Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma

Abstract

Although chimeric antigen receptor T cell (CAR-T) therapy has been successful for hematological malignancies, it is less effective for solid tumors. The primary reason is that the immune microenvironment restricts CAR-T cells from infiltrating and proliferating in tumors. Oncolytic virotherapy has emerged as a novel immunogenic therapy to augment antitumor immune response. Here we combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) to perform the antitumor activity for renal cancer cells. We found that OAV-Decorin combined with CAIX-CAR-T exhibited significantly reduced tumor burden, altered the composition of extracellular matrix (ECM) by inhibiting the distribution of collagen fibers, decreased the expression of TGF-β in tumor cells, enhanced IFN-γ secretion, and obtained higher numbers of CAR-T cells. The combination treatment modality showed prolonged mice survival. The intratumoral injection of OAV-Decorin into tumor-bearing immunocompetent mice activated the inflammatory immune status and resulted in tumor regression. These data supported further investigation of the combination of OAV-Decorin and CAIX-CAR-T cells in solid tumors.

The Influence of Oncogenic Viruses in Renal Carcinogenesis: Pros and Cons

“…In the last 5 years, there have been several studies [ 89 , 90 , 91 , 92 ] which have presented their results after using different OVs in treating RCC. Zhang C et al, combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) for renal cancer cell therapy.…”

“…Zhang C et al, combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) for renal cancer cell therapy. This therapeutical association was evaluated as efficient, as the authors recorded tumor regression and activation of the inflammatory immune system [ 89 ]. A multidisciplinary team from Finland designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 which is able to elicit effector mechanisms of an IgG1 as well as IgA1 and consequently activate neutrophils.…”

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

“…Similar payload-based strategies are being developed using small molecules targeting CAIX for delivery of therapeutic agents [ 11 , 12 ]. Immunotherapy approaches using CAIX-targeted chimeric antigen receptor T (CAR-T) cells are also currently gaining traction, with the development of new generations of CAIX CAR-T cells resulting in the initiation of Phase I clinical trials evaluating these agents for treatment of advanced renal cell carcinoma (NCT04969354) [ 13 , 14 , 15 ]. Administration to renal cancer patients of autologous dendritic cells transduced by adenovirus with a granulocyte-macrophage colony-stimulating factor/CAIX fusion construct (DC-AdGMCAIX) elicited a CAIX-specific immune response in Phase I trials, further highlighting the potential promise of CAIX-targeted immune therapy [ 16 ].…”

CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future

“…It suggests that CAR-T cells combined with targeted drugs may also be a way to treat solid tumors in the future. In addition, Chen Zhang et al (46) studied the binding of a decorin-carrying oncolytic adenovirus (OAV-decorin) to CAIX-CAR-T to perform antitumor activity against renal cancer cells. Oav-decorin in combination with CAIX-CAR significantly reduced tumor load, altered extracellular matrix (ECM) composition by inhibiting collagen fiber distribution, reduced TGF-b expression, enhanced IFN-a secretion, and generated more CAR-T cells.…”