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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

Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea.
Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea.
SillaJen, Inc., Seoul, Republic of Korea.
Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
Contributed equally


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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