Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner.

Lewis Zhichang Shi,Derek Ng Tang,Liangwen Xiong,Tihui Fu,Jianjun Gao,Baoxiang Guan,Xuejun Zhang,Jorge Blando,Jan Zhang,Padmanee Sharma,Renata Collazo,Luis Vence,James P Allison,Sangeeta Goswami,Jianfeng Chen

doi:10.1158/2326-6066.cir-18-0873

Lewis Zhichang Shi, Derek Ng Tang + Show 13 more

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https://doi.org/10.1158/2326-6066.cir-18-0873

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Abstract

Adoptive transfer of tumor-reactive T cells (ACT) has led to modest clinical benefit in the treatment of solid tumors. Failures with this therapy are primarily due to inadequate infiltration and poor function of adoptively transferred cells in the tumor microenvironment. To improve the efficacy of ACT, we combined ACT with dual blockade of CTLA-4 and PD-1. Treatment with anti-CTLA-4 plus anti-PD-1 compared with monotherapy resulted in durable antitumor responses, enhanced effector function of ACT, utilizing PMEL-1 transgenic (Tg+) CD8+ T cells, and improved survival. Using PMEL-1ICOS-/- mice, we showed that deletion of the inducible T-cell costimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (Eomes), interferon gamma (IFNγ), and perforin. Higher expression of IFNγ and Eomes was noted in human ICOShi CD8+ T cells compared with ICOSlow counterparts. Together, our data provide direct evidence that ACT combined with immune-checkpoint therapy confers durable antitumor responses, which largely depended on CD8+ T-cell-intrinsic expression of ICOS. Our study provides a foundation of testing combinatorial therapy of ACT of CD8 T cells and dual blocking of CTLA-4 and PD-1 in patients with melanoma.

Highlights

Adoptive transfer of autologous ex vivo–expanded T cells and genetically engineered tumor-reactive T cells [chimeric antigen receptor T cells (CAR-T cells); refs. 1–5], collectively known as adoptive T-cell therapy (ACT), is being used to eradicate tumor cells in patients
We demonstrated that the combination of anti–CTLA-4 plus anti–PD-1 therapy with ACT consisting of ICOSþPMEL-1 CD8þ T cells, compared with monotherapy using either anti–CTLA–4 or anti–PD-1 or ACT alone, led to improved antitumor responses and durable survival benefit
Dual blockade of PD-1 and CTLA-4 increased infiltration of adoptively transferred PMEL-1 Tgþ CD8 T cells into the tumor microenvironment (Fig. 1B), and increased interferon gamma (IFNg) secretion by PMEL-1 Tgþ CD8 T cells (Fig. 1C) in comparison with the ACT monotherapy or ACT combined with either immune-checkpoint blockade (ICB)

Summary

Introduction

Adoptive transfer of autologous ex vivo–expanded T cells and genetically engineered tumor-reactive T cells [chimeric antigen receptor T cells (CAR-T cells); refs. 1–5], collectively known as adoptive T-cell therapy (ACT), is being used to eradicate tumor cells in patients. Adoptive transfer of autologous ex vivo–expanded T cells and genetically engineered tumor-reactive T cells [chimeric antigen receptor T cells (CAR-T cells); refs. 1–5], collectively known as adoptive T-cell therapy (ACT), is being used to eradicate tumor cells in patients. ACT with autologous ex vivo–expanded T cells has shown modest clinical benefits in solid malignancies including metastatic melanoma [6, 7]. Treatment failures with this therapy are primarily due to inadequate migration of adoptively transferred cells into the tumor microenvironment and poor function and persistence of transferred T cells. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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