Immunotherapy

for Cancer
 General
principles T cell responses to tumors

• The immune system recognizes and

reacts against cancers

• The immune response against tumors is

often dominated by regulation or
tolerance
– Evasion of host immunity is one of the
hallmarks of cancer

• Some immune responses promote cancer

growth

• Defining the immune response against

cancers will help in developing new
immunotherapies
Tumor-infiltrating T cell
subpopulations include
CD4+ and CD8+ T cell subsets
(Table 2). CD4+ T cells are
represented by T helpers,
such as TH1, TH2, TH9, TH1 7
and Tfh, and Tregs. The
CD8+ T cell subsets consist of
cytotoxic cells and mucosal-
associated invariant T cells
(MAIT).

These T cell subpopulations

are highly important for
prognosis and prediction of
treatment efficiency.
CD8+ cytotoxic cells migrate
into the tumor tissue and
display cytotoxic activity
against tumor cells
1. γδ T cells, a T cell subset involved in both innate and adaptive immunity, may have
both anti-tumor and pro-tumor functions .

2. Anti-tumor effects are mediated via their differentiation into cytotoxic T cells. Vδ1
and Vγ9Vδ2 T cells are two populations of γδ T cells, which are present in the tumor
microenvironment. Both subsets develop cytotoxic capabilities

3. Among the T helpers, TH9 cells are known to secrete IL-9 and IL-10 and inhibit tumor
growth.

4. Low expression of IL-9R induces melanoma growth. Moreover, some TH9 cells can
secrete IFNg. Also, TH9 cells, which infiltrate colorectal tumors, may be regulated
through PD-1/PD-L1 pathway and may stimulate the proliferation of CD8+ cells.

5. Tregs are known to infiltrate tumor sites and demonstrate immunosuppressive

activity. Tumor-infiltrating Tregs were found to have high expression of CTLA-4, GITR
and PD-1

6. Mucosal-associated invariant T cells (MAIT) belong to innate T cells and are present
mainly in mucosal tissues. They express a semi-invariant T cell receptor, which
contains rearranged TCRβ chains with Vβ gene segments
Cross-presentation of tumor antigens
The spectrum of target antigens associated with tumor immunity and allo-immunity after
allogeneic hematopoietic stem cell transplantation. Host-derived T and B cells can be induced to
recognize tumor-associated antigens, whereas donor-derived B and T cells can recognize both
tumor-associated antigens and alloantigens.
Classes of human tumor antigens recognized by T lymphocytes, with their genetic process
Tumor antigens, because of their relative abundance in tumor cells
are useful in identifying specific tumor cells. Certain tumors have
certain tumor antigens in abundance.
Immune phenotypes that predict better survival

Analysis of 124
published articles on
correlation of T cell
subsets and
prognosis of 20
cancer types

Fridman et al. Nat Rev Cancer 12:298, 2012

 Types of tumor antigens
• Most tumor antigens that elicit immune
responses are neoantigens
– Not present normally, so no tolerance
– Produced by mutated genes that may be involved
in oncogenesis (driver mutations) or reflect
genomic instability (passenger mutations)
– In tumors caused by oncogenic viruses (HPV,
EBV), neoantigens are encoded by viral DNA

• Some are unmutated proteins (tyrosinase,

cancer-testis antigens)
– Derepressed (epigenetic changes), over-
expressed
Identification of tumor neoantigens

Next gen sequencing and/or

RNA-seq

Identification of HLA-
binding peptides

MHC-peptide multimer
and/or functional assays

Ton N. Schumacher, and Robert D. Schreiber Science 2015;348:69-74

Immune responses that promote tumor growth

M2

Coussens et al. Science 339:286, 2013

 The history of cancer immunotherapy: from empirical
approaches to rational, science-based therapies

Treatment of
cancer with
bacterial Treatmen FDA approval of
products t of Adoptive Adoptive sipuleucel-T (DC FDA approval
(“Coley’s bladder cell T cell vaccine) in of anti-PD1
toxin”) cancer therapy therapy prostate cancer for melanoma
with BCG

1863 1898 1957 1976 1983 1985 1991, 4 2002 2009 2010 2011 2014

Description of Cancer IL-2 Discovery HPV FDA approval of Breakthrough

immune immuno- therapy of human vaccination anti-CTLA4 status for
infiltrates in surveillance for tumor in VIN (ipilumimab) for CAR-T cells
tumors by hypothesis cancer antigens melanoma in leukemia
Virchow (Burnet, (Boon,
Thomas) others)
Passive immunotherapy
Chimeric antigen receptors

• Remarkable
success in B cell
acute leukemia
(targeting CD19);
up to 90%
complete remission

