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Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model.

ABSTRACT: BACKGROUND:T cells have been recognized as core effectors for cancer immunotherapy. How to restore the anti-tumor ability of suppressed T cells or improve the lethality of cytotoxic T cells has become the main focus in immunotherapy. Bispecific antibodies, especially bispecific T cell engagers (TCEs), have shown their unique ability to enhance the patient's immune response to tumors by stimulating T cell activation and cytokine production in an MHC-independent manner. Antibodies targeting the checkpoint inhibitory molecules such as programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1) and cytotoxic lymphocyte activated antigen 4 are able to restore the cytotoxic effect of immune suppressed T cells and have also shown durable responses in patients with malignancies. However, both types have their own limitations in treating certain cancers. Preclinical and clinical results have emphasized the potential of combining these two antibodies to improve tumor response and patients' survival. However, the selection and evaluation of combination partners clinically is a costly endeavor. In addition, despite advances made in immunotherapy, there are subsets of patients who are non-responders, and reliable biomarkers for different immunotherapies are urgently needed to improve the ability to prospectively predict patients' response and improve clinical study design. Therefore, mathematical and computational models are essential to optimize patient benefit, and guide combination approaches with lower cost and in a faster manner. METHOD:In this study, we continued to extend the quantitative systems pharmacology (QSP) model we developed for a bispecific TCE to explore efficacy of combination therapy with an anti-PD-L1 monoclonal antibody in patients with colorectal cancer. RESULTS:Patient-specific response to TCE monotherapy, anti-PD-L1 monotherapy and the combination therapy were predicted using this model according to each patient's individual characteristics. CONCLUSIONS:Individual biomarkers for TCE monotherapy, anti-PD-L1 monotherapy and their combination have been determined based on the QSP model. Best treatment options for specific patients could be suggested based on their own characteristics to improve clinical trial efficiency. The model can be further used to assess plausible combination strategies for different TCEs and immune checkpoint inhibitors in different types of cancer.

SUBMITTER: Ma H

PROVIDER: S-EPMC7454244 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model.

Ma Huilin H Wang Hanwen H Sové Richard J RJ Wang Jun J Giragossian Craig C Popel Aleksander S AS

Journal for immunotherapy of cancer 20200801 2

<h4>Background</h4>T cells have been recognized as core effectors for cancer immunotherapy. How to restore the anti-tumor ability of suppressed T cells or improve the lethality of cytotoxic T cells has become the main focus in immunotherapy. Bispecific antibodies, especially bispecific T cell engagers (TCEs), have shown their unique ability to enhance the patient's immune response to tumors by stimulating T cell activation and cytokine production in an MHC-independent manner. Antibodies targetin ...[more]

PMID: 32859743

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Project description:Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition-resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition-resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTβR (lymphotoxin β receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

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Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model.

Publications

Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model.

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