Chimeric antigen receptor–engineered T cells as oncolytic virus carriers

Abstract

The use of engineered T cells in adoptive transfer therapies has shown significant promise in treating hematological cancers. However, successes treating solid tumors are much less prevalent. Oncolytic viruses (OVs) have the capacity to induce specific lysis of tumor cells and indirectly impact tumor growth via vascular shutdown. These viruses bear natural abilities to associate with lymphocytes upon systemic administration, but therapeutic doses must be very high in order to evade antibodies and other components of the immune system. As T cells readily circulate through the body, using these cells to deliver OVs directly to tumors may provide an ideal combination. Our studies demonstrate that loading chimeric antigen receptor–engineered T cells with low doses of virus does not impact receptor expression or function in either murine or human T cells. Engineered T cells can deposit virus onto a variety of tumor targets, which can enhance the tumoricidal activity of the combination treatment. This concept appears to be broadly applicable, as we observed similar results using murine or human T cells, loaded with either RNA or DNA viruses. Overall, loading of engineered T cells with OVs represents a novel combination therapy that may increase the efficacy of both treatments.

Oncolytic viruses: overcoming translational challenges

“…Specifically, T cells loaded with VSV (77), reovirus (78), HSV (79), and Newcastle disease virus (80) have been delivered to tumors in mouse models. Previous studies have demonstrated that engineering T cells with chimeric antigen receptors (CARs) increases the delivery of VSV and VV to tumor cells and that CAR expression and function are not affected by the cell's infection with OV (81). Despite the efficient homing of T cells to tumors, carrier T cells have limited ability to amplify OVs (81), and moreover this clinical application is challenging and expensive.…”

“…Previous studies have demonstrated that engineering T cells with chimeric antigen receptors (CARs) increases the delivery of VSV and VV to tumor cells and that CAR expression and function are not affected by the cell's infection with OV (81). Despite the efficient homing of T cells to tumors, carrier T cells have limited ability to amplify OVs (81), and moreover this clinical application is challenging and expensive. A few studies have shown that the viability of carrier T cells can be significantly improved by attaching VSV to the membrane of T cells, allowing gradual release of oncolytic VSV into the tumor mass (82,83).…”

CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge

“…Finally, in a totally different and very preliminary approach, CAR-T cells have been used to deliver OV to the tumor ( 92 ). Circulating cells such as lymphocytes, monocytes, erythrocytes, or even platelets can bind viruses and have shown tumor-targeting properties ( 93 – 96 ).…”

Viroimmunotherapy for Colorectal Cancer: Clinical Studies

“…Although they did not use CAR-T cells in their study, the concept of their study could be extrapolated for CAR-T cells as CIKs show inherent characteristics of tumor homing and cancer cell killing [86]. In line with this, a recent study by VanSeggelen et al shows that oncolytic viruses with either RNA or DNA genome can be loaded onto CAR-T cells and efficiently transferred to tumor cells [87]. The anti-tumor effect of these novel combinations of oncolytic virus and CAR-T cells is yet to be evaluated in case of colorectal cancer.…”