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

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

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

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

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

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

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

Goal of cancer immunotherapy Bend the immune system curve Eliminate Cancer Avoid Autoimmunity

You know about this!!! Cancer Prevention HPV Hep B 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 HPV Hep B You know about this!!!

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?

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

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”!

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

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?

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

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

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

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

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

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

Immunity Outside Cells Immunity Inside Cells Antibodies T Cells

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

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

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

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

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

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

Immune Checkpoints Regulate Strength and Type of Anti-Tumor Immune Response CTL, cytotoxic T lymphocyte. Pardoll, Nat Rev Cancer 2012

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 (Proc AACR 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 Wolchok JD et al. N Engl J Med 2013;369:122-133 Sznol M et al, Proc ASCO LBA9003 2014

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

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 Thank you for giving me the opportunity to present today I will discuss the role of chimeric antigen receptor T cells or commonly referred to as CAR T cells in cancer treatment CAR T cells are a type of Adoptive T cells therapy in which T cells are manipulated ex vivo and then infused into the patient The earliest form of adoptive T cell therapy was stem cells transplant T cells clones were obtained from Tumor infiltrating lymphocytes in Melanomas and were infused into the patient after in-vitro expansion The T cells clones manipulation techniques are being superseded by genetically engineered T cells Marcela V. Maus et al. Blood 2014;123:2625-2635

Production and treatment with CAR T cells This shows schema of a patient treated with CAR T cells  (1) harvest a patient’s white blood cells in a process called leukapheresis, and while ex vivo we (2) select and activate certain T cells of interest. (3) Gene sequences for the CAR or TCR construct are transferred into the T cell DNA using a viral vector, such as a lentivirus or a gamma retrovirus. The number of cells is (4) expanded until it reaches the desired dose. These genetically engineered cells are (5) infused back into the patient. https://junotherapeutics.com/our-science/scientific-platform/

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

Goal of cancer immunotherapy Bend the immune system curve Eliminate Cancer Avoid Autoimmunity

In reality, some patients develop autoimmunity

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 Myocarditis Endocrinopathies Management very different from approach used for cancer patients after chemotherapy!

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

Pillars of Cancer Therapy Immuno Chemo Surgery Radiation