Vulcan, the great attraction at the
Marylebone Gardens some twenty years earlier. The scene
represented Mount Etna and the Cavern of Vulcan with the ‘Cyclops’
forging the armour of Mars, “as described (the advertisements add)
in the Aeneid of Virgil.” To an accompaniment of music “compiled
from Gluck, Haydn, Giardini, and Handel,” we see the ‘Cyclops’
going to work. “The smoke thickens, the crater on the top of Etna
vomits forth flames, and the lava rolls dreadful along the side of the
mountain. This continues with increasing violence till there is a
prodigious eruption, which finishes with a tremendous explosion.”
On June 27th, 1793, the Chevalier D’Eon fenced in the Rotunda
with M. Sainville, and received the congratulations of the Prince of
Wales and Mrs. Fitzherbert.[238]
In 1797 (April) there was an enjoyable masquerade, at which
there reigned (we are told) “good nature and pleasant hilarity, without
riot”: all this, in spite of a crowd of imaginary Dutch skippers,
lunatics, coachmen, quack doctors and watercress girls.
At a concert in 1798 (June) Incledon and Madame Mara sang. In
1799 a January masquerade was diversified by a drawing for fifty
twelfth cakes as prizes for the masks.
The Directors now began to offer prizes for regattas and volunteer
shooting-matches, and a few splendid entertainments mark the
closing years of Ranelagh.
On 2 June, 1802, Boodle’s Club gave an elegant dance at which
the ladies “wore white and silver, ornamented with laurel”—and
diamonds, and amused themselves by drawing prizes of trinkets in a
Lottery Booth. On the 28 June (1802) the Picnic Society gave an
“afternoon breakfast,” and at five o’clock Garnerin, the French
aeronaut, and Captain Sowden ascended in a balloon from the
gardens.[239]
On 23 September (1802) Mr. Thomas Todd descended into a
reservoir of water twenty-five feet deep, prepared for him in the
gardens. His awkward diving-tub, and his dress of leather and metal
excited the laughter of spectators born too early to know the diver of
the Polytechnic. Nor is this praiseworthy experiment to be counted
among the splendid entertainments of Ranelagh, for Mr. Todd was
“misfitted by his coppersmith,” forgot to take down his lamp, and did
not remain under water more than five minutes.[240]
On 1 June, 1803, a ball in commemoration of the Installation of
the Knights of the Bath took place and proved one of the finest of the
entertainments. Yet these were only ‘struggles for happiness,’ and
attempts to galvanise a nearly lifeless Ranelagh. The unending
promenade, with its sentimental songs and elegant regale of tea and
coffee, had ceased to attract, and the lamp-hung trees, the Chinese
House and the music on the Canal had lost their ancient charm. On
8 July, 1803, the Rotunda of Ranelagh was opened for the last time
as a place of amusement.
On 30 September, 1805, the proprietors gave directions for the
demolition of Ranelagh House and the Rotunda; the furniture was
sold by auction shortly afterwards, and the buildings were removed.
The organ was bought for Tetbury Church, Gloucestershire, where it
remained till 1863, when it was purchased by a builder.
The Ranelagh grounds had extended from the old Burial Ground
(east of Chelsea Hospital) to the rivermarshes on the south, and the
Chelsea Bridge Road now crosses their eastern boundary. When the
buildings were removed the grounds were, by degrees, purchased of
the shareholders by General Richard R. Wilford to add to his
property adjoining. A poet of the Gentleman’s Magazine in June
1807 laments the Fall of Ranelagh, and the site already overgrown
with weeds. The foundation walls of the Rotunda and the arches of
some of the cellars could, however, be traced as late as 1813, and
part of the site was a favourite playground for Chelsea children. By
1826, the Ranelagh grounds had become by purchase the property
of Chelsea Hospital and were parcelled out into allotments. The
ground is, at the present time, once more a ‘Ranelagh Garden,’ in
which the public are admitted, as the old advertisements would say,
“to walk gratis.”
All traces of Ranelagh have been thus obliterated, and a London
historian (Jesse, London, iii, 420) on visiting the site in 1871, could
find as its memorial only a single avenue of trees with one or two of
the old lamp-irons—the ‘firetrees’ of the early advertisements—still
attached.
[From the numerous authorities, the following may be selected:—
Gent. Mag. 1742, 418, ff.; Ranelagh House: a Satire in prose, London,
1747 (W. Coll.); Dodsley’s London, 1761; Sir John Fielding’s Brief
Description of London, 1776; Burney’s Hist. of Music, iv. 668, ff.;
Kearsley’s Strangers’ Guide (1793?); Lysons’s Environs, Supplement,
p. 120; Faulkner’s Chelsea, ii. 299, ff.; Blanchard in The Era
Almanack, 1870; Grove’s Dict. of Music, art. “Ranelagh House,” by W.
H. Husk; L’Estrange’s Village of Palaces, ii. 296; Walford, v. 76, ff.;
Austin Dobson’s Eighteenth Century Vignettes, 2nd ser. p. 263, ff.;
collections relating to Ranelagh in British Museum and Guildhall
libraries, and a large series of cuttings from newspapers, magazines,
&c., W. Coll.]
VIEWS.
A good representative series of the principal early views of
Ranelagh is in the Crace Collection (Catal. p. 164; pp. 312–314). The
site is well marked in Horwood’s Plan A, 1794.
STROMBOLO HOUSE AND GARDENS, CHELSEA
Strombolo House[241] was a minor place of entertainment, dating

