Modulation of the tumor microenvironment with an oncolytic adenovirus for effective T-cell therapy and checkpoint inhibition

Abstract

Despite exciting proof-of-concept data mediated by adoptive T-cell transfer and checkpoint blockade, major challenges imposed by the tumor microenvironment restrict clinical benefits to a minority of patients with advanced or metastatic solid malignancies. While employment of toxic pre- and postconditioning regimens to circumvent the inefficacy of T-cell transfer presents a fundamental problem for heavily pretreated cancer patients, for checkpoint blockade, the main issue relates to low single-agent response rates. To overcome these hurdles, combination therapy with oncolytic adenovirus is becoming an attractive solution given multiple intrinsic modulatory effects on the intratumoral immune compartment, engineering capabilities and safety profile. Here, we provide a short overview on the tumor microenvironmental challenges in solid tumors, and how oncolytic adenoviruses can counteract these barriers. Finally, the immunotherapeutic potential of oncolytic adenoviruses will be discussed in the context of clinical experience with adoptive T-cell therapy and immune checkpoint inhibitors.

Keywords: Adenovirus; Adoptive T-cell therapy; CAR-T cells; Checkpoint inhibition; Clinical trials; Immunotherapy; Oncolytic virus; T-cell receptor (TCR)-engineered T cells; Tumor microenvironment; Tumor-infiltrating lymphocytes.