Cancer vaccines 20_july2020
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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.
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Cancer vaccines 20_july2020
- 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 START COURSE TAKE A DEEP DIVE INTO:
- 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 CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 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. CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer 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 CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer • 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 CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer 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 CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer 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’ CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer 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! CANCER VACCINES Lesson 1 Lesson 2 Lesson 3 Lesson 4 Lesson 5 Lesson 6 Disclaimer Türeci Ö et al. Nature Biomedical Engineering; 2018.