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.
Highlights
Renal cell carcinoma (RCC) is one of the most common tumors in the urinary system.[1,2] Recently many research papers support that the tumor microenvironment (TME) plays a critical role in tumor development and progression.[3,4] Various factors among TME can produce physical and immune barriers to the host immune system
These results demonstrated that the armed oncolytic adenovirus OAV-DEC can efficiently infect renal cancer cells to produce and secrete high level of functional decorin
In recent years, immunotherapy represented by Chimeric antigen receptor (CAR)-T gradually emerges as the fourth major tumor treatment mode after surgery, In this study, we constructed an oncolytic adenovirus arming decorin and CAR-T cells targeting human carbonic anhydrase IX (CAIX)
Summary
Renal cell carcinoma (RCC) is one of the most common tumors in the urinary system.[1,2] Recently many research papers support that the tumor microenvironment (TME) plays a critical role in tumor development and progression.[3,4] Various factors among TME can produce physical and immune barriers to the host immune system. Immunotherapies have provided remarkable clinical benefit to patients with different types of cancer.[5,6] Chimeric antigen receptor T cell (CAR-T) is a landmark achievement of tumor immunotherapy in recent years.[7,8] Chimeric antigen receptor (CAR) is an artificial receptor that mimics the function of a T cell receptor (TCR) It artificially integrates TCR binding signals, CD28 and CD137 co-stimulatory signals required for T cell activation into a single signal receptor composed of target recognition domains, hinge and transmembrane domains, and intracellular signal domains.[9] CAIX (carbonic anhydrase IX), known as G250, is a transmembrane glycoprotein that is highly expressed in renal cancer cells.[10] Weijtens et al constructed a CAR composed of scFv (variable fragment of single chain antibody) of mouse anti-human CAIX in tandem with FCRg, and carried out in vitro CAR-T experiments.[11] Lamers et al used CAIX CART in a phase I/II clinical trial for renal cancer, and the results showed that plasma levels of interferon (IFN)-g, interleukin (IL)-2, and tumor necrosis factor-a increased in most patients, but no clinical efficacy was observed.[12] There were some factors, such as the tumor immunosuppressive microenvironment, that limited the effectiveness of the CAR-T cells
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