Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue OncoImmunology Année : 2024

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

Marta Compte
Shaukat Khan
  • Fonction : Auteur
Takeshi Tsuda
  • Fonction : Auteur

Résumé

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.
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hal-04583762 , version 1 (22-05-2024)

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Antonio Tapia-Galisteo, Iñigo Sánchez-Rodríguez, Javier Narbona, Patricia Iglesias-Hernández, Saray Aragón-García, et al.. Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses. OncoImmunology, 2024, 13 (1), pp.2338558. ⟨10.1080/2162402X.2024.2338558⟩. ⟨hal-04583762⟩
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