Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager

Area of Science:

• Immunology
• Oncology
• Virology
• Gene Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic cancers but has limited efficacy in solid tumors.
• Oncolytic viruses can synergize with immunotherapy due to their oncolytic properties and capacity for transgene incorporation.
• Tumor heterogeneity and antigen escape are significant challenges for CAR T-cell therapy in solid tumors.

Purpose of the Study:

• To investigate the efficacy of combining an oncolytic adenovirus expressing an EGFR-targeting bispecific T-cell engager (OAd-BiTE) with FR-α-targeting CAR T-cell therapy for solid tumors.
• To evaluate if this combination therapy can overcome limitations of monotherapy approaches, including antigen escape and tumor heterogeneity.

Main Methods:

• CAR T-cells targeting folate receptor alpha (FR-α) were used in combination with an oncolytic adenovirus armed with an EGFR-targeting bispecific T-cell engager (OAd-BiTE).
• Studies were conducted in xenograft tumor models to assess tumor infiltration, CAR T-cell activation, proliferation, cytokine production, and cytotoxicity.
• In vitro safety profiles were compared between combination therapy and EGFR-targeting CAR T-cells.

Main Results:

• OAd-BiTE-mediated oncolysis significantly enhanced CAR T-cell activation, proliferation, cytokine production, and cytotoxicity against FR-α-targeted tumors.
• Secreted BiTEs redirected both FR-α-targeting CAR T-cells and CAR-negative T cells towards EGFR-expressing tumor cells, addressing tumor heterogeneity and antigen escape.
• The combinatorial approach demonstrated improved anti-tumor efficacy and prolonged survival in mouse models compared to monotherapies.

Conclusions:

• Combining OAd-BiTE with adoptive CAR T-cell therapy overcomes key limitations of monotherapies in solid tumors.
• This strategy effectively addresses tumor heterogeneity and enhances T-cell-mediated anti-tumor responses.
• The results support further clinical evaluation of this combinatorial approach for solid tumor treatment.