Combining Immunotherapy and Targeted Therapy in Melanoma

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1 Combining Immunotherapy and Targeted Therapy in Melanoma 8:45 am - 9:15 am Antoni Ribas, M.D., h.d. rofessor of Medicine rofessor of Surgery rofessor of Molecular and Medical harmacology Director, Tumor Immunology rogram, Jonsson Comprehensive Cancer Center (JCCC) University of California Los Angeles (UCLA)

2 Disclosure Information Antoni Ribas I have the following financial relationships to disclose: Consultant for: Kite harma Speaker s Bureau for: None Grant/Research support from: None Stockholder in: Kite harma Honoraria from: Amgen, Celgene, Genentech-Roche, GSK, Millennium, Novartis, rometheus Employee of: None -and - I will discuss the following off label use and/or investigational use in my presentation: vemurafenib

3 Limitations of Tumor Immunotherapy Dendritic Cell CD4 3. Limited CD8+ CTL activation and expansion (CTLA4, D1) CD8 CD8 CD8 CD8 1. Suboptimal antigen presentation 2. Low frequency of tumor antigenspecific T cells Cancer Immunotherapy 4. Lack of antigen CD8 recognition (Low TA, MHC) erforin/gzb Immunosensitization 5. Immune suppressive tumor milieu (Treg, MDSC, IDO, VEGF, IL- 10, ge2, TGF- ) Death Receptors Cancer Cell 6. Insensitivity to pro-apoptotic signals from immune cells

4 Immunosensitization with Targeted Therapies Desired features for an immune sensitizing agent: On tumor cells: Target a key oncogenic pathway Inhibit anti-apoptotic molecules Increase pro-apoptotic molecules Increase ligands for immune cells (tumor antigen, MHC, NK activating receptors) On immune system cells: Not kill immune cells No interference on key signaling events in immune system cells (TCR, NK receptor)

5 Testing of the Concept of Immunosensitization in Animal Models Bortezomib (proteasome inhibitor) to sensitize to NK cells Schumacher et al. JI 2005 ABT-737 (Bcl-2 inhibitor) to sensitize to T cells Begley et al. CII 2008 LAQ824 (HDAC inhibitor) to sensitize to T cells Vo et al. CR 2009

6 erforin Grn B Grn B rocaspase-8 DISC Caspase-8 Death Receptor FADD Bid Mitochondria Cytochrome C tbi d Apoptosis Effector Caspases Grn B Apaf-1 Ba x/b ak IA s Caspase-9 Caspase-8 CD8+ T Cell Bcl-2/Bcl-x L /Bcl-w FLI Melanoma Cell Receptor Tyrosine Kinase Signal Transduction athway

7 Grn B Grn B erforin Death Receptor rocaspase-8 Grn B DISC HDAC Inh Caspase-8 FADD Bid Caspase-8 Apoptosis Mitochondria CD8+ T Cell Melanoma Cell FLI Bcl-2/Bcl-x L /Bcl-w Cytochrome C Apaf-1 Ba x/b ak tbi d IA s Caspase-9 Effector Caspases Receptor Tyrosine Kinase Signal Transduction athway TKi? Bcl-2 Inh roteasome Inh

8 Testing of the Concept of Immunosensitization in Animal Models Bortezomib (proteasome inhibitor) to sensitize to NK cells Schumacher et al. JI 2005 ABT-737 (Bcl-2 inhibitor) to sensitize to T cells Begley et al. CII 2008 LAQ824 (HDAC inhibitor) to sensitize to T cells Vo et al. CR 2009 LX4032 (BRAF inhibitor) to sensitize to T cells Comin-Anduix et al. CCR 2010 Koya et al. CR 2012

9 re-clinical evidence supporting the feasibility of combinations of BRAFi + immunotherapy J Exp Med 2006 June 26; 203 (7): Oncogenic BRAF-induced production of immune suppressive factors (IL-6, IL-10, VEGF) is inhibited with a MEK inhibitor Vemurafenib increases melanosomal antigen expression and T cell recognition Cancer Res 2010 Jul 1; 70 (13): Human T cells exposed to vemurafenib are fully functional Clin Cancer Res 2010 Dec 15; 16 (24):

