CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress

ABSTRACT

Introduction

Most breast cancer-related deaths arise from triple-negative breast cancer (TNBC). Molecular heterogeneity, aggressiveness and the lack of effective therapies are major hurdles to therapeutic progress. Chimeric antigen receptor (CAR)-T cells have emerged as a promising immunotherapeutic strategy in TNBC. This approach combines the antigen specificity of an antibody with the effector function of T cells.

Areas covered

This review examines the opportunities provided by CAR-T cell therapies in solid tumors. Emerging targets, ongoing clinical trials, and prospective clinical implications in TNBC are considered later. An emphasis is placed on the key challenges and possible solutions for this therapeutic approach.

Expert Opinion

A challenge for CAR-T cell therapy is the selection of the optimal targets to minimize on-target/off-tumor toxicity. Tumor escape via antigen loss and intrinsic heterogeneity is a further hurdle. TROP2, GD2, ROR1, MUC1 and EpCAM are promising targets. Persistence and trafficking to tumor cells may be enhanced by the implementation of CARs with a chemokine receptor and/or constitutively activated interleukin receptors. Fourth-generation CARs (TRUCKs) may redirect T-cells for universal cytokine-mediated killing. Combinatorial approaches and the application of CARs to other immune cells could revert the suppressive immune environment that characterizes solid neoplasms.

KEYWORDS:

• Triple negative breast cancer
• breast cancer
• CAR-T cell
• translational
• clinical trials
• drug targets
• drug discovery
• solid tumors

Article highlights

• Many challenges still the hamper application of chimeric antigen receptor (CAR)-T cell therapy in solid tumors, despite the progress in the treatment of refractory hematologic malignancies.

• Approaches to increase (i) trafficking to the tumor and (ii) persistence of CAR-T cells are under investigation in triple-negative breast cancer (TNBC).

• Numerous antigens have been identified as potential targets for CAR-T cell therapy in TNBC via preclinical models and early-phase clinical trials.

• Strategies to improve CAR-T cell specificity for breast cancer cells are under evaluation to reduce off-tumor toxicity.

• An enhanced understanding of the immune environment of TNBC and technological breakthroughs in CAR-T cell manufacturing, will be key to further clinical development.

This box summarizes key points contained in the article.

Declaration of interest

N Fusco has received honoraria for consulting, advisory roles, and/or speaker bureau from Merck Sharp & Dohme.

G Curigliano served as consultant or advisor for Roche, Lilly, and Bristol-Myers Squibb, served on the speaker<apos;>s bureau for Roche, Pfizer, and Lilly, received travel funding from Pfizer and Roche, and received honoraria from Roche, Pfizer, Lilly, Novartis, and SEAGEN, all outside the submitted work. (MSD), Boehringer Ingelheim, and Novartis, all outside the submitted work.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer received research funding from Pfizer and Roche, sits on Advisory boards for Roche, Seagen, Astra Zeneca, Daichi-Sankyo and receives speakers fees from Pfizer, Lilly, Seagen, and Gilead. They also receives conference support from Astra-Zeneca/Daichi-Sankyo, and Lilly.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.