Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.
Contributed by Shishir Pant
ABSTRACT: Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.
Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duar
Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (3) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (4) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (5) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (6) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (7) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (8) Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (9) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (10) Cellular Immunotherapy Program Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. yshi@coh.org.
