MEK inhibitor augments antitumor activity of B7-H3-redirected bispecific antibody

Abstract

Background Targeting cancer antigens by T cell-engaging bispecific antibody (BiAb) or chimeric antigen receptor T cell therapy has achieved successes in haematological cancers, but attempts to use them to fight solid cancers have been disappointing, in part due to antigen escape. MEK inhibitor had limited activity as a single agent, but enhanced antitumor activity when combined with other therapies, such as targeted drugs or immunotherapy agents. This study aimed to analyze the expression of B7-H3 in non-small-cell lung cancer (NSCLC) and bladder cancer (BC) and to evaluate the combinatorial antitumor effect of a B7-H3 × CD3 BiAb with MEK inhibitor trametinib. Methods We analyzed the mRNA expression of B7-H3 in NCSLC and BC using Oncomine database and validated its expression by immunohistochemistry staining of clinical samples. B7-H3 expression and the effects of trametinib on RAS-mutated NSCLC and BC cell lines were determined by flow cytometry. Antitumor efficacy of B7-H3 × CD3 BiAb alone and its combination with trametinib were evaluated both in vitro and in vivo. Results B7-H3 was highly expressed in NSCLC and BC compared with normal samples and its increased expression was associated with poor prognosis. Treatment with trametinib alone could induce apoptosis in tumor cell, while has no effect on T cell proliferation, and a noticeable elevation of B7-H3 expression in tumor cells was also observed following treatment. B7-H3 × CD3 BiAb specifically and efficiently redirected their cytotoxicity against B7-H3-overexpressing tumor cells both in vitro and in xenograft mouse models, which was synergized by trametinib. While trametinib treatment alone affected tumor growth, the combined therapy increased T cell infiltration and significantly suppressed tumor growth. Conclusion Together, these data suggest that combination therapy with B7-H3 × CD3 BiAb and MEK inhibitor may serve as a new therapeutic strategy in the future clinical practice for the treatment of NSCLC and BC.

Effective killing of cells expressing CD276 (B7-H3) by a bispecific T cell engager based on a new fully human antibody

“…Li H et al. also verified that CD276 × CD3 BiTE specifically and efficiently redirected their cytotoxicity against CD276 overexpressing tumor cells both in vitro and in xenograft mouse models [35] . Besides BiTE, Liu J et al.…”

Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma

“…The first generation MEK inhibitor, trametinib, remarkably improved the progression‐free and overall survival rates among melanoma patients, 28 and various efforts have been made to apply MEK inhibitors to other cancers, including lung, ovarian, and pancreatic cancers, as a monotherapy or in combination with another molecular‐targeting drugs 42,43 . The combined treatment of MEK inhibitor and ICI or T cell‐mediated immunotherapy has also been investigated; however, the effect of MEK inhibitors on the functioning of T cells in in vitro studies remains controversial 9,41,44 . Previous reports revealed that MEK inhibitor is likely to inhibit the T‐cell effector function in vitro, 9 which has limited the assessment combinations of MEK inhibitors and immunotherapies, even though the study lacked in vivo validation in a murine xenograft model.…”

“…42,43 The combined treatment of MEK inhibitor and ICI or T cell-mediated immunotherapy has also been investigated; however, the effect of MEK inhibitors on the functioning of T cells in in vitro studies remains controversial. 9,41,44 Previous reports revealed that MEK inhibitor is likely to inhibit the T-cell effector function in vitro, 9 45 or B7-H3 redirected bispecific Ab, even in an in vitro study. 44 This controversy could be explained by the fact that trametinib selectively blocked the activation of naive T cells but did not suppress effector T cells, which were already activated.…”

“…9,41,44 Previous reports revealed that MEK inhibitor is likely to inhibit the T-cell effector function in vitro, 9 45 or B7-H3 redirected bispecific Ab, even in an in vitro study. 44 This controversy could be explained by the fact that trametinib selectively blocked the activation of naive T cells but did not suppress effector T cells, which were already activated. 45 Because the PB-GD2-CAR-T cells used by us showed a dominant fraction of naïve/stem cell memory T cells, the function of CAR-T cells was susceptible for impairment by trametinib, at least in our in vitro study.…”

“…Nevertheless, recent studies have also determined the effectiveness of concurrent and sequential combinations of MEK inhibitors and ICI or T cell-mediated immunotherapy in murine xenograft models and also in clinical trials. [44][45][46] The precise mechanisms for the synergistic effect of MAPK pathway inhibition and ICI or T cell-mediated immunotherapy in vivo remain underexplored; however, recent studies have revealed that MEK inhibitor would augment the infiltration of CTLs at tumor sites, potentiate the antitumor function of T cells by impairing the activation-induced cell death, and upregulate the expression of MHC and PD-L1 on tumor cells, 31,[47][48][49] which highlight the usefulness of MEK inhibitor in combination with ICI or T cell-mediated immunotherapy. However, our in vitro experiments revealed that the downregulation of PD-L1 on NB cells by trametinib was poorly involved with the mechanisms of enhanced antitumor effect of PB-GD2-CAR-T cells (Figure S6).…”