• Risk of cytokine
storm
• Outgrowth of
antigen-loss
variants of
tumors?
Development of chimeric antigen receptors
 Limitations and challenges of CAR-T
cell therapy
• Cytokine storm – many T cells respond to
target antigen
– Requires anti-inflammatory therapy (anti-IL-6R)
– Risk of long-term damage (especially brain)
• Unclear how well it will work against solid
tumors
– Problem of T cells entering tumor site
• Will tumors lose target antigen and develop
resistance?
• Technical and regulatory challenges of
producing genetically modified CAR-T cells for
each patient
– Prospect of gene-edited “universal” CAR-T cells?
 Limitations and challenges of CAR-T
cell therapy -- 2
• Exhaustion of transferred T cells
– Use CRISPR gene editing to delete PD-1 from T cells
– Increased risk of autoimmune reactions from endogenous
TCRs
– Use CRISPR to delete TCRs
– Result is PD-1- T cells expressing tumor-specific CAR
 Dendritic cell vaccination

These peptides are often given in combination with adjuvants (highly immunogenic
substances) to increase the immune and anti-tumor responses. Other adjuvants include
proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte
macrophage colony-stimulating factor (GM-CSF). The most common source of antigens used
for dendritic cell vaccine in Glioblastoma (GBM) as an aggressive brain tumor were whole
tumor lysate, CMV antigen RNA and tumor associated peptides like EGFRvIII.

Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This
can be achieved by either genetically engineering tumor cells to produce GM-CSF or by
infecting tumor cells with an oncolytic virus that expresses GM-CSF.
Blocking CTLA-4 promotes tumor rejection:
CTLA-4 limits immune responses to tumors

Administration of antibody that blocks CTLA-4 in

tumor-bearing mouse leads to tumor regression
Checkpoint blockade: Removing the brakes on
the immune response

ipilimumab

Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing

immune responses against tumors)
Even more impressive results with anti-PD-1 in cancer patients
The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker
approved in the United States in 2011.- for the treatment of melanoma, a type of skin cancer. It is
undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung
cancer (SCLC), bladder cancer and metastatic hormone-refractory prostate cancer
 Checkpoint blockade for cancer immunotherapy

Checkpoint blockade
Priming phase
Effector phase
 Why do tumors engage CTLA-4 and PD-1?

• CTLA-4: tumor induces low levels of B7

costimulation  preferential engagement of
the high-affinity receptor CTLA-4

• PD-1: tumors may express PD-L1

• Remains incompletely understood

– These mechanisms do not easily account for all
tumors
 Is checkpoint blockade more effective
than vaccination for tumor therapy?
• Tumor vaccines have been tried for many
years with limited success

• Immune evasion is a hallmark of cancer

– Multiple regulatory mechanisms

• Vaccines have to overcome regulation

– Tumor vaccines are the only examples of
therapeutic (not prophylactic) vaccines
– Vaccination after tumor detection means
regulatory mechanisms are already active
 The landscape of T cell activating and
inhibitory receptors
Inhibitory receptors Activating receptors
(coinhibitors) (costimulators)
CTLA-4
CD28
PD-1 ICOS

TIM-3
OX40

TCR
T cell

TIGIT GITR

LAG-3 CD137 (4-1BB)

BTLA CD27
 Targeting inhibitory receptors for
cancer immunotherapy
• Blocking inhibitory receptors induces tumor
regression
– Partial or complete responses in up to 40%
– Biomarkers for therapeutic responses?

• May be more effective than vaccination

– Vaccines have to overcome tumor-induced
regulation/tolerance

• Adverse effects (inflammatory autoimmune

reactions)
– Typically manageable (risk-benefit analysis)
 Combination strategies for cancer
immunotherapy

• Combinations of checkpoint blockers, or bispecific

antibodies targeting two checkpoints
• Already done with CTLA-4 and PD-1

• Checkpoint blockade (anti-PD1 or -CTLA-4) +

vaccination (DCs presenting tumor antigen)

• Checkpoint blockade + agonist antibody specific for

activating receptor

• Checkpoint blockade + kinase inhibitor to target

oncogene
 Checkpoint blockade: prospects and
challenges

• Exploiting combinations of checkpoints

– Poor biology underlying choice of combinations
to block
– Difficult to reliably produce agonistic
antibodies

• Typically, 20-40% response rates; risk

of developing resistance?
 Checkpoint blockade: prospects and
challenges
• Exploiting combinations of checkpoints
• Typically, 20-40% response rates; risk of developing
resistance?
• Possible biomarkers of response vs
resistance:
– Nature of cellular infiltrate around tumor
– Expression of ligands for inhibitory receptors
(e.g. PD-L1) on tumor or DCs
– Frequency of neoantigens (HLA-binding
mutated peptides) in tumors from different
patients
– Frequency of tumor-specific “exhausted” T
cells
 References
Slide courtesy:
PRP wishes to than the following scientists for their slides and
study material being used in this B.Tech immunology class.
1. Dr. Abul K. Abbas, UCSF
Abul.Abbas@ucsf.edu
2. Dr.Vinay Kumar is the Lowell T. Coggeshall Distinguished
Service Professor of Pathology at the University of Chicago
3. https://www.labome.com/method/T-Cell-Markers-and-B-
Cell-Markers.html