SnapShot

Advances in cancer immunotherapies

Oula K. Dagher,1 Robert D. Schwab,2 Shawna K. Brookens,1 and Avery D. Posey, Jr.1,3
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2Department of
1

Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Therapeutic cancer vaccines Adoptive cell therapies

DNA Naked

NKG2D CD16
Nanoparticle

mRNA APC
5´ G A A A 3´ αβTCR Transgenic (NKT) γδTCR CAR TCR-like
αβTCR TCR TRAIL Antibody
CAR

MHC- TM: Transmembrane

peptide TAA: Tumor-associated antigen
Autologous dendritic cell TSA: Tumor-surface antigen
Peptide TCR
TCRv: TCR variable
αGalCer: Alpha-galactosylceramide

T cell MHC I CD1d Cell surface CD277 CD8

antigen

Irradiated tumor cell

Tumor cells Costimulatory

domains

CAR
αβ CD8 + CAR-T
TIL cell

Intracellular scFv TM CD3ζ

tumor antigen
Immune checkpoint blockade domain

APC T cell Tumor cell Engineered

TCR-T cell
TAA, TSA, or scFv or
neoantigen TCRv
MHC- MHC-
TCR TCR
peptide peptide TCR-like
CD80/86 CD28 CAR-T cell
Neoantigen
CD80/86 CTLA-4
PD-1 PD-L1
CAR-
macrophage CAR-NK
cell

Anti-CTLA-4 mAb Anti-PD-1 mAbs Anti-PD-L1 mAbs

CAR-γδT CAR-NKT
Ipilimumab Pembrolizumab Atezolizumab
cell cell
Nivolumab Durvalumab
Cemiplimab Avelumab Non-MHC
restricted

αGalCer

Promote T cell reactivation

DC or
TAM

Bi-specific T cell engagers (BiTEs)

19

Tecartus Breyanzi
D

T cell Tumor cell

C

2020 2021
Blinatumomab
Anti-CD3 Anti-CD19
Yescarta Abecma
2017 2021
FDA approved
BCMA

CD19
TCR
CAR-T cell
therapies
BCMA Kymriah Carvykti
2017 2022
Anti-CD3 Anti-BCMA

Teclistamab

Blood malignancies
Promotes MHC-independent tumor lysis ALL, NHL, MCL, MM

See online version for legends, references,

1814 Cell 186, April 13, 2023 © 2023 Elsevier Inc. DOI https://dx.doi.org/10.1016/j.cell.2023.02.039 and declaration of interests
SnapShot
Advances
Title of snapshotin cancer title immunotherapies
of snapshot title of snapshot title
of snapshot title of snapshot title of snapshot title
Oula K. Dagher, Robert D. Schwab, Shawna K. Brookens, and Avery D. Posey, Jr.
1
1 2 1 1,3

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2Department of Medicine,
Perelman
Author1,2School of Medicine,
Author, 1,2 University1,2of Pennsylvania, Philadelphia, PA; 3Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
and Author
Affiliation #1; ²Affiliation #2; ³Affiliation #3
1

Therapeutic
Paragraph text modalities that engage the immune system to recognize and eliminate cancer, known as cancer immunotherapy, have emerged as a distinct pillar of cancer
therapy. Among the most promising treatment approaches are therapeutic cancer vaccines, immune checkpoint blockade, bi-specific T-cell engagers (BiTEs) and adoptive cell
therapies (ACT). These approaches share a common mechanism of action, which is elicitation of a T-cell-based immune response, either endogenous or engineered, against
Section header
tumor antigens.
Paragraph textMoreover, interactions between the innate immune system, particularly antigen-presenting cells, and immune effectors also underlie the efficacy of cancer
immunotherapies and approaches engaging these cells are also under development.
Section header
Therapeutic
Paragraph textcancer vaccines
Therapeutic cancer vaccines elicit endogenous T cell immune responses against tumor antigens through uptake, processing, and presentation by dendritic cells.1 Tumor
antigens may either be shared amongst several cancer types, such as commonly mutated variants of KRAS or p53, or personalized neoantigens specific to somatic mutations of
Section header
an Paragraph tumor. 2 Methods to induce immune activation include delivery of antigen through injection of naked or nanoparticle encapsulated DNA, RNA, or peptides, ex vivo
individual’stext
pulsed autologous dendritic cells, and irradiated tumor cells.1 Irradiated autologous tumor cells are often genetically engineered to secrete immune activating factors, such as
GVAX.
Section Antigenic
header presentation relies upon the peptide-binding properties of specific human leukocyte antigens (HLA) in major histocompatibility complexes (MHC) I and II, which
elicit reactivitytext
Paragraph of antigen-specific CD8+ and CD4+ T cells, respectively. Sipuleucel-T, a dendritic cell vaccine, was approved in 2010 for the treatment of metastatic, castration-
resistant prostate cancer and is the only FDA-approved vaccine therapy in the United States.3
ACKNOWLEDGMENTS
Immune checkpoint blockade
Acknowledgements
Activated T cells,text.
which play a central role in anti-tumor immunity, express surface inhibitory receptors, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and
programmed death 1 (PD-1). Binding to their cognate ligands results in non-redundant inhibitory signaling pathways and attenuation of T cell cytotoxic activity.4 Many tumors
REFERENCES
evade T cell responses by increasing expression of PD-L1. Interception of this inhibitory interaction results in increased T cell activation and proliferation, inducing anti-tumor
responses. Humanized
[Author list with monoclonal
“surname, blocking
first/middle antibodies
initial” followed bytargeting
“et al.” if CTLA-4
needed] (ipilimumab), PD-1 (pembrolizumab,
(year in parentheses). nivolumab,
[article title]. Journal and cemiplimab),
title volume or PD-L1 (atezolizumab,
number, page–range durvalumab,
or article number.
and avelumab) as single agents or in combination with chemotherapies have been utilized in nearly 50 cancer types, with the highest success observed in melanoma.4,5 Despite
Example: Asp, M., Bergenstråhle, J., and Lundeberg, J. (2020). Spatially Resolved Transcriptomes—Next Generation Tools for Tissue Exploration. Bioessays 42, 1900221.
the promise of checkpoint blockade therapy, only a minority of patients achieve complete responses, as its efficacy is contingent on tumor mutational burden and proper anti-
tumor T cell function.6 Furthermore, though PD-1/PD-L1 inhibition exerts less adverse effects than CTLA-4 blockade, both therapies have the potential for promoting autoimmune
conditions and life-threatening toxicities, such as checkpoint-induced pneumonitis.

