1. Personalized Cancer Therapy Immunotherapy
George Weiner, MD
Director, Holden Comprehensive Cancer Center
Professor, Department of Internal Medicine

2. George Weiner, MD Disclosure
Consultant and Research Funding Checkmate Pharmaceuticals Advisory Board Sandoz

3. 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

4. The Fight Against Cancer
Takes place in every cancer patient
Between the cancer and the immune system

5. Distinguishes “self” from “non self”
Immune system
Distinguishes “self” from “non self”
Eliminate
Infection
Attack Own Cells
Rejection of
Invaders
Autoimmunity

6. Over-active immune response
Immune system
Over-active immune response
Infection
Autoimmunity

7. Under-active immune response
Immune system
Under-active immune response
Autoimmunity
Infection

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

9. Immunity
Outside Cells
Immunity
Inside Cells
Antibodies
T Cells

10. Ideal Cancer Immunotherapy Target
Overcome fact that cancer is “self”
Need to break tolerance (help immune system see the target as “non-self”)
Expression
Selectively on malignant cells (or non-vital tissues)
On all malignant cells in a tumor
Function
Necessary for cell survival or malignant phenotype

11. The “War on Cancer” at the individual level…
Primary Combatants:
Malignant cells
Host immune system
The host immune system is an active enemy faced by a developing cancer
All “successful” cancers must avoid immune destruction
Weapons
Target on surface of cell – Antibody-based treatment
Target inside cancer cell – T cell-based treatment

12. 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

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

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

15. Most cancers have many mutations
Mutated proteins represent potential targets for immune recognition and destruction
Lawrence, Nature 499:

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

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

18. 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

20. 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
Figure 1. Clinical Activity in Patients Who Received the Concurrent Regimen of Nivolumab and Ipilimumab. Representative spider plots in Panel A show changes from baseline in the tumor burden, measured as the sum of the products of perpendicular diameters of all target lesions, in patients who received the concurrent regimen of nivolumab (at a dose of 1 mg per kilogram of body weight) and ipilimumab (3 mg per kilogram), the maximum doses that were associated with an acceptable level of adverse events. Red triangles indicate the first occurrence of a new lesion. Dashed lines indicate 50% and 80% improvement from baseline (gray line) in target lesions, as assessed by means of modified World Health Organization criteria. Panel B shows a representative waterfall plot of the maximum percentage change in target lesions, as compared with baseline measurements, in patients who received the concurrent regimen. A total of 47 patients had a response that could be evaluated in this analysis; 46 had a positive or negative change in target lesions from baseline, and 1 had no change. The dashed line denotes 80% tumor reduction in target lesions from baseline.
Wolchok JD et al. N Engl J Med 2013;369: Sznol M et al, Proc ASCO LBA

21. 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:

22. 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.

23. 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

24. Change the tumor micro-environment
Make a virus-like particle that is non-infectious but the stimulates the immune system
Inject it directly into the cancer
The immune system is stimulated to identify the cancer as foreign
T cells travel throughout the body to fight the cancer
The Qb and G10 components self-assemble into highly-ordered icosahedral VLPs (~30 nm)

25. Clinical response of anti-PD1 refractory melanoma patient treated with anti-PD1 plus in situ CMP-001
Photos courtesy of M. Milhem
Pretherapy
Week 4
Week 6
Injected lesion

26. Pillars of Cancer Therapy
Targeted
Immuno
Chemo
Surgery
Radiation