Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors

Abstract

Immunotherapy with bispecific Tcell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific Tcell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated invitro. When TILT-321 was combined with allogeneic Tcells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased Tcell activity and its binding to MUC1 and CD3. Invivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral Tcell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific Tcell engager delivery for solid tumor treatment.