Immunotherapy and Cancer

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Immunotherapy and Cancer

• Mauricio Burotto MD
• National Cancer Institute
• National Institutes of Health

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DISCLOSURE

• Nothing to disclose

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Nature 2001
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Nature 2008
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Applied Biosystems 3730xl
Illumina (Solexa) sequencing
Ion Proton Machine
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GENOMICS
TRANSCIPTOMICS
OMICS
EPIGENOMICS
PROTEOMICS
METABOLOMICS
IMMUNOMICS
MICROBIOMICS
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The Hot topic
Stem Cells
Genomics Deep sequencing
Target Therapy
Clonal evoution
Inmunotherapy
Epigenomics
Cancer Metabolism
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Cancer Immunotherapy Cancer Immunotherapy Cancer Immunotherapy Cancer Immunotherapy Cancer Immunotherapy
Type Specific Tumor Stage FDA
Interleuquines IL-2 IL-15 Melanoma IV yes No
Vaccines Sipileucel-T Prosvac Prostate IV yes No
Check point inhibitors Anti-CTLA4 Anti-PD1 Anti-PDL1 Melanoma NSCLC IV yes yes yes
Adoptive Cell Therapy CARs TILs ALL NHL IV No
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Target therapy in Cancer

• Bevacizumab Antiangiogenic therapy
• FDA approved for
• RCC
• NSCLC
• CRC
• Ovarian Cancer
• Cervical Cancer
• Gliobastoma

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The Real Target therapy

• Cancer therapy pardigm in 2000
• CML Philadelphia cromosome 9/22
• NSCLC and history of EGFR
• Melanoma and the BRAF

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Science 2002
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• Evolucion clonal
• Heterogeneidad molecular

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Gerlinger NEJM 2012
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Immune system

• Innate immune system
• Neutrophiles
• Complement
• NK
• Adaptive immune system
• B cell
• T cell
• Antibodies

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Immune system

• Innate immune system
• Neutrophiles
• Complement
• NK
• Adaptive immune system
• B cell
• T cell
• Antibodies

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Therapeutic Cancer Vaccines

• Designed to generate a targeted anti-tumor
  immune response
• Associated with minimal toxicities
• May have delayed effects relative to standard
  cytotoxic chemotherapy
• May have an impact beyond the period of
  administration

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Slide 4
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Sipuleucel-T Activates Immune Cells Ex Vivo
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Prostvac Off the Shelf Vaccine
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Phase II Trial Prostvac ltbr /gtExtended Overall
Survival in mCRPC
Presented By Ravi Madan at 2014 ASCO Annual
Meeting
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Immune Checkpoint Inhibitors

• Checkpoint molecules are the immune system s way
  to auto-regulate
• Blocking these molecules can enhance T-cell
  activity
• Immune Checkpoint Targets
• CTLA-4 (activated T cells)
• PD-1 (activated T and B cells)
• PDL-1 ( can be expressed on tumor cells)

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CTLA-4 Checkpoint Inhibition
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CTLA-4 Checkpoint Inhibition
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Slide 14
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Slide 35
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Impressive Activity for Anti-PD-1 in RCC
Pretreatment
6 months

• 57-year-old patient had developed progressive
  disease after receiving sunitinib, temsirolimus,
  sorafenib, and pazopanib
• Rx with Nivolumab (anti-PD-1) at 1 mg/kg q 2 wks
  x 2 years
• Completed 12 cycles now with PET Complete
  Response

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Anti-PD-1 (MK-3475) ltbr /gtexample of a clinical
responses
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Immunotherapies combination
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Cellular therapies

• TMO
• Allogeneic
• DLI
• T Cell adoptive therapy
• TILs
• CARS ( Chimeric antigen receptor)

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Adoptive cell transfer immunotherapy
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CARs
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Perspective on how treatments in cancer are
built
NCI
Academic centers
Industry
EMA
FDA
ASCO
ESMO
NCCN
CCO
More than 90 of cancer drugs approved since 2004
cost more than 20000 for 12 weeks of treatment.
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Latin America and the Caribbean
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• By 2020, it is estimated that more than 100
  million people older than 60 years will be living
  in S.A
• 1.7 million new cases of cancer will be
  diagnosed by 2020
• 6 of the Latin American population is covered by
  national cancer registries, by contrast with 96
  in the USA and 32 in Europe
• In three years, up to 65 of FDA-regulated
  clinical trials will be conducted outside the
  U.S.

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Incidence of cancer is lower in Latin America
163 per 100 000 (rate) than in Europe 264 or the
USA 300
But
Cancer mortality-to-incidence ratio for Latin
America is 0.59, compared with 0.43 for the
Europe and 0.35 in the USA HIGH LETHALITY
Ferlay et al , GLOBOCAN 2008 http//globocan.iarc
.fr (2012)
Goss et al. Lancet Oncol. 2013 14391
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Challenges to Conducting Clinical Trials in Latin
America

• Longer regulatory activities
• Regulatory authorization and ethics committee
  approval
• Different local requirements between countries
• Lack of infrastructure
• The need for electronic data collection systems.
• Better training for the research team
  (radiologist, pathologist, nurses etc.)

Outlook 2008. Tufts Center for the Study of Drug
Development
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Potential advantages to Conducting Clinical
Trials in Latin America

• Patient enrollment
• Shorter enrollment time
• Fewer or non competing studies in the region
• Most patients are treatment and trial naïve
• Up to 80 of the population is concentrated in
  big cities.
• Latin America is one of the most diverse regions
  in the world
• Diversity in ethnicity
• However there are regions with very homogenous
  population (indigenous)
• Example Chile has the highest incidence of
  gastric and gallbladder cancer in the world

Outlook 2008. Tufts Center for the Study of Drug
Development
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Cancer Research in Latin America and the Caribbean

• Accrual opportunities
• Novel designs and concepts
• Pharmacogenomics studies

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Agradecimientos
Tito Fojo Maureen Edgerly Giuseppe Giaccone Arun
Rajan Wilfred Stein Krastan Blagoev John
Marshall Eva Szabo Maureen Edgerly James
Gulley Robert Motzer
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Clinical Research Center Staff