Radiation and Immunotherapy

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Radiation and Immunotherapy What s it All About? Encouse Golden, MD, PhD Assistant Professor of Radiation Oncology DISCLAIMER The information contained in this presentation
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Radiation and Immunotherapy What s it All About? Encouse Golden, MD, PhD Assistant Professor of Radiation Oncology DISCLAIMER The information contained in this presentation is not intended as a substitute for professional medical advice, diagnosis or treatment. It is provided for educational purposes only. You assume full responsibility for how you choose to use this information. 2 2 Proportion of U.S. Population Dying of Cancer Has Not Changed Since 1960 nicalkey https://webvpn.med Print 3 What Is Cancer Immunotherapy? Standard cancer therapy (chemotherapy, radiation) attacks the tumor cell directly Immunotherapy is a treatment that activates the immune system to fight cancer 4 5 The Immune System Has a Natural Ability to Recognize and Kill Cancer IGNORE Immune System ATTACK NORMAL MARKERS ( Self, Safe ) Normal Cell ABNORMAL CANCER MARKERS ( Foreign, Dangerous ) Dead Normal Cancer Cell Cancer Cell 6 Adapted from Cancer Research Institute Killer T Cells Attacking a Cancer Cell 7 But Sometimes the Immune System Shuts Down Prematurely or the Attack is Insufficient ATTACK Immune System Don t Attack Me, I m You!! 8 Adapted from Cancer Research Institute Breast cancer: The Immune System is Present at the Tumor Site But Incapable of Rejecting Cancer Immunologic phenotypes of tumor/host in 481 TNBC patients from ECOG trials E2197/E1199 0% 20% 50% 80% for every 10% increase in TILs, a 14% reduction of risk of recurrence or death Adams et al JCO 2014 Sep 20;32(27): Breast Cancer The immune system is present at the tumor site but incapable of rejecting cancer; immunosuppression dominates in established tumors For every 10% increase in tumor infiltrating immune cells, a 14% reduction of risk of recurrence or death Adams et al JCO 2014 Sep 20;32(27): CAN RADIOTHERAPY RESET THE IMMUNOLOGIC PHENOTYPES OF A TUMOR? IJT Lymphocytepoor Lymphocyterich IJROBP 2004, Lancet Oncology 2009, JNCI How is Radiotherapy Delivered in the Modern Era? 12 12 Can Radiation Therapy Help the Immune System to Reject Cancer? Abscopal effects (ab-scopus = away from the target) Abscopal response 13 : only 46 abscopal cases WHY ARE ABSCOPAL EFFECTS SO RARE? 14 IMMUNOSUPPRESSION DOMINATES IN ESTABLISHED TUMORS 15 Vesely MD, 2011, Annu.Rev.Immunol 29:235-71 Of Mice and Men 16 Pioneers in Translating Radiation and Immunotherapy from the Lab to the Clinic Silvia Formenti M.D. Chairman, Department of Radiation Oncology Associate Director, Meyer Cancer Center Sandra and Edward Meyer Professor Weill Cornell Medicine Sandra Demaria M.D. Professor of Radiation Oncology and Pathology Weill Cornell Medicine IJROBP , Lancet Oncology 2009, JNCI 2012 Radiation Stimulates the Immune System to Attack and Shrink a Distant Tumor Right irradiated Left non-irradiated Radiation Therapy X TSA Breast cancer mouse model 18 RADIATION AND FLT-3L INDUCE AN ABSCOPAL EFFECT Irradiated Non-irradiated 19 Radiation with Immunotherapy, can stimulate the Immune System to Attack and Shrink a Distant Tumor A proof-of-principle trial: Local radiotherapy and GM-CSF an immunotherapy to generate abscopal responses in patients with metastatic solid tumors 26.8% abscopal responses Median overall survival: months versus 8.33 months Golden et al Lancet Oncology ABSCOPAL RESPONSE AFTER RADIATION AND GM-CSF RT: 3.5 GyX10 GM-CSF: 125 mg/m 2 Daily X 14 days 21 Unleashing the Immune System to Fight Cancer James P. Allison, Ph.D Lasker-DeBakey Clinical Medical Research Award 22 Instead of Pressing on the Accelerator, Release the Brakes Accelerator Tumor Cell T Cell Brakes Inhibitory Receptor = Brake 23 Immune Checkpoint Blockade + Radiotherapy Immune checkpoint blockade is a type of immunotherapy that uses antibodies against the brakes in T cells, activating them and killing cancer cells We have shown that radiotherapy and immune checkpoint blockade complement each other Only with the combination of the two did we see improved survival, due to T cell-mediated control of the irradiated tumor and metastases 24 Strategies to Establish Patient-Specific Anti-tumor Immunity Ton N. Schumacher, and Robert D. Schreiber Science 2015;348: Mr. P: Patient with Lung Cancer Metastasized To Liver, Lung and Bone achieves a complete response Treated with Radiation Plus Checkpoint Blockade Radiation to one lesion August 2012 January Golden et al Cancer Immuno Res 2013 Mr. P: Four Years After Treatment Currently at 4 years without any other therapy and with no evidence 27 of disease 28 Un-irradiated distant sites Key Points Cancer kills by metastatic spread Cancer is the result of a failure of the immune system to reject it Cancer often blinds the immune system Radiation therapy can un-blind the immune system and restore an immune response Radiation and checkpoint blockade or other immunotherapies can lead to tumor rejection in patients with metastatic disease Radiation is a new class of immunotherapy 29 80 Clinical Trials are Now Testing the Combination of Radiotherapy and Immunotherapy 30 Thank You! 31
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