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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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OMICS GENOMICS TRANSCIPTOMICS EPIGENOMICS PROTEOMICS METABOLOMICS
IMMUNOMICS MICROBIOMICS
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Genomics Deep sequencing
The Hot topic… Stem Cells Genomics Deep sequencing Target Therapy Clonal evoution Inmunotherapy Epigenomics Cancer Metabolism
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Cancer Immunotherapy Type Vaccines Check point inhibitors
Specific Tumor Stage FDA Interleuquines IL-2 IL-15 Melanoma IV yes No Vaccines Sipileucel-T Prosvac Prostate Check point inhibitors Anti-CTLA4 Anti-PD1 Anti-PDL1 NSCLC Adoptive Cell Therapy CARs TILs ALL NHL
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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 Adaptive immune system Neutrophiles
Complement NK Adaptive immune system B cell T cell Antibodies
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Immune system Innate immune system Adaptive immune system T cell
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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Sipuleucel-T: Activates Immune Cells Ex Vivo
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Prostvac: Off the Shelf Vaccine
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Presented By Ravi Madan at 2014 ASCO Annual Meeting
Phase II Trial: Prostvac <br />Extended 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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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): <br />example of a clinical responses
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Immunotherapies combination
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Cellular therapies T Cell adoptive therapy TMO Allogeneic DLI TILs
CARS ( Chimeric antigen receptor)
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Adoptive cell transfer immunotherapy
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CARs Chimeric antigen receptors. a | CARs usually include a T‑cell activation domain, one or more co-stimulatory domains, a hinge region, a cell membrane-spanning transmembrane domain, and an antigen-recognition moiety that is usually derived from an antibody. b | A schematic of an anti-CD19 CAR-expressing T cell recognizing a CD19+ malignant cell is shown. Abbreviation: CAR, chimeric antigen receptor.
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Perspective on how treatments in cancer are built
Academic centers NCI Industry FDA EMA ASCO NCCN ESMO 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 (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 (2012) Goss et al. Lancet Oncol ;14:391
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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 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 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 James Gulley Robert Motzer
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Clinical Research Center Staff
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