Targeting tumor cells with antibodies enhances anti-tumor immunity

Zhichen Sun,Hua Peng,Yang-Xin Fu

doi:10.1007/s41048-018-0070-2

Abstract

Tumor-targeting antibodies were initially defined as a group of therapeutic monoclonal antibodies (mAb) that recognize tumor-specific membrane proteins, block cell signaling, and induce tumor-killing through Fc-driven innate immune responses. However, in the past decade, ample evidence has shown that tumor-targeting mAb (TTmAb) eradicates tumor cells via activation of cytotoxic T cells (CTLs). In this review, we specifically focus on how TTmAbs induce adaptive anti-tumor immunity and its potential in combination therapy with immune cytokines, checkpoint blockade, radiation, and enzyme-targeted small molecule drugs. Exploring the mechanisms of these preclinical studies and retrospective clinical data will significantly benefit the development of highly efficient and specific TTmAb-oriented anti-tumor remedies.

Highlights

The first generation of tumor-targeting antibodies approved by US Food and Drug Administration (FDA), including trastuzumab, cetuximab, and rituximab, were initially known as signal blockers to target oncogenic receptors of tumor cells and have great potential for effective cancer immunotherapy (Hynes and Lane 2005; Li et al 2005)
Our laboratory’s research and the work of other research groups show that tumor-targeting Ab can be effectively combined with traditional small molecule chemo- and targeted therapy as well as newly developed checkpoint blockades, providing new potential for creating highly specific therapies
These new therapies would address the fundamental mechanism behind tumor growth and metastasis, namely breaking immune tolerance

Summary

INTRODUCTION

The first generation of tumor-targeting antibodies approved by US Food and Drug Administration (FDA), including trastuzumab, cetuximab, and rituximab, were initially known as signal blockers to target oncogenic receptors of tumor cells and have great potential for effective cancer immunotherapy (Hynes and Lane 2005; Li et al 2005). Targeting DCs will be another important strategy for improving the efficacy of cancer immunotherapy This can be achieved by providing type I IFNs, the key players linking innate and adaptive antitumor immunity, to induce Ab-mediated tumor regression. Killing more tumor cells by enhanced CTLs can create a positive feedback loop for anti-tumor immune responses All these studies conclude that blocking inhibitory PD-L1 upregulated by Ab–cytokine treatment may further improve the antitumor effect via recruiting more Ab–cytokine molecules and open new avenues for future clinical cancer treatment. IFN–anti-PD-L1 may elicit a positive feedback loop to enhance targeting effects by upregulating PD-L1 expression, which is beneficial for treating tumors with lower levels of PD-L1 This strategy of PD-L1 antibody armed with IFN can overcome resistance to checkpoint blockade therapy in advanced tumors. Safety and efficacy must be carefully evaluated for development of the combination of EGFR TKI and immunotherapy

SUMMARY AND PERSPECTIVES

Findings

Compliance with ethical standards