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1. CANCER
VACCINES
ZEENA NACKERDIEN

2. OVERVIEW
Importance of
Immunotherapy
in Cancer
Definitions of
Cancer Vaccines
Influence of
Tumor
Microenvironmen
t
Criteria for a
Successful
Therapeutic
Cancer Vaccine
Key Milestones in
the Development
of Cancer
Vaccines
Therapeutic
Cancer Vaccines
Lessons from
Other
Immunotherapies
Next-Generation
Cancer Vaccines

3. Globally, cancer is the
2nd leading
(8.8 million in 2015)of death.
Cancer-causing infections are responsible for up to
25%of cases in low- and middle-income countries.
Late-stage presentation is one of the reasons for these statistics.
The use of effective and
safe cancer vaccines is one way
to reduce this in the future.
x x x x x
xx x x
This module
provides
an introduction to
cancer vaccines.
IMPORTANCE OF CANCER VACCINES
EPIDEMIOLOGY

4. DEFINITIONS OF CANCER VACCINES
Prophylactic Cancer Vaccines Therapeutic Cancer Vaccines
• Hepatitis B shots can reduce the risk of
hepatocellular carcinomas
• Cervical cancer and other HPV-caused
cancer risks can be reduced with HPV
vaccines
• Non-viral prophylactic and therapeutic cancer vaccines
are important because tumors that are viral in origin
account for only 10 to 20% of all human cancers.
• Non- virus-associated prophylactic vaccines (NVP)
target inflammatory pathways within
the TME that propel the onset of cancer.

5. IMPACT OF TUMOR MICROENVIRONMENT (TME) ON VACCINES
What vaccines can do How TME thwarts vaccines
• Typically, vaccines target host DCs for
effective presentation of tumor-associated
antigens
– Next step is priming of CD8+ CTLs and
CD4+-T-helper cells
• TME can overcome the immune-boosting
properties of cancer vaccines
• Immunosuppressive soluble factors (TGF-β,
IL-10, IDO, galectin, and VEGF) are produced
• Cells expand or recruit immune regulatory
cells (MDSCs, Tregs, and TAMs)
Tumor amenable to immunotherapies
incl. vaccines: More infiltrate
Tumor not amenable to
immunotherapies incl. vaccines:
Developed suppressive
mechanisms to exclude immune
cells; This includes immune
checkpoint blockade, myeloid
suppressor cells,
immunosuppressive cytokines
such as transforming growth
factor-β and interleukin-1 and
metabolic enzymes such as
indoleamine 2,3- dioxygenase.
Immune
modulators/combination
treatment may boost efficacy.

6. VACCINE CRITERIA AND OTHER
INGREDIENTS
• To be a success, the active
ingredient(s) must
overcome:
— A corrupted tumor
microenvironment
containing regulatory T cells
and aberrantly matured
myeloid cells
— A tumor‐specific T‐cell
repertoire that is prone to
immunologic exhaustion and
senescence
— Highly mutable tumor
targets capable of antigen
loss and immune evasion
• Other ingredients

7. KEY VACCINE MILESTONES
Key research milestones
In 1891, Coley’s Toxins caused shrinkage of a
malignant tumor. The rush from Coley’s Toxins to
the discovery of more tumor-associated antigens
accelerated between 1990 and 2010. Among the
milestones, is the FDA approval of the first
therapeutic cancer vaccine in 2010 for men with
advanced prostate cancer.
First Immunotherapy
William B. Coley, a New York bone surgeon, began
injecting cancer survivors with crude bacterial
preparations in the 1890s. He treated almost 900 patients
and claimed that about 40% achieved lengthy
remissions.

8. Types General mechanism
• Optimal vaccine platforms include:
— DNA
— RNA
• Synthetic Long Peptides
• Antigens are targeted for two reasons:
— Antigens can elicit a tumor-specific
immune response
— Antigens are (over-) expressed on
tumor cells
• Antigens of choice include:
— Mutant sequences
— Selected cancer testis antigens
— Selected viral antigens
• A rational vaccine design is needed,
including the appropriate vaccine platform
and adjuvant, to achieve concentrated
tumor antigen delivery to dendritic cells
which, in turn, can drive both CD4+- and
CD8+-T-cell responses
• Following administration via any of the
preferred routes, antigen-presenting cells
travel to the lymph nodes where they
prime T cells. The activated T cells travel
via the blood to reach the tumor. During
this passage, vaccine-induced T cells have
to overcome hostile elements, such as the
tumor microenvironment, including
immunosuppressive cells and other factors
released by the tumor, e.g., chemokines
and cytokines that may interfere with T cell
migration, function, and expansion.

9. LESSONS FROM OTHER
IMMUNOTHERAPIES (1)
• 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 approved by 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

10. LESSONS
FROM
OTHER
IMMUNO-
THERAPIES
(2)
• 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

11. Next-generation 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.
Individualizing 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’.
Novel vaccine holds promise in preclinical studies
Potential efficacy and scalability of vaccination using a “Coley’s Toxins” approach; intra-tumoral vaccine
delivery may bypass side effects associated with systemically administered immunotherapies; may reduce
local suppression, inducing enough tumor cell death to cross-prime strong immune responses; Proof-of-
concept study with a TLR-9 ligand and agonistic anti-OX40 antibody showed that this combination could
cure multiple types of cancer in animals and prevent spontaneous genetically-driven cancers.

12. Sources
1. World Health Organization. Cancer. [http://www.who.int/news-room/fact-sheets/detail/cancer]
2. Papaioannou NE et al. "Harnessing the immune system to improve cancer therapy." Annals of Translational Medicine, 4;
2016 (261).
3. American Cancer Society. What’s new in cancer immunotherapy research?
[https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/whats-new-in-
immunotherapy-research.html]
4. Rosenberg SA. "IL-2: the first effective immunotherapy for human cancer." J Immunol, 192; 2014 (5451-5458).
5. Chu NJ et al. "Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets
for Cancer Immunoprevention." Clinical Cancer Research, 21; 2015 (1549-1557).
6. US Centers for Disease Control and Prevention. 6 Reasons to Get HPV Vaccinations for Your Child
[https://www.cdc.gov/hpv/infographics/vacc-six-reasons.html]
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Vaccines and Immunotherapy, 6; 2018 (31-47).
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10. Bou Nasser Eddine F et al. "Tumor Immunology meets...Immunology: Modified cancer cells as professional APC for
priming naive tumor-specific CD4+ T cells." Oncoimmunology, 6; 2017 (e1356149).

13. CANCER VACCINES
Sources
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12. Melero I et al. "Therapeutic vaccines for cancer: an overview of clinical trials." Nat Rev Clin Oncol, 11; 2014 (509-524).
13. Finn OJ. "The dawn of vaccines for cancer prevention." Nat Rev Immunol, 18; 2018 (183-194).
14. Cheever MA et al. "PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine." Clin
Cancer Res, 17; 2011 (3520-3526).
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16. Pardoll DM. "The blockade of immune checkpoints in cancer immunotherapy." Nature Reviews Cancer, 12; 2012 (252).
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18. Türeci Ö et al. "Challenges towards the realization of individualized cancer vaccines." Nature Biomedical Engineering; 2018.
19. Nelson D et al. "The "Trojan Horse" approach to tumor immunotherapy: targeting the tumor microenvironment." J Immunol
Res, 2014; 2014 (789069).
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(eaan4488).
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