from 1762, or earlier, with tea-gardens and “a fine fountain”[242]
attached to it. The gardens[243] are said to have been most
frequented about 1788. They were open chiefly in the afternoons of
week-days and Sundays for tea-drinking during the summer season.
The house, opposite the famous Royal Bun House, Chelsea, in
Jew’s Row (now Pimlico Road), was still standing in 1829, when
Faulkner’s Chelsea (second edition) was published, but it appears to
have been disused as a place of amusement long before that date.
The ground was afterwards occupied by the Orange Tavern and
tea-gardens to which was attached the Orange Theatre, a small
private playhouse, where local geniuses performed (1831–32). St.
Barnabas Church, Pimlico, built 1848–1850, standing off the south
side of Pimlico Road (entrance in Church Street) is now nearly on
the site.
[O’Keefe’s Recollections, i. p. 88; Faulkner’s Chelsea, ii. p. 357;
Davis’s Knightsbridge (1859), p. 263; Wheatley’s London P. and P. s.v.
“Strombello”; Timbs’s Club Life (1866), ii. p. 260.]
STAR AND GARTER TAVERN AND GARDENS, CHELSEA
In the grounds attached to the Star and Garter Tavern in the Five
Fields between Chelsea and Pimlico,[244] displays of fireworks and
horsemanship took place in 1762 (July-September) to celebrate the
birth of the Prince of Wales, and the visit of the chiefs of the
Cherokee Indians[245] who were duly exploited by the proprietor.
Carlo Genovini, an Italian artificer, exhibited stars and moving suns,
a guilloche of a varied coloured rose, reprises of water cascades and
many pyrotechnic devices, together with the Temple of Liberty, a
machine thirty-two feet long and forty high “painted in a theatrical
manner” with Britannia triumphant over the portico. The fireworks
began at eight or nine and the tickets were usually half-a-crown.
On other evenings at seven o’clock Thomas Johnson, the well-
known equestrian, performed feats with two and three horses similar
to those undertaken by him at the Three Hats, Islington. The
admission was one shilling. The proprietor of the Star and Garter
also kept the neighbouring Dwarf’s Tavern, with Coan, “the jovial
Pigmy,” as Major Domo,[246] and to this place visitors were invited to
adjourn after the fireworks, there to sup on “a most excellent ham,
some collared eels, potted beef, etc., with plenty of sound old bright
wine and punch like nectar.”[247]
[Faulkner’s Chelsea, ii. 354–356, where further details of the
fireworks and horsemanship may be found; Davis’s Knightsbridge, p.
264.]
JENNY’S WHIM, PIMLICO
St. George’s Row, near Ebury Bridge, formerly called The

