Emerging vistas in CAR T-cell therapy: challenges and opportunities in solid tumors

ABSTRACT

Introduction

Despite advances in modern evidence-based medicine, cancer remains a major cause of global disease-associated mortality. CAR T-cell therapy is a major histocompatibility complex (MHC)-independent immunotherapy involving adoptive cell transfer. Cancer immunotherapy witnessed a major breakthrough with the US FDA approval of the first chimeric antigen receptor (CAR) T-cell therapy Kymriah^TM (tisagenlecleucel) for relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) in August 2017 followed by approval of Yescarta® (axicabtagene ciloleucel) for R/R non-Hodgkin’s lymphoma (NHL) in October 2017.

Areas covered

We review the potential of CAR T-cell therapy which, despite showing great promise in hematological malignancies, faces significant challenges in targeting solid tumors. We address these challenges and discuss proposed strategies to overcome them in solid tumors. We highlight the potential of CAR T-cell therapy as cancer precision medicine and briefly discuss the ‘financial toxicity’ of CAR T-cell therapy.

Expert opinion

Taken together, we discuss various strategies to circumvent the limitations of CAR T-cell therapy in solid tumors. Despite the rapid advances in CAR NK-cell therapies, there is immense scope for CAR T-cell therapy in solid tumors. We provide a synthetic review of CAR T-cell therapy that will drive future research and harness its full potential in cancer precision medicine for solid tumors.

KEYWORDS:

• Adoptive cell transfer
• cancer
• CAR T-cell therapy
• chimeric antigen receptor
• immunotherapy
• Kymriah
• solid tumors
• Yescarta

Article highlights

• CAR T-cell therapy has demonstrated clinical success in pediatric and adult hematological malignancies but has had limited success in treating solid tumors.

• Challenges in targeting solid tumors with CAR T-cells include identifying and targeting a precise tumor antigen, trafficking and infiltration into solid tumors, and immunosuppressive tumor microenvironment.

• Strategies to identify and target a precise tumor antigen for solid tumors with CAR T-cells include modification of CAR T-cell structure, mutant tumor antigen targeting, suicide genes, and vaccination with CAR T-cells.

• Strategies for trafficking towards and infiltration into solid tumors include the use of CAR T-cells with oncolytic viruses, heparanase, chemokine receptors, and regional delivery of CAR T-cells

• Strategies for circumventing the immunosuppressive tumor microenvironment in solid tumors by CAR T-cells include protein kinase A blockade, targeting the immune checkpoints by CRISPR/Cas9-mediated gene knockout, GSK3 inhibition, combination therapy with immune checkpoint inhibitors, and switchable CAR T-cell therapy, amongst others.

• Financial toxicity and geographical availability of CAR T-cell therapy need to be addressed globally

This box summarizes key points contained in the article.

Reviewer disclosures

One of the peer reviewers on this manuscript is a chief scientific officer of a CAR-T company. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Declaration of interest

The authors have no 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.

Additional information

Funding

This paper is not funded.