Bijoy Telivala, MD 904-438-4545 Bijoy.Telivala@csnf

1. Advances in Immunotherapy Bijoy Telivala, MD 904-438-4545 Bijoy.Telivala@csnf.us

2. Introduction • One of the first reported events was when Dr Coley in the late 19th century reported insertion of dead bacteria cells lead to shrinkage of sarcoma cell • Since then immunotherapy has been the “ holy grail “ in the fight against cancer • Over the last few years there has been a greater understanding of how to harness the immune system to combat cancer • Disclosures: none

3. Tumor Immunology • CD4 and CD8 T cells usually initiate distinction between self and non self antigens • Natural Killer cells do not require antigen presentation by MHC for cytotoxic activity • Macrophages play an important role in phagocytosis

4. Tumor synapse

5. Tumor Evasion of Immune Surveillance • Loss of MHC 1 expression by tumor • Tumor can promote immune tolerant micro environment which leads to production of cytokines which can suppress production of CD 4 and CD 8 T cells • Tumors can upregulate the expression immune check point inhibitors like PD-1 or PDL1 which can promote peripheral T cell exhaustion

8. Classes of Drugs • PD-1 Inhibitors • Opdivo • Keytruda • Avelumab • PDL-1 Inhibitors • Tecentriq • CTLA 4 Antibodies • Yervoy • Chimeric Antigen Receptors ( CAR-T ) are genetically modified T cells using the patients own T cells.

9. Yervoy • First developed immunotherapy • Currently approved as a single agent or in combination with Opdivo to treat advanced/ metastatic melanoma • Also approved as adjuvant treatment for high risk/Stage 3 melanoma especially those with Lymph node involvement • Works by blocking CTLA-4 ( Cytotoxic T lymphocyte Antigen 4 )

10. Yervoy

11. Yervoy- Toxicity • Not a benign drug • Significant diarrhea, pneumonitis and skin toxicities • Can also cause auto immune hepatitis and nephritis • Can see delayed toxicities

12. Yervoy- Summary • Hardly used as a single agent except for adjuvant melanoma • In metastatic melanoma it has been essentially replaced by PD1/PDL1 inhibitors • Biggest advantage is that a small number ( 10-15 % ) of patients are thought to be cured or in a very deep remission • Cost is around $ 100,000 for entire treatment

14. PD1/PDL1 Inhibitors • Biggest excitement in oncology in the last decade • Has made dramatic improvements in survival and patient quality of life • They will form back bone of majority of treatment regimens in the future

15. Opdivo- FDA Indications • Metastatic melanoma as a single agent or in combination with Yervoy • Metastatic Non small cell lung cancer • Relapsed Hodgkins Lymphoma • Relapsed Head & neck cancer • Relapsed/Metastatic Bladder cancer • Metastatic Kidney cancer

16. Keytruda- FDA Indications • Metastatic melanoma • Metastatic head & neck cancer • Metastatic Non small cell lung cancer. First Immunotherapy to be approved in combination with chemotherapy in front line metastatic lung cancer • Hodgkins Lymphoma

17. Tecentriq- FDA Indications • Metastatic Bladder Cancer • Metastatic Non small cell lung cancer

18. Avelumab- FDA Indications • New kid on the block • Only drug to be approved for Merkel cell carcinoma • Metastatic bladder cancer

19. Opdivo Plus Yervoy • Approved in combination for metastatic melanoma • Clinical trial ( Checkmate -067) compared Yervoy vs Opdivo vs the combination • Overall survival at 2 years was higher ( 64 % for combination vs 45 % for Yervoy) • However toxicities especially GI were much higher • Probably a good combination but only for the right patient • Combination is being evaluated in lung ca/kidney ca

20. Opdivo Plus yervoy

23. Side Effects of PD1 Inhibitors • Pneumonitis • Diarrhea • Skin toxicities • Endocrine abnormalities including hypothyroidism and hypo pitutarism • Rarely it can cause renal and liver failure

24. CAR- T Therapy • In clinical development • Not routinely available except in few select centers • Involves engineering patients own immune cells to recognize and attack the tumors • Uses adoptive cell transfer

25. Car- T Therapy • Adoptive cell transfer is like giving patients a living drug • After collection from body T cells are genetically modified to produce specific receptors called chimeric antigen receptors (CAR) • More than a billion CAR T cells are grown in the lab • T cells are then infused into the body and then if if all goes as planned, the T cells multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces • In clinical trials for ALL and some Lymphoma patients

27. CAR- T Therapy Side Effects • Cytokine storm • Fever • Nausea • Skin reaction • Hypotension • Needs close monitoring and early recognition

28. Take Home Points for PCP • Immunotherapy is the 4th pillar in treating cancer patients • More patients are going to be on immunotherapy in the future • Side effects are unique and very different from traditional chemotherapy • Steroids help with side effects but should be used judiciously

29. Take Home Points for PCP • We are only scratching the surface of immunotherapy • Different cancers respond differently to immunotherapy • Melanoma have the best responses while others like prostate cancer have minimal responses • Enrollment in clinical trials is very important

30. Clinical Trials at CSNF • We have over 8 open immunotherapy clinical trials and have participated in many more • Disease sites : • Breast cancer • Multiple Myeloma • Non small cell Lung cancer • Kidney cancer • Bladder cancer • Small cell Lung Cancer

31. Questions ???