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Presentation Overview
� Why Immunotherapy?
� Historical use : Case for IL-2
� Use of CTLA-4 inhibition: Focus on Yervoy
� Use of checkpoint inhibitors : Focus on anti-PD1
� Use of smart vaccines: Focus on Provenge
Immunotherapy
� Cancer immunotherapy attempts to stimulate the
immune system to reject and destroy tumors
� Hallmark of cancer pathogenesis: Avoid immune
destruction
� Patients on immunosuppressant have a two-fold increase
risk of common cancers and up to 20 fold increase of
non-melanoma skin cancer and NHL
Cytokine Therapy
� Interleukin-2 for RCC and Melanoma
since 1998
� 5-10% long-term responders
�High toxicity and mortality, frequent ICU
admissions
�Use limited to medically fit patients who
can tolerate the side effects
Yervoy Side Effects
� Clinically-significant inflammatory and immune toxicities
in approximately 15-20% of patients
� Most serious side effects include severe enterocolitis,
hepatitis, dermatitis, thyroiditis,……..any “itis”
� Black Box Warning for severe and fatal immune-mediated
adverse reactions due to T-cell activation and proliferation.
� High-dose corticosteroids therapy for severe immune-
mediated reactions
Programmed Cell Death-1
� PD-1 is a protein on the surface of activated T cells
� If another molecule, called PD-L1, binds to PD-1, the
T cell dies or becomes docile
� This is a way that the body regulates the immune system,
to avoid an overreaction.
� Since many cancer cells make PD-L1, the cancer cells
can disarm the T cells and inhibit them from attacking
the tumor
Anti-PD-1 and Anti-PDL-1
� Many molecules currently in
clinical trials
� Impressive results in kidney
cancer, melanoma and most
importantly LUNG cancer
� Combination with Anti-CTLA4
lead to a rapid and significant
shrinkage of melanoma tumors in
more than third of the patients
� First approval is expected in 2014
Provenge Safety
� No evidence of increased incidence of autoimmune events
� No evidence of increased incidence of secondarymalignancies
� No deaths attributed to product, as reported bystudy Investigators
Provenge Side Effects
� Most frequent events associated with product infusion: chills and pyrexia
� Generally mild to moderate in severity
� Majority resolved within 24 hours
� < 3% of patients unable to receive all 3 infusionsdue to treatment-related adverse events
� Increased survival by 4 months on average
� Survival improved by up to a year when used in early stage
� FDA approval in 2012
Provenge Benefits
Where do we go from here
� Immunotherapy marks an entirely different way of
treating cancer—by targeting the immune system, not
the tumor itself.
� The field hums with stories of lives extended: the woman
with a grapefruit-size tumor in her lung from
melanoma, alive and healthy 13 years later; the 6-year-
old near death from leukemia, now in third grade and in
remission; the man with metastatic kidney cancer whose
disease continued fading away even after treatment
stopped.
� A corner has been turned and we won't be going back!