Advances in Immunotherapy
Bijoy Telivala, MD
904-438-4545
[email protected]
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
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
Tumor synapse
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
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.
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 )
Yervoy
Yervoy- Toxicity
• Not a benign drug
• Significant diarrhea, pneumonitis and skin
toxicities
• Can also cause auto immune hepatitis and
nephritis
• Can see delayed toxicities
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 ( 1015 % ) of patients are thought to be cured or
in a very deep remission
• Cost is around $ 100,000 for entire treatment
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
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
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
Tecentriq- FDA Indications
• Metastatic Bladder Cancer
• Metastatic Non small cell lung cancer
Avelumab- FDA Indications
• New kid on the block
• Only drug to be approved for Merkel cell
carcinoma
• Metastatic bladder cancer
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
Opdivo Plus yervoy
Side Effects of PD1 Inhibitors
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Pneumonitis
Diarrhea
Skin toxicities
Endocrine abnormalities including
hypothyroidism and hypo pitutarism
• Rarely it can cause renal and liver failure
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
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
CAR- T Therapy Side Effects
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Cytokine storm
Fever
Nausea
Skin reaction
Hypotension
Needs close monitoring and early recognition
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
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
Clinical Trials at CSNF
• We have over 8 open immunotherapy clinical
trials and have participated in many more
• Disease sites :
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Breast cancer
Multiple Myeloma
Non small cell Lung cancer
Kidney cancer
Bladder cancer
Small cell Lung Cancer
Questions ???