10 re-clinical evidence against the feasibility of combinations of BRAFi + immunotherapy LX4720 treatment leads to a decreased frequency of immune cells in BRAFV600E/TEN-/- melanomas and this cannot be restored by CTLA-4 blockade Addition of anti-ctla-4 mab treatment to LX4720 treatment does not further improve tumor growth control

11 Clinical evidence supporting the feasibility of combinations of BRAFi + immunotherapy CD8+ T cell infiltration in regressing melanoma lesions after BRAFi therapy Clin Cancer Res 2012 March 1; 18 (5). T cells from patients treated with dabrafenib are fully functional Clin Cancer Res 2012 April 15; 18 (8):

12 How can BRAF targeted therapy increase the activity of tumor immunotherapy? Increased antigen Cross-presentation DC Increased direct antigen presentation BRAF BRAFi Activation of T cells and increased homing Decreased immune suppressive factor release

13 SM1: A BRAFV600E-driven Melanoma Syngeneic to Immunocompetent Mice Goel, Haluska et al. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene. 2009; 28 (23): BRAFV600E mutation Richard Koya, MD, hd Stephen Mok Koya et al. Cancer Res 2012

14 Gene copy number variations (CNV) in SM1 is similar to human melanomas Chromosome Cdkn2a Braf Mitf CNV comparing SM1 with 108 human melanomas CDKN2A BRAF MITF

15 pmel-1 ACT immunotherapy+braf targeted therapy against SM1 (murine melanoma driven by BRAF V600E ) pmel-1 ACT+LX4032 (n = 19) Vehicle LX4032 Alone mel-1 ACT Alone LX mel-1 ACT 60 % Tumor-Free Animals 40 pmel-1 ACT (n = 19) 20 LX4032 (n = 14) 0 < Vehicle Control (n = 14) Days < replicate experiments, p < by log rank test

16 How can BRAF targeted therapy increase the activity of tumor immunotherapy? Increased antigen Cross-presentation DC Increased direct antigen presentation BRAF BRAFi Activation of T cells and/or increased homing Decreased immune suppressive factor release Koya et al. CR 2012: - No change in gp100 or MHC expression by SM1 exposed to vemurafenib - No change in adoptively transferred T cell distribution by BLI - No increase in intratumoral infiltrates by adoptively transferred T cells

17 Differential effects of BRAF inhibition in BRAF V600 mutant melanoma and activated T cells BRAF V600 mutant melanoma Activated T cells BRAFi BRAFi CRAF BRAF V600 CRAF BRAF V600 CRAF BRAF CRAF BRAF MEK1/2 MEK1/2 MEK1/2 MEK1/2 ERK ERK ERK ERK MAK signaling MAK signaling MAK signaling MAK signaling aradoxical MAK activation with RAF inhibitors Modeled from Hatzivassiliou et al. Nature 2010, Heidorn et al. Cell 2010, oulikakos et al. Nature 2010

18 aradoxical activation of perk with exposure of lymphocytes to vemurafenib SM1 pmel-1 BRAFi BRAFi CRAF BRAF V600 CRAF BRAF MEK1/2 MEK1/2 ERK ERK MAK signaling MAK signaling LX (µm) LX4032 (µm) perk VC perk VC Erk ERK Tubulin Koya et al. Cancer Res 2012

19 Conclusions Novel targeted therapies may synergize with immunotherapy: Improve antigen presentation Sensitize cancer cells to apoptotic death Inhibit suppressive factors in the tumor Improve lymphocyte function In a mouse model, increased benefit of a BRAF inhibitor with ACT immunotherapy is mediated by: Increased immune cell functionality (paradoxical MAK activation) Modulation of the tumor microenvironment?

20 Acknowledgements Richard Koya, MD, hd Stephen Mok Ribas lab Begonya Comin-Anduix, hd Thinle Chodon, MD, hd Tom Graeber, hd Ashley Cass Aspram Minasyan Nick Graham, hd

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