Oncolytic Vaccinia Virus Expressing IL15/IL15Rα Fusion Protein Induces Immune Cell Infiltration into Tumor and Improves Anti-tumor Efficacy Stacy J. Kowalsky.

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Presentation transcript:

Oncolytic Vaccinia Virus Expressing IL15/IL15Rα Fusion Protein Induces Immune Cell Infiltration into Tumor and Improves Anti-tumor Efficacy Stacy J. Kowalsky MD, Z. Sheng Guo PhD, Roshni Ravindranathan MS, David L. Bartlett MD University of Pittsburgh, Department of Surgery/Division of Surgical Oncology University of Pittsburgh Cancer Institute

Disclosures All authors deny conflicts of interest

Background Vaccinia Virus DNA virus, transcribed in cytoplasm using viral-derived proteins vvDD = tumor-selective Vaccinia virus Attenuated Oncolytic activity1 Accepts 25 kb foreign DNA2 Novel virus design (GM-CSF3) 1-McCart et al. 2001, Cancer Research; 2-Smith and Moss 1983, Gene; 3-Heo et al. 2013, Nat Med

Interleukin 15 Proliferation/activation of CD4+/CD8+ T cells and NK cells Memory CD8+ T cells Shared β and γ receptor chains with IL2 Unique α chain Transpresentation to NK and memory T cells Fusion protein improved activity over IL15 alone4 Tosic and others5 (University of Illinois-Urbana Champaign) Myxoma expressing functional IL15/IL15Rα B16-F10 melanoma model CD8+ T and NK cells infiltration Improved survival 4-Dubois et al. 2008, J Immunol; 5-Tosic et al. 2014, PLoS One

Hypothesis A novel Vaccinia virus expressing IL15/IL15Rα fusion protein (vvDDIL15Rα) will induce CD8+ T and NK cell infiltration to the tumor microenvironment (TME), enhancing anti-tumor efficacy over vvDD

Experimental Designs MC38 murine colorectal cancer model Examine TME of transplantable tumor following IV administration of vvDDIL15Rα or vvDD Monitor tumor progression/survival in carcinomatosis model with locoregional virus Combine virus with immunotherapy (PD1 blockade) In vitro replication analysis

TME Analysis Control Tumor Tissue 1e8 pfu vvDD IV Day 2, 4, 6 1e8 pfu vvDDIL15Rα IV

A34R IL15/IL15Rα *** p=0.0001 * p<0.05, ** p<0.005

CD8 D2 D4

NK cell Markers D2 NKG2D NKp46 D4 D4 D6 D6 * p<0.05 *** p<0.001

GZMB TGFβ D4 D6 ** p=0.001 *** p=0.0001

Carcinomatosis Model Day 0 Day 5 Tumor Progression Survival MC38luc Control Day 0 Tumor Progression Survival MC38luc 2e8 pfu vvDD Day 5 2e8 pfu vvDDIL15Rα

Control vvDD vvDDIL15Rα D4 D9

Tumor Progression

*** p<0.0010

MC38 Tumor Rechallenge IP MC38-inoculated mice “cured” with vvDDIL15Rα MC38luc IP MC38-inoculated mice “cured” with vvDDIL15Rα (Day 132 after previous IP MC38) MC38luc Naïve WT mice

Tumor Growth

PD1 blockade T cell Tumor cell PDL-1 Response to PD1 inhibitors correlates with PDL-1 expression in TME6 Chronic viral infection associated with PD-1/PDL-1 immune escape7 vvDD treatment → enhanced PDL-1 expression in TME PD-1 blockade 6-Topalian et al. 2012, NEJM; 7-Shin and Wherry 2007, Curr Opion Immunol

Carcinomatosis Model with PD1 Blockade Control Anti-PD1 Ab 7 days 2e8 pfu vvDD IP Anti-PD1 Ab IP MC38luc 2e8 pfu vvDDIL15Rα IP Anti-PD1 Ab

Tumor progression

*** ** *** p=0.0003, ** p=0.002 *** p=0.0007, **** p<0.0001

In vitro MC38 Replication Assays MOI 0.1 MOI 1

Conclusions vvDDIL15Rα Improved anti-tumor efficacy over vvDD Replicates in MC38 in vitro and in vivo Induces changes in TME, with ↑ expression of CD8 and activating NK cell receptors Improved anti-tumor efficacy over vvDD “Cured” mice show anti-tumor immune memory Combination with PD1 blockade dramatically improves effect

Questions?

Sources McCart JA, Ward JM, Lee J, Hu Y, Alexander HR, Libutti SK et al. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Research. 2001;61:8751-7. Smith GL and Moss B. Infectious poxvirus vectors have capacity for at least 25000 base pairs of foreign DNA. Gene. 1983;25:21-8. Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Medicine. 2013;19(3):329-36. Dubois S, Patel HJ, Zhang M, Waldmann TA, Müller JR. Preassociation of IL-15 with IL-15Rα-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44highT cells and its antitumor action. Journal of Immunology. 2008;180:2099-106. Tosic V, Thomas DL, Kranz DM, Liu J, McFadden G, Shisler JL, et al. Myxoma virus expressing a fusion protein of interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity. PLoS One. 2014;9(10):e109801. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New England Journal of Medicine. 2012;366(26):2443–54 Shin H and Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Current Opinion in Immunology. 2007;19:408-15.