한빛사논문
- 조회2,148
Hong Jae Chon1,2,3, Won Suk Lee1,2, Hannah Yang1,2, So Jung Kong1,2, Na Keum Lee1,2, Eun Sang Moon4, Jiwon Choi4, Eun Chun Han2, Joo Hoon Kim1,2, Joong Bae Ahn3, Joo Hang Kim1 and Chan Kim1,2,*
1 Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
2 Laboratory of Translational Immuno-Oncology, Seongnam 13488, Republic of Korea
3 Yonsei Graduate School, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
4 SillaJen, Inc., Seoul, 07325, Republic of Korea
HJ Chon and WS Lee contributed equally to this article.
*Corresponding Author: Chan Kim, Medical Oncology, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam, 13496.
Abstract
Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we employed 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 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 anti-cancer 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 non-inflamed 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 anti-cancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anti-cancer immune response, regardless of various treatment schedules. Of note, triple-combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anti-cancer immunity and induced complete tumor regression and long-term overall survival. Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of TME and more potently suppresses cancer progression with immune checkpoint blockades by overcoming resistance to immunotherapy.
Keywords: oncolytic virus, vaccinia virus, immune checkpoint inhibitor, combination immunotherapy, tumor microenvironment
논문정보
- Research article
- 2018년 12월 (BRIC 등록일 2018-12-17)
- 국내 연구진
- 의약학 > 종양의학
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