Adoptive Cell Therapy in Breast Cancer: A Current Perspective of Next-Generation Medicine.

Jesús Fuentes-Antrás,José ÁNgel García-Sáenz,Atanasio Pandiella,Kissy Guevara-Hoyer,Pedro Pérez-Segura,Alberto Ocaña,Mariona Baliu-Piqué

doi:10.3389/fonc.2020.605633

Abstract

Immunotherapy has become a cornerstone in the treatment of cancer and changed the way clinicians and researchers approach tumor vulnerabilities. Durable responses are commonly observed with immune checkpoint inhibitors in highly immunogenic tumors, while the infusion of T cells genetically engineered to express chimeric antigen receptors (CARs) has shown impressive efficacy in certain types of blood cancer. Nevertheless, harnessing our own immunity has not proved successful for most breast cancer patients. In the era of genomic medicine, cellular immunotherapies may provide a more personalized and dynamic tool against tumors displaying heterogeneous mutational landscapes and antigenic pools. This approach encompasses multiple strategies including the adoptive transfer of tumor-infiltrating lymphocytes, dendritic cells, natural killer cells, and engineered immune components such as CAR constructs and engineered T cell receptors. Although far from permeating the clinical setting, technical advances have been overwhelming in recent years, with continuous improvement in traditional challenges such as toxicity, adoptive cell persistence, and intratumoral trafficking. Also, there is an avid search for neoantigens that can be targeted by these strategies, either alone or in combination. In this work, we aim to provide a clinically-oriented overview of preclinical and clinical data regarding the use of cellular immunotherapies in breast cancer.

Highlights

Breast cancer (BC) is a leading cause of death worldwide and remains mostly incurable in advanced stages [1]
Gene transfer-based strategies have been developed to overcome the main challenges of Tumor-Infiltrating Lymphocytes (TIL) therapy, including the low yield of TIL expansion, the low affinity of human T Cell Receptor (TCR) for tumor antigens (TAs), and the immune tolerance elicited by the downregulation of MHC molecules and TAs [30]
In order to bypass the limitations of MHC restriction of conventional abTCRs, intensive research has focused on the development of chimeric antigen receptors (CARs) and, more recently, on the gdT cell

Summary

INTRODUCTION

Breast cancer (BC) is a leading cause of death worldwide and remains mostly incurable in advanced stages [1]. Gene transfer-based strategies have been developed to overcome the main challenges of TIL therapy, including the low yield of TIL expansion, the low affinity of human TCRs for TAs, and the immune tolerance elicited by the downregulation of MHC molecules and TAs [30] Both TCR and chimeric antigen receptor (CAR) gene transfer endow polyclonal T cells with reactivities that are not naturally present against TAs of choice and provide an adaptable and highly subtle tool for personalized medicine (Figures 1A, B) [31]. Mounting clinical evidence on several tumor types along with preclinical data on BC underscores the rationale for TCR use in BC patients [34,35,36,37] Of note, in both hormone-dependent and independent BC cell lines and in xenograft mice, Li et al reported a notable enhancement of anti-tumor cytotoxicity by CD8+ T cells transduced with an MHC-A2-restricted placenta-specific 1 (PLAC1)TCR molecule [38]. In order to bypass the limitations of MHC restriction of conventional abTCRs, intensive research has focused on the development of CARs and, more recently, on the gdT cell

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Findings

CONCLUDING REMARKS