Cancer Immunotherapy Comes of Age Implications for cancer prevention, therapy and survivorship

1. Cancer Immunotherapy Comes of AgeImplications for cancer prevention, therapy and survivorship George Weiner, MD Director, Holden Comprehensive Cancer Center Professor, Department of Internal Medicine

2. We Have Been at War Against Cancer Throughout Human History Vice President Biden Cancer Moonshot Medieval Saxon man with a large tumor of the left femur President Nixon declares a “War on Cancer” in 1971

3. The Fight Against Cancer The war within… Takes place in every cancer patient Between the cancer and the immune system

4. Basic Cancer Immunology • We all have unique immune systems • Makes it harder for infections to spread within a community • Why transplanted organs get rejected • Why you can’t “catch” cancer from someone else

5. Immune system Distinguishes “self” from “non self” Eliminate Infection Don’t Attack Our Own Cells

6. Immune system Under-active immune response Don’t Attack Our Own Cells Infection

7. Immune system Over-active immune response Eliminate Infection Autoimmunity

8. Goal of cancer immunotherapyBend the immune system curve Eliminate Cancer Avoid Autoimmunity

9. Cancer Prevention • Use immune system to prevent infections that eventually can lead to cancer • Less complex, and more effective than using immunotherapy to treat established cancers • Don’t need to bend the curve since infectious organizms are not “self” and viruses contain foreign targets • Vaccination is given PRIOR TO infection • HPVHep B You know about this!!!

10. Immunotherapy for Established Cancers • Traditional vaccine • Immunize patient with an antigen (e.g. protein found in HPV) or a killed virus that includes the target antigen • Why can’t we immunize against cancer in a similar way?

11. Immunotherapy for Established Cancers Challenge Overcome fact that cancer is “self” Need to break tolerance (help immune system see the target as “non-self”) Immune system recognizes targets Need to have a unique target to induce an effective immune response

12. Immune system needs a target • Traditional vaccine • Immunize patient with an antigen (e.g. protein found in HPV) or a killed virus that includes the target antigen • Why can’t we immunize against cancer in a similar way? • There is no shared target antigen between patients • All cancer antigens are “self” • For these reasons, for many decades, esteemed cancer researchers said “Cancer immunotherapy will never work”!

13. Most cancers have many mutations in their DNA Lawrence, Nature 499:214 2013 Every cancer cell has approximately 3,000 megabases of DNA Typical lung cancer has 30,000 individual mutations in its DNA Genetic mutations can result in abnormal proteins that serve as neoantigens With rare exception, every cancer will have its own unique set of mutations

14. So… • Mutations can lead to expression by the cancer of “Neoantigens” • Neoantigens can serve as an immune system target that the immune system has not seen before, i.e. is not on normal cells • No “immune tolerance” • Why does a cancer that expresses “Neoantigens” escape the immune system in first place?

15. Question • (most oncology trainees get this wrong) What is the most common large tumor that is not rejected despite expressing large numbers of unique antigens the immune system has never seen before? Hint – It only occurs in women

16. Immunity and pregnancy The mother’s immune system does not reject the fetus despite the expression of many different molecules by the fetus The immune system has evolved so it ignores the developing fetus Cancer cells can usurp these mechanisms to hide from the immune system

17. Cancer’s “invisibility cloak” Cancer cells express molecules that prevent immune system from recognizing and eliminating cancer

18. New concepts in cancer immunotherapy • Develop a tailor-made vaccine for each patient’s own tumor • Enhance the ability of the immune system to take a fresh look at the cancer and so recognize and eliminate the cancer cells that express neoantigens

19. Ideal immune system target • Ideal target - expression • Selectively on malignant cells (or non-vital tissues) • On all malignant cells in a tumor • Ideal target - function • Necessary for cell survival or malignant phenotype

20. Tools in the “War on Cancer” at the individual level… • Primary Combatants: • Malignant cells • Host immune system • The host immune system is present as the cancer develops • All “successful” cancers must avoid immune destruction • Tools to turn the immune system tide against the cancer • Target on surface of cell – Antibody-based treatment • Target inside cancer cell – T cell-based treatment

21. Immunity OutsideCells Immunity InsideCells Antibodies T Cells

22. Major approaches to cancer immunotherapy • Antibodies • Administer anti-cancer antibodies to patients • Administer antibodies that alter the immune response to the cancer • T-cells • Cancer vaccines • Change tumor environment so the immune system recognizes and eliminates the cancer (in situ immunization) • Take out T cells, change them so they are specific for the cancer, and give them back to the patient

23. Building better monoclonal antibody-based therapeutics George J. Weiner Nature Reviews Cancer June 2015

24. Steps Necessary for Antibody-Drug Conjugate to be Effective ADC Receptor-Mediated Endocytosis Target Antigen Lysosome

25. Building better monoclonal antibody-based therapeutics George J. Weiner Nature Reviews Cancer June 2015

26. Remove cancer’s “invisibility cloak” Cancer cells express molecules that prevent immune system from recognizing and eliminating cancer x We now can block these molecules with mAb allowing the immune system to recognize and eliminate the cancer

27. Turning on and off T cells – Its complicated Topalian, Weiner, Pardoll JCO 2012

28. Immune Checkpoints Regulate Strength and Type of Anti-Tumor Immune Response Pardoll, Nat Rev Cancer 2012

29. Wolchok JD et al. N Engl J Med 2013;369:122-133Sznol M et al, Proc ASCO LBA9003 2014 Clinical Activity of the Concurrent Regimen of Nivolumab and Ipilimumab in Advanced Melanoma Combination blockade of PDL1-PD1 and B7-CTLA4 interactions aiming to overcome “defensive” checkpoint inhibitors Follow Up April 2015 (ProcAACR 2015) Overall response rate ~ 60% Complete response rate ~ 25% Median survival > 40 mos (expected survival ~ 7 mos) Few relapses in responders But – many patients develop autoimmunity

30. Building better monoclonal antibody-based therapeutics George J. Weiner Nature Reviews Cancer June 2015

31. Chimeric Antigen Receptor T-cells (CAR T cells) • CAR T-cells are genetically engineered T cells • Antibody fragment is used to retarget T cells towards cancer Marcela V. Maus et al. Blood 2014;123:2625-2635

32. Production and treatment with CAR T cells https://junotherapeutics.com/our-science/scientific-platform/

33. Combination cancer immunotherapy Multiple mechanisms that limit autoimmunity need to be overcome in cancer immunotherapy Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge Makkouk and Weiner Cancer Research 2015

34. Goal of cancer immunotherapyBend the immune system curve Eliminate Cancer Avoid Autoimmunity

35. In reality, some patients develop autoimmunity Autoimmunity Autoimmunity

36. Side Effects of Cancer Immunotherapy Some reversible Most manageable Vary based type of therapy Related to overactive immune system Just learning about long term side effects Colitis Dermatitis Pneumonitis Colitis Myocarditis Endocrinopathies Management very different from approach used for cancer patients after chemotherapy!

37. Side Effects of Cancer Immunotherapy • Most Common Fatal Toxicities • Anti-PD1 • Pneumonitis • Neurotoxicity • Anti-CTLA4 • Colitis • Hardest to treat • Myocarditis • Generally manageable but with long term sequellae • Endocrine

38. Pillars of Cancer Therapy Immuno Chemo Surgery Radiation