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

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 ( % ) 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 ???