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

ABSTRACT: 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.

SUBMITTER: Tapia-Galisteo A

PROVIDER: S-EPMC11018002 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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

Tapia-Galisteo Antonio A Sánchez-Rodríguez Iñigo I Narbona Javier J Iglesias-Hernández Patricia P Aragón-García Saray S Jiménez-Reinoso Anaïs A Compte Marta M Khan Shaukat S Tsuda Takeshi T Chames Patrick P Lacadena Javier J Álvarez-Vallina Luis L Sanz Laura L

Oncoimmunology 20240413 1

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 ...[more]

PMID: 38623463

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Project description:BackgroundDespite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion of patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several immune evasion mechanisms. Our earlier research demonstrated the efficacy of YM101, an anti-TGF-β/PD-L1 bispecific antibody, in stroma-rich tumors. Nevertheless, YM101 has demonstrated reduced effectiveness in non-inflamed tumors characterized by poor immune cell infiltration. This study investigated the potential synergy between RT and YM101 in overcoming immunotherapy resistance and mitigating RT-induced pulmonary fibrosis.MethodsThe antitumor activity and survival outcomes of RT plus YM101 treatment in vivo were explored in several non-inflamed murine tumor models. Furthermore, the inhibition of pulmonary metastases was assessed in a pulmonary metastasis model. The impact of RT on dendritic cell (DC) maturation was quantified by flow cytometry, whereas cytokine and chemokine secretions were measured by ELISA. To comprehensively characterize changes in the tumor microenvironment, we utilized a combination of methods, including flow cytometry, IHC staining, multiplex inmunofluorecence and RNA sequencing. Additionally, we evaluated the impact of YM101 on RT-induced pulmonary fibrosis.ResultsRT plus YM101 significantly inhibited tumor growth, prolonged survival and inhibited pulmonary metastases compared with monotherapies in non-inflamed tumors with poor immune infiltration. RT promoted DC maturation in a dose-dependent manner and increased the secretions of multiple proinflammatory cytokines. Mechanistically, RT plus YM101 simultaneously increased the infiltration and activation of intratumoral DCs and tumor-infiltrating lymphocytes and reshaped the tumor microenvironment landscape. Notably, YM101 attenuated both RT-induced peritumoral fibrosis and pulmonary fibrosis.ConclusionsOur findings suggest that RT combined with YM101 enhances antitumor immunity and overcomes resistance in non-inflamed tumors in preclinical models, while simultaneously showing potential in mitigating RT-induced fibrosis. This combination therapy demonstrates promise in overcoming ICI resistance, while potentially sparing normal pulmonary tissue, thereby providing a strong rationale for further clinical investigations.

Project description:BackgroundBispecific antibody has garnered considerable attention in the recent years due to its impressive preliminary efficacy in hematological malignancies. For solid tumors, however, the main hindrance is the suppressive tumor microenvironment, which effectively impedes the activation of infiltrating T cells. Herein, we designed a bispecific antibody AP203 with high binding affinity to PD-L1 and CD137 and assessed its safety and anti-tumor efficacy, as well as explored the mechanism of action.MethodsThe optimal antibody binders against PD-L1 and CD137 were screened from the OmniMab phagemid library. The binding affinity of the constructed AP203 were evaluated using enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry (BLI). T-cell stimulatory capacity was assessed using the allogeneic mixed lymphocyte reaction (MLR), antigen-specific recall response, and coculture with PD-L1-expressing cells. In vivo antitumor efficacy was evaluated using two models of tumor-xenografted humanized mice with profiling of tumor infiltrating lymphocytes (TILs). The possible toxicity of AP203 was examined using in vitro cytokine release assay by human PBMCs.ResultsAP203, which simultaneously targeted PD-L1 and costimulatory CD137, elicit superior agonistic effects over parental antibodies alone or in combination in terms of T cell activation, enhanced memory recall responses, and overcoming Treg-mediated immunosuppression (P < 0.05). The agonistic activity of AP203 was further demonstrated PD-L1-dependent by coculturing T cells with PD-L1-expressing cells. In vivo animal studies using immunodeficient or immunocompetent mice both showed a dose-related antitumor efficacy superior to parental antibodies in combination (P < 0.05). Correspondingly, AP203 significantly increased tumor infiltrating CD8 + T cells, while decreased CD4 + T cells, as well as Treg cells (P < 0.05), resulting in a dose-dependent increase in the CD8 + /CD4 + ratio. Moreover, either soluble or immobilized AP203 did not induce the production of inflammatory cytokines by human PBMCs.ConclusionsAP203 exerts potent antitumor activity not only by blocking PD-1/PD-L1 inhibitory signaling, but also by activating CD137 costimulatory signaling in effector T cells that consequently counteracts Treg-mediated immunosuppression. Based on promising preclinical results, AP203 should be a suitable candidate for clinical treatment of solid tumors.

Dataset Information

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

Publications

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

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