Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

• Published in: Oncoimmunology 2024, Vol.13 (1), p.2338558-2338558
• Main Authors: Tapia-Galisteo, Antonio, Sánchez-Rodríguez, Iñigo, Narbona, Javier, Iglesias-Hernández, Patricia, Aragón-García, Saray, Jiménez-Reinoso, Anaïs, Compte, Marta, Khan, Shaukat, Tsuda, Takeshi, Chames, Patrick, Lacadena, Javier, Álvarez-Vallina, Luis, Sanz, Laura
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific - pharmacology; Antibodies, Bispecific - therapeutic use; Antineoplastic Agents - pharmacology; B7-H1 Antigen; Bispecific antibody; Cancer; cancer immunotherapy; CAR-T cell; colorectal cancer; Colorectal Neoplasms - drug therapy; combination therapy; Human health and pathology; Humans; Hépatology and Gastroenterology; Immunology; Immunotherapy; Life Sciences; Mammals; Original Research; T-cell engager; T-Lymphocytes; Transforming Growth Factor beta; trispecific antibody; Tumor Microenvironment
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2024.2338558

T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-β play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-β inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-β, termed AxF (scFv) 2 , under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv) 2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv) 2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-β by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression.