Investigating the use of T cells engineered with a T cell antigen coupler (TAC) receptor as cellular carriers of oncolytic maraba virus

Abstract

The field of immuno-oncology has made tremendous advances in the treatment of cancer. Adoptive cellular transfer (ACT) of tumor-specific T cells and oncolytic viruses (OVs) are powerful anti-tumor agents, but each modality faces significant challenges. Despite the promise of ACT against hematological malignancies, success has been limited in solid tumors. OVs preferentially lyse tumor cells, but have difficulty overcoming antiviral host factors when delivered systemically – therapeutic doses must therefore be quite high to achieve tumor delivery. One means of overcoming viral neutralization is by loading OV onto cellular carriers prior to treatment. Since engineered T cells and OVs both possess anticancer activity, and since viruses naturally associate with nearby circulating immune cells, employing T cells engineered with a T cell antigen coupler (TAC) receptor as viral carriers may offer an ideal combination. Our studies indicated that loading oncolytic maraba virus (MRB) onto T cells – engineered with a TAC receptor targeting HER2 – had no impact on the functionality or receptor expression of these T cells. OV loaded on the surface of these TAC-T cells enabled killing of a variety of tumor targets that may be otherwise resistant to TAC-T cell therapy. Efficacy remains to be elucidated in vivo using xenograft murine models due to the lack of a protective antiviral immune response, which ultimately resulted in encephalopathy. These observed toxicities were likely model-specific, as MRB has shown to be highly attenuated in healthy tissues of wild type models. While conceptually attractive, using TAC-T cells as viral carriers to deliver a multi-pronged, one-pot antitumor therapy directly to the site of the tumor requires further evaluation before considering human studies.