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Clin Cancer Res. 2018 Dec 11. doi: 10.1158/1078-0432.CCR-18-1932. [Epub ahead of print]

Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade.

Chon HJ#1,2,3, Lee WS#1,2, Yang H1,2, Kong SJ1,2, Lee NK1,2, Moon ES4, Choi J4, Han EC2, Kim JH1,2, Ahn JB3, Kim JH1, Kim C5,2.

Author information

1
Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
2
Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea.
3
Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
SillaJen, Inc., Seoul, Republic of Korea.
5
Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea. chan@cha.ac.kr.
#
Contributed equally

Abstract

Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy.Experimental Design: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses.Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival.Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.

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