Interleukin-7 loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma

Abstract

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-CART 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-CART 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-CART 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-CART showed prolonged survival and reduced tumor burden. According to the ex vivo study, oAD-IL7 improved the proliferation and persistence of tumor-infiltrating B7H3-CART, 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-CART 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.

Therapeutic Efficacy of Oncolytic Viruses in Fighting Cancer: Recent Advances and Perspective

“…Huang et al also developed an oncolytic adenovirus containing IL7 and integrated it with B7H3-targeting CAR-T cells to investigate its efficiency in treating glioblastoma. They found that the combined use of them presents synergistic antitumor impact in vitro and in vivo by supporting T cell persistence, resulting in longer survival of tumor-bearing mice [122].…”