Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 70, Issue 9, Pages 2453-2465Publisher
SPRINGER
DOI: 10.1007/s00262-021-02856-0
Keywords
CAR; Oncolytic virus; IL7; Cancer
Categories
Funding
- National Natural Science Foundation of China [31471286, 81772693]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2015ZX09102010]
- Postdoctoral Research Fund of Sichuan University [2018SCU12035]
- Technology Innovation Project of Chengdu Science and Technology Bureau [2019-YF05-00459-SN]
Ask authors/readers for more resources
The combination of oncolytic adenovirus loaded with interleukin-7 and B7H3-targeted CAR-T showed enhanced T cell proliferation and reduced apoptosis, leading to prolonged survival and reduced tumor burden in glioblastoma-bearing mice. The study indicated that the oncolytic adenovirus could improve the therapeutic efficacy of CAR-T by providing activating signals for tumor-infiltrating T cells, laying the foundation for future clinical trials in glioblastoma treatment.
Background T cell with chimeric antigen receptors (CAR-T) has presented remarkable efficacy for blood cancer as an emerging immunotherapy. However, for solid tumors, the therapeutic efficacy is much impaired due to the lack of infiltration and persistence of CAR-T in tumor tissue. Thus, we constructed an interleukin-7-loaded oncolytic adenovirus and combined the use of oncolytic virus and CAR-T to improve the therapeutic outcome. Methods We constructed an interleukin-7-loaded oncolytic adenovirus (oAD-IL7) and a B7H3-targeted CAR-T and explored the efficacy of the single use of oAD-IL7, B7H3-CAR-T, or the combined therapy for glioblastoma in vitro and in vivo. The improved CAR-T anti-tumor efficacy was evaluated according to the proliferation, survival, persistence, exhaustion of T cells, and tumor regression. Results Constructed oAD-IL7 and B7H3-CAR-T presented moderate cytotoxicity during in vitro study, but failed to induce a thorough and persistent anti-tumor therapeutic efficacy in vivo. The combination of oAD-IL7 and B7H3-CAR-T in vitro resulted in enhanced T cell proliferation and reduced T cell apoptosis. The joint efficacy was further confirmed using tumor-bearing xenograft mice. During in vivo study, the mice treated with both oAD-IL7 and B7H3-CAR-T showed prolonged survival and reduced tumor burden. According to the ex vivo study, oAD-IL7 improved the proliferation and persistence of tumor-infiltrating B7H3-CAR-T, but failed to reverse the exhaustion. Conclusions Our results indicated that oAD-IL7 is a promising auxiliary therapy to improve the therapeutic efficacy of B7H3-CAR-T in glioblastoma by providing the activating signals for tumor-infiltrating T cells. Our results also lay the basis for the future clinical trials for the combination of IL7-loaded oncolytic adenovirus and CAR-T therapy for glioblastoma.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available