Wooden Bridge or Jenny’s Whim Bridge, marks the site of Jenny’s
Whim, a tavern and pleasure-garden popular in the last century.
Jenny’s Whim is said to have been established as a place of
amusement by a firework artificer and theatrical machinist, in the
reign of George II. About 1750 it appears to have been a good deal
frequented during the day-time, and people of rank and fashion
occasionally visited it. Walpole once encountered Lord Granby
“arrived very drunk from Jenny’s Whim,” where he “had dined with
Lady Fanny [Seymour] and left her and eight other women and four
other men playing at Brag.”
A writer in The Connoisseur comparing it in 1755 with Ranelagh
and Vauxhall, describes it, however, as a resort of “the lower sort of
people,” rather than of the quality.
A West View of Chelsea Bridge ... Un Vue du Pont de Chelsea du
cote du ‘Vest.
SHOWING JENNY’S WHIM, 1761.
The gardens possessed, in addition to the usual bowers, alcoves

and prim flowerbeds, a bowling-green, a grotto, a cock-pit and a
ducking pond. In the centre was a large fish pond. Mechanical
devices, similar to those at New Georgia, Hampstead, attracted
many visitors. A Harlequin, a Mother Shipton, or some terrific
monster, started up in the recesses of the garden when an
unsuspected spring was trodden upon, and huge fish and mermaids
rose at intervals from the water of the pond.
The admission about 1755 appears to have been sixpence.
Before the close of the eighteenth century, the popularity of the
place had declined, though it was still frequented as a summer tea-
garden, and by 1804 Jenny’s Whim had become a mere public-
house. The house, a red brick building with lattice work, containing a

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Gene Regulation and Therapeutics for

Cancer 1st Edition Surinder K. Batra

Cancer Genetics and Therapeutics Focus on

Post Transcriptional Gene Regulation 2nd Edition Erik

Epigenetics and Gene Expression in Cancer Inflammatory

Advancing Gene Fusion Detection Towards Personalized

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Cancer Driver Genes: Methods and Protocols Timothy K.

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Furthermore, two individual chapters focus on prostate cancer biology, and

1. Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory

9. Molecular Drivers in Lung Adenocarcinoma: Therapeutic

Ashu Shah1, Catherine Orzechowski1 and Maneesh Jain1,2*

*Corresponding author: mjain@unmc.edu

progression of pancreatic cancer [3]. The disease is believed to originate

Immune System in Pancreatic Cancer

Checkpoint Blockade Receptor Programmed Death-1

and coinhibitory molecules on immune cells called immune checkpoints.

while murine Panc02 tumors are hypermutated, human pancreatic tumors

PD-1 Regulation in Pancreatic Cancer

cells exhibited enhanced H3K4 methylation by histone methylase MLL1

Immune Cells Mediated PD-1 Regulation in

Myeloid Cells in Mediating PD-1/PD-L1 Activation

Fig. 1: Signaling axes implicated in the regulation of PD-1/PD-L1 expression and

made to target these signaling pathways using pharmacological inhibitors in

JAK2/STAT3 signaling pathway, promoted the upregulation of PD-1 and

Regulatory B- and T-cells Mediated PD-1 Regulation

Type of therapy Name Target population Clinical trial Phase (status)

Type of therapy Name Target population Clinical trial Phase (status)

through Tregs. Despite extensive Teffector cell infiltration in the PDAC

Pathobiological Significance of PD-1 Expression in

Resistance to Anti-PD-1 Based Immunotherapy in

checkpoint inhibitor immunotherapies. Given that a majority of checkpoint

Current Progress in Anti-PD-1 Therapy in

colony-stimulating factor (GM-CSF) secreting, allogeneic PDAC vaccine),

using a sensitive nanoparticle based immunodetection method but these

improves response to T-cell checkpoint immunotherapy in pancreatic cancer

76. Patnaik, A., S.P. Kang, D. Rasco, K.P. Papadopoulos, J. Elassaiss-Schaap,

Belsize House was a large Elizabethan mansion, modified in the

The Welsh Ambassador was the nickname of the proprietor,

The spring known as Kilburn Wells was situated in the Abbey

About 1773 Kilburn Wells began to be more widely known, and

§ 3. The entertainments and the company.

The Chinese House, the Rotunda, & the Company in Masquerade in

§ 4. Annals of Ranelagh 1742–1769.

In 1762–1764 the principal singer was the Italian Tenducci,[230]

§ 5. Later history of Ranelagh, 1770–1805.

Strombolo House[241] was a minor place of entertainment, dating

St. George’s Row, near Ebury Bridge, formerly called The

The gardens possessed, in addition to the usual bowers, alcoves

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