Bi-specific T cell engagers

BiTEs have emerged as a key therapeutic in oncology, particularly in hematologic malignancies. BiTEs are recombinant proteins with two unique antigen-binding modules
connected in series by a short linker sequence or shared Fc domain. One antigen-binding module targets a tumor-associated antigen (TAA), while the other binds against a T cell
activating molecule, such as the CD3 molecules of the T cell receptor (TCR) complex.7 Simultaneous binding of the BiTE to the tumor antigen and TCR causes T cell activation
and formation of immune synapses between T cells and tumor cells, inducing tumor cell lysis. BiTEs can be designed to target any cell surface TAA, providing a high potential
for utility in a variety of cancers. Currently, there are three FDA-approved BiTE molecules. Blinatumomab targets CD19, a B lymphocyte antigen, and is approved for treatment
of relapsed or refractory (r/r) B cell precursor (BCP)-acute lymphoblastic leukemia (ALL) and BCP-ALL with minimal residual disease. Teclistamab, a bispecific monoclonal
antibody, targets BCMA (B cell maturation antigen) and is approved for treatment of r/r multiple myeloma.8 Unlike blinatumomab and teclistamab, which target TAAs through
antibody-derived binding domains, tebentafusp utilizes a soluble high-affinity T cell receptor to target a gp100-derived peptide within MHC class I complexes and is approved
for the treatment of uveal melanoma.9 Notable side effects from clinical trials with BiTEs are cytokine release syndrome and neurotoxicity, with a variety of other lesser toxicities
that may be target dependent.

Adoptive cell therapies

ACT refers to a versatile group of ex vivo-expanded, autologous or allogeneic immune cells that are infused into a patient to promote tumor eradication. The most widely used
adoptive cell therapies include tumor-infiltrating lymphocytes (TILs), or gene modified T cells, such as those expressing a transgenic TCR or chimeric antigen receptor (CAR).10 Unlike
TILs and transgenic TCR T cells, CAR-T cells are MHC independent and can be modified to target any TAA. As of 2022, there are six FDA-approved CAR-T cell therapies, with four
targeting CD19 for the treatment of B cell leukemia and lymphoma and two targeting BCMA for the treatment of r/r myeloma. Prominent acute side effects of CAR-T cell therapy
include neurotoxicity, cytokine release syndrome, and chronic hypogammaglobinemia. Thus far, the efficacy of CAR-T cells in hematologic malignancies has not been paralleled
in solid tumors, likely due to tumor heterogeneity, poor lymphocyte infiltration, and the immunosuppressive tumor microenvironment. A wide range of gene modification strategies
have been exploited to increase ACT efficacy in solid tumors as well as engineering innate killer cells or macrophages to express transgenic TCRs, NK cell receptors (NKR), CARs,
or TCR-like CARs.

REFERENCES
1. Saxena, M., van der Burg, S.H., Melief, C.J.M., and Bhardwaj, N. (2021). Therapeutic cancer vaccines. Nat Rev Cancer 21, 360–378.
2. Verdon, D.J., and Jenkins, M.R. (2021). Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy. Cancers (Basel) 13.
3. Kantoff, P.W., Higano, C.S., Shore, N.D., Berger, E.R., Small, E.J., Penson, D.F., Redfern, C.H., Ferrari, A.C., Dreicer, R., Sims, R.B., Xu, Y., Frohlich, M.W., Schellhammer, P.F., and
Investigators, I.S. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363, 411–422.
4. Wang, J., Yang, T., and Xu, J. (2020). Therapeutic Development of Immune Checkpoint Inhibitors. Adv Exp Med Biol 1248, 619–649.
5. Robert, C. (2020). A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 11, 3801.
6. Li, B., Chan, H.L., and Chen, P. (2019). Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem 26, 3009–3025.
7. Tian, Z., Liu, M., Zhang, Y., and Wang, X. (2021). Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J Hematol Oncol 14, 75.
8. Moreau, P., Garfall, A.L., van de Donk, N., Nahi, H., San-Miguel, J.F., Oriol, A., Nooka, A.K., Martin, T., Rosinol, L., Chari, A., Karlin, L., Benboubker, L., Mateos, M.V., Bahlis, N.,
Popat, R., et al. (2022). Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 387, 495–505.
9. Nathan, P., Hassel, J.C., Rutkowski, P., Baurain, J.F., Butler, M.O., Schlaak, M., Sullivan, R.J., Ochsenreither, S., Dummer, R., Kirkwood, J.M., Joshua, A.M., Sacco, J.J., Shoushtari,
A.N., Orloff, M., Piulats, J.M., et al. (2021). Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med 385, 1196–1206.
10. Finck, A.V., Blanchard, T., Roselle, C.P., Golinelli, G., and June, C.H. (2022). Engineered cellular immunotherapies in cancer and beyond. Nat Med 28, 678–689.

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DOI https://dx.doi.org/10.1016/j.cell.2023.02.039