Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice.

Satoshi Ueha,Francis H.W Shand,Satoru Ito,Kosuke Hachiga,Haru Ogiwara,Krishant Chand,Yuya Terashima,Etsuko Toda,Kazuhiro Kakimi,Kouji Matsushima,Takuya Nakajima,Shigeyuki Shichino,Yoshiro Ishiwata,Shoji Yokochi

doi:10.1158/2326-6066.cir-14-0190

Satoshi Ueha, Francis H.W Shand + Show 12 more

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https://doi.org/10.1158/2326-6066.cir-14-0190

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Abstract

Depletion of CD4(+) cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4(+) cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25(+) Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8(+) cell depletion. CD4(+) cell depletion led to the proliferation of tumor-specific CD8(+) T cells in the draining lymph node and increased infiltration of PD-1(+)CD8(+) T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.

Highlights

Immune checkpoint modulators such as those targeting cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have attracted attention due to their extraordinary antitumor effects in patients with advanced melanoma, lung cancer, and renal cancer [1, 2]
We report that treatment with an anti-CD4 mAb alone induces strong antitumor effects and expansion of tumor-specific CD8þ T cells, and that combination of an anti-CD4 mAb with anti–PD-1 or anti–PD-L1 mAbs results in striking synergy in the suppression of tumor growth
Tumor growth in the anti-CD25 mAb-treated group was almost equivalent to that observed in untreated mice (Fig. 3A and B). These results suggest that the tumor-specific CD8þ T cells that are induced by anti-CD4 mAb treatment are responsible for the antitumor effects of the treatment, and that anti-CD4 mAb treatment might deplete immunosuppressive populations more efficiently than anti-CD25 mAb treatment

Summary

Introduction

Immune checkpoint modulators such as those targeting cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have attracted attention due to their extraordinary antitumor effects in patients with advanced melanoma, lung cancer, and renal cancer [1, 2]. An mAb against CTLA-4 (ipilimumab) that enhances both early T-cell activation and CTL function was approved for treatment of patients with advanced melanoma in the United States in 2011. An anti–PD-1 mAb (nivolumab) that protects activated T cells from exhaustion in peripheral tissues was approved for treatment of patients with melanoma in Japan and in the United States in 2014. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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