Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy
Abstract
Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation–associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell–intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 16, 2021
- Source ID
- 10.1158/0008-5472.can-20-2604
Entities
People
- Anjan K. Pradhan
- Chunqing Guo
- Harry D Bear
- Jolene Windle
- Masoud H Manjili
- Paul B Fisher
- Shixian Chen
- Swadesh K. Das
- Wenjie Liu
- Xia Li
- Xiang-Yang Wang
- Xiaofei Yu
- Yanxia Ning
- Zheng Liu
Organizations
- National Cancer Institute
- United States Department of Defense
- Virginia Commonwealth University