This is a brief overview of the evolving field of prophylactic and therapeutic cancer vaccines. Cancer vaccines are active immunotherapies. As seen in the accompanying figure, the distinction from passive immunotherapies is based on different mechanisms of action. Passive immunotherapies and adoptive T-cell transfer, for example, are made/modified outside of the body. Once inside the body they can compensate for missing or deficient functions. Active immunotherapies, on the other hand, stimulate effector functions in vivo. What this means, is that the patient’s immune system can respond to the challenge and be stimulated to mediate effector cells that defend the body in an immune response. Examples of active immunotherapies include peptide, dendritic cell, and allogeneic whole-cell vaccines.

1. Learning Objectives
• Definitions of Cancer Vaccines
• Tumor Microenvironment (TME)
• Therapeutic Cancer Vaccine Criteria
• Key Milestones
• Therapeutic Cancer Vaccines
• Lessons from Other Immunotherapies
• Next-Gen Cancer Vaccines (Challenges)
Cancer Vaccines
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2. Definitions
Prophylactic and Therapeutic Cancer Vaccines
• Approved prophylactic cancer vaccines are based on viral antigens:
– Hepatitis B virus (HBV) immunization can reduce the risk of liver cancer
– Cervical cancer and other human papilloma virus (HPV)-caused cancer risks can be reduced with HPV
vaccines
• Therapeutic cancer vaccines target tumor-associated (TAA) or tumor-
specific (TSA) antigens:
– Most cancer vaccines to date have targeted TAAs e.g., cancer/germline antigens that are normally
expressed only in immune privileged germline cells not expressed in adult tissue, and antigens that are
overexpressed in cancer cells
– Cellular vaccines using either killed cancer cells or autologous antigen-presenting cells (APCs) loaded with
cancer antigens have been developed and yielded some efficacy in patients
– Although viral vector vaccines have been derived from poxviruses, adenoviruses, and alphaviruses, and
replication-defective or attenuated versions, the antiviral immune response may neutralize the vector
– Efforts to improve potency and quality of peptide vaccines include constructs with amphiphilic peptides,
peptide fusions to toll-like receptor (TLR) agonists, addition of powerful inflammatory adjuvants, and
combinations with other immune modulators
– Several clinical studies are evaluating synergies between therapeutic cancer vaccines and other anticancer
immunomodulators
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Disclaimer
Hollingsworth RE, Jansen K. Nature Vaccines. 2019;4(1):7.

3. Tumor Microenvironment (TME)
Cross-talk between
cancer cells and the
proximal immune cells
ultimately results in an
environment that
fosters tumor growth
and metastasis.
This results in a
reprogramming of the
surrounding cells,
enabling them to play
a determinative role in
tumor survival and
progression.
Cancer cells can
functionally sculpt
their
microenvironments
through the secretion
of various cytokines,
chemokines, and
other factors.
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Hinshaw DC, Shevde LA. Cancer Research. 2019.
Understanding the nature of cross-talk between cancer cells
and proximal immune cells will allow for development of
Improved therapeutics

4. Key Milestones
• 1950s: Discovery of antitumor immunity in
mice
• 1960s: Burnett and Thomas
immunosurveillance hypothesis; development
of mouse tumor models
• 1970s: Discovery and ascension of dendritic
cells
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• 1980s: Development of vaccines based on
tumor cells; introduction of the HBV vaccine
• 1990s: Discovery of toll-like receptors; clinical
trials of therapeutic cancer vaccines
• 2000s: FDA approves human papilloma virus
vaccines
• 2010 and beyond: , an autologous cellular
immunotherapy, for the treatment of
patients with asymptomatic or minimally
symptomatic metastatic castration-
resistant prostate cancer approved by
the FDA; development of mutated
neoantigens as personalized therapeutic
cancer vaccines
Finn OJ. et al. Nat Rev Immunol, 18; 2018 (183-194); Image (Tumor-associated immune cells in the tumor microenvironment (TME) of
breast cancer models): Vanessa Barriga, Nyanbol Kuol, Kulmira Nurgali, and Vasso Apostolopoulos;
https://creativecommons.org/licenses/by/4.0/

5. Therapeutic Vaccine Criteria
Criteria:
• Overcome a corrupted TME containing
regulatory T cells and aberrantly matured
myeloid cells
• Overcome a tumor-specific T-cell repertoire
that is prone to immunologic exhaustion and
senescence
• Overcome highly mutable tumor targets
capable of antigen loss and immune evasion
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Melero I, Gaudernack G, Gerritsen W, et al. Nat Rev Clin Oncol. 2014;11(9):509-524.

6. Lessons From Other Immunotherapies
Tumors co-opt certain immune checkpoint pathways as
one mechanism of tumor resistance:
• Many checkpoints consist of ligand-receptor interactions
• A cytotoxic-T-lymphocyte-associated-antigen 4 (CTLA-4) antibody was the first immune checkpoint inhibitor class to be approved by the FDA
• Additional immune checkpoint inhibitors to programmed cell death protein 1 (PD-1) and its associated ligand (PD-L1) have since been approved
• Mechanism of action involves interference with or supplanting normal T-cell signaling and regulation
A mechanism of action also relevant to vaccines:
• Implies that combining appropriate vaccines plus other immunotherapies may be more efficient that each agent alone
• Vaccines increasing the number of tumor-specific T cells plus agents that enable infiltration or lysis of tumor cells, may theoretically be of greater
benefit than solo treatments
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Pardoll DM. Nature Reviews Cancer, 12; 2012 (252);
McNeel DG. "BioDrugs, 32; 2018 (1-7)

7. Next-Gen Cancer Vaccines
T-cell activities restored by immune
checkpoint inhibitors can also target cancer
mutations.
• Clinical studies have shown immune checkpoint inhibitors to be more successful in tumors with higher mutational
loads
• However, patients have spontaneous T-cell immunity only against <1% of their mutations
• This repertoire may be expanded by vaccines
Engineering a vaccine tailored to the
patient’s genetic makeup to mobilize the
immune response is one of the next steps.
• Next-generation sequencing of relevant mutations in animal models have revealed 20 to 50% to be immunogenic
and have potent therapeutic activity
• Challenges in clinic include genetically profiling each patient’s tumor, predicting neoantigens, and selecting those to
be included in a unique vaccine produced ‘on command’
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Türeci Ö et al. Nature Biomedical Engineering; 2018.

8. Disclaimer
This work product is for informational
purposes only and should not be regarded
as a substitute for medical advice. In
addition, the information therein comes from
publicly available references and do not
reflect the views of any organization with
whom the author may have an affiliation. As
always, science is an evolving field, and
information may have changed by the time
this slide deck is posted. Thanks for the gift
of your time!
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Türeci Ö et al. Nature Biomedical Engineering; 2018.