1. 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

2. 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

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

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

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

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

9. 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!!!

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
Every cancer cell has approximately 3,000 megabases of DNA
Typical lung cancer has 30,000 individual mutations in its DNA
Lawrence, Nature 499:
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
Outside Cells
Immunity
Inside Cells
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
CTL, cytotoxic T lymphocyte.
Pardoll, Nat Rev Cancer 2012

29. 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: Sznol M et al, Proc ASCO LBA

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
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:

32. 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.

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 immunotherapy Bend the immune system curve
Eliminate
Cancer
Avoid
Autoimmunity

35. In reality, some patients develop 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
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