Rationale and results from. BRAFi and immunotherapy
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1 Rationale and results from emerging combinations of BRAFi and immunotherapy Antoni Ribas, M.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) Disclosures I have received honoraria from advisory boards with Roche-Genentech, h BMS, GSK, Merck, Millennium and Amgen 1
2 Combining immunotherapy and targeted therapy for melanoma? Immunotherapy Targeted therapy Combination ercent aliv ve ercent aliv ve ercent aliv ve Years Years Years Activated human lymphocytes are highly resistant to vemurafenib IC5 IC5 of human of human melanoma vs. cell lymphocytes lines vs lymphocytes exposed exposed to RG724 to LX432 x 72hx 72h 25 >25 >25 2 LX432 LX432 IC Bioluminescence cell viability assay Comin-Anduix, Chodon et al. CCR 21 5 M229 M233 BRAF V6E melanoma. GA2 GA17 H GA21 Resting lymphocytes.. GA2_ H_ Activated lymphocytes 2
3 Differential effects of BRAF inhibition in BRAF V6 mutant melanoma and activated T cells BRAF V6 mutant melanoma Activated T cells LX432 LX432 CRAF BRAF V6 CRAF BRAF V6 CRAF BRAF CRAF BRAF MEK1/2 MEK1/2 MEK1/2 MEK1/2 ERK ERK ERK ERK MAK signaling MAK signaling MAK signaling MAK signaling Modeled from Hatzivassiliou et al. Nature 21, Heidorn et al. Cell 21, oulikakos et al. Nature 21 Vemurafenib as an Immunosensitization Agent Target a key oncogenic pathway Specific cancer cell apoptotic p death Increase ligands for immune cells (tumor antigen, MHC, NK activating receptors) Not kill immune cells No interference on key signaling events in immune system cells Bollag et al. Nature 21 Flaherty et al. NEJM 21 Wargo et al. Cancer Res 21 Comin-Anduix et al. Clin Cancer Res 21 3
4 FSC-H, subset TUF V A+I AGAIN.14 Event Count: FSC-H, subset TUF LX A+I.12 Event Count: SM1: A BRAF V6E -driven Melanoma Syngeneic to Immunocompetent Mice Goel, Haluska et al. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV6E mice. Oncogene. 29; 28 (23): BRAF V6E mutation SM1is moderately sensitive to vemurafenib SM-1 SM-1 LX432 No adverse effects against murine splenocytes ropidium Iodide M22 FL2-H M22 LX432 FL2-H LX 19.3 Annexin V 4
5 Vemurafenib inhibits oncogenic MAK signaling in SM1 but does not change gp1 melanoma antigen expression 1hr 24hr 1hr 24hr VC LX (µm) VC LX (µm) perk Erk pmek Mek TEN gp1 Tubulin VC LX (µm) VC LX (µm) pakt(ser) Akt ps6k(thr/ser) ps6k(thr) S6K Tubulin Antitumor Activity of Vemurafenib Against the SM1 BRAF V6E -driven Murine Melanoma Goel, Haluska et al. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV6E mice. Oncogene. 29; 28 (23): SM-1: BRAF V6E mutant murine melanoma cell line syngeneic to C57BL/6 mice DMSO LX432 Effect of LX432 on Tumor Xenograft on B6-9 Average Tumor Volume (mm^3) 25 LX Days 5
6 OT-1 ACT immunotherapy+braf targeted therapy against SM1-OVA (murine melanoma driven by BRAF V6E and expressing OVA) OVA L1 L2 L3 ~ 45-5 kda LX432 Alone OT1 ACT Alone LX432 + OT1 ACT =.2 =.4 pmel-1 ACT immunotherapy+braf targeted therapy against SM1 (murine melanoma driven by BRAF V6E ) 1hr 24hr VC LX (µm) VC LX (µm) gp1 Tubulin LX432 Alone mel-1 ACT Alone LX432 + mel-1 ACT <.8 <.8 6
7 How can BRAF targeted therapy increase the activity of tumor immunotherapy? Increased antigen Cross-presentation DC Increased direct antigen presentation Activation of T cells and increased homing Decreased immune suppressive factor release BLI imaging of f-luc-labeled TCR transgenic pmel-1 lymphocyte ACT SM1 tumor No difference in the T cell expansion with the addition of vemurafenib (LX432) 7
8 H No difference in the cellintrinsic cytotoxic activity in vivo Ova control with low CFSE labeling gp1 targets with high CFSE labeling +/- LX432 mel-1 reconstituted mouse OVA peptide pulsed + pmel-1 ACT re-infusion cells Mouse: LX432+ pmel-1 ACT , subset cell OVA gp1.11 Event Count: , subset at 4.4 Event Count: gp1 peptide pulsed , subset at 5.5 Event Count: /Mock ACT , subset vc 7.7 Event Count: #1 #2 #3 6.89, subset plx at 1.1 Event Count: , subset plx at 2.2 Event Count: , subset at 6.6 Event Count: , subset plx at 3.3 Event Count: Functional analysis of TILs LX432 # #2 #3 2, subset LX4A+.8 Event Count: , subset LX4B+.1 Event Count: , subset LX1A+.2 Event Count: , subset LX1B+.4 Event Count: SSC C-H At day 5 post-act of pmel-1 and treatment with LX432, tumors were harvested and TILs isolated for intracellular IFNγ staining and FACS analysis 2 2, subset LX5A+.12 Event Count: , subset LX2+.6 Event Count: IFN-γ Treatment with vemurafenib increases the cytokine production by TILs 8
9 Conclusions Vemurafenib does not adversely effect the function of human or murine lymphocytes Combination of vemurafenib with ACT immunotherapy is mediated by improved intratumoral infiltration by activated lymphocytes: Increased IFN-g production by TILs Modulation of the tumor microenviroment? The clinical testing of a combination of vemurafenib and ipilimumab, and/or vemurafenib and ACT therapy, is warranted Acknowledgements Begonya Comin-Anduix, hd Thinle Chodon, MD, hd Stephen Mok Richard Koya, MD, hd Earl Avramis Mohammad Atefi, h.d. Charles Ng Nicholas Otte 9
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