novel immunotherapy approaches - store & retrieve data ... · moxr0916 + atezolizumab infante...
TRANSCRIPT
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Novel Immunotherapy Approaches
Suresh S. Ramalingam, MDProfessor of Hematology and Medical Oncology
Assistant Dean for Cancer ResearchEmory University School of Medicine
Deputy Director, Winship Cancer Institute
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Disclosures
• Scientific advisory board meetings
– Astra Zeneca, Amgen, Abbvie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Genentech, Merck, Novartis.
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Immune Recognition
Yao S, et al. Nat Rev Drug Discov. 2013;12(2):130-146.
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Antitumor Effects
Yao S, et al. Nat Rev Drug Discov. 2013;12(2):130-146.
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T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
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Other Combinations
Cully et al, Nature Rev Drug Disc, 2015
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IDO/TDO Inhibitors
Nature Biotechnology, 2015
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Role of IDO1 in Immune Regulation
1. Moretti et al. J Clin Endocrinol Metab. 2014:jc20133351; 2. Yu et al. Clin Dev Immunol. 2011;2011:469135; 3. Uyttenhove et al. Nat Med. 2003; 9(10):1269-1274; 4. Munn et al. J Clin Invest. 2007;117(5):1147-1154; 5. Godin-Ethier et al. Clin Cancer Res. 2011;17(22):6985-6991; 6. Spranger et al. J Immunother Cancer. 2014 Feb 18;2:3.
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Epacadostat + Pembrolizumab
Gangadhar et al, Annual SITC Mtg, 2015
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Baseline Characteristics
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Efficacy
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Anti-cancer Activity
• No grade 4 events• DLT: rash, transaminitis, neurotoxicity
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T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
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Targeting OX40
Infante et al, ASCO 2016
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MOXR0916 + Atezolizumab
Infante et al, ASCO 2016
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Anti-Cancer Activity
Infante et al, ASCO 2016
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Induction of PDL-1 Expression
Infante et al, ASCO 2016
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MOXR0916 + Atezo: Conclusions
• Combination was tolerated well
– Minimal grade 3/4 toxicity
• 300 mg/iv Q 21 days is the recommended dose
• PDL-1 induction was observed in tumor biopsy following OX40 activation
• Further evaluation is ongoing
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T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
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Varlilumab + Nivolumab: Phase 1 Study
• Varlilumab is a fully human agonist IgG1k antibody targeting CD27
• Phase 1 study in combination with Nivolumab
Sanborn et al, AACR 2016
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Tolerability Profile
Sanborn et al, AACR 2016
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Changes in Circulating Lymphocytes
Sanborn et al, AACR 2016
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PD Evaluation in Paired Tumor Biopsies
Sanborn et al, AACR 2016
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Conclusions
• Several promising targets to modulate T-cell responses
• Agents targeting co-stimulatory and co-inhibitory signals are in development
• Combination studies provide promising data regarding target modulation and induction of enhanced anti-tumor immunity