CAR-T cells: the Chinese experience

ABSTRACT

Introduction

Chimeric antigen receptor T (CAR-T) cells are harnessed to identify and lyse malignant cells specifically, efficiently, and independently of the major histocompatibility complex (MHC). As a result, prognoses of relapsed or refractory (R/R) B cell hematological malignancies as well as limited types of solid tumors, have been ameliorated to a great extent. In China, a rising number of clinical trials that contribute to the development of novel CAR-T therapeutic strategies have been conducted on an extensive scale.

Areas covered

We summarize registered clinical trials related to CAR-T therapy conducted in China by evaluating various parameters such as distribution, study phase, CAR structure, target antigen, and disease. The efficacy, toxicity, and, more importantly, the new strategies for optimization of CAR-T therapy of Chinese studies and clinical trials are elaborated in detail.

Expert opinion

In terms of the number of CAR-T clinical trials, China is second to the USA, registering approximately 33% of trials worldwide. China’s extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy.

KEYWORDS:

• CAR-T
• cell-based therapy
• clinical trial
• Chinese experience
• hematological malignancy
• solid tumor
• efficacy
• toxicity
• novel strategy

Article highlights

• Apart from the USA, China is the dominant driver contributing to chimeric antigen receptor T (CAR-T) therapy, registering approximately 33% of global clinical trials concerning CAR-T therapy.

• Several leading hospitals across China are engaged in clinical trials of CAR-T therapy in the treatment of hematological malignancies, most notably B cell maturation antigen (BCMA)-targeted CAR-T therapy for multiple myeloma (MM).

• In China, approaches, such as the use of humanized or fully human CARs, CARs with ‘safety switches’, CARs with high-affinity antigen-binding domains, CARs coupled with an anti-apoptosis domain, CARs with co-stimulatory ligands, and CARs with cytokine-secreting domains, are being investigated to optimize CAR design.

• Novel target antigens are increasingly being pursued in Chinese clinical programs. For example, in addition to BCMA, CD38 and CD138 are promising candidate antigens for the treatment of MM.

• Combinatorial treatment is another vital strategy being pursued in China to achieve superior therapeutic efficacy. Illustrating this, CAR-T therapies are being evaluated in combination with hematopoietic stem cell transplantation (HSCT), PD-1 immune checkpoint blockade, decitabine, dasatinib, or radiotherapy.

• For solid tumors, Chinese investigators are pursing novel targets and combination strategies to overcome the obstacles imposed by adverse microenvironments, intra-tumoral heterogeneity, and the risk of ‘on-target, off-tumor’ toxicity.

This box summarizes key points contained in the article.

Declaration of interest

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

Additional information

Funding

This work was supported by the grants from 973 Program (2015CB964900), the National Natural Science Foundation of China (81470341, 81770201, 81730008), the Key Project of Science and Technology Department of Zhejiang Province (2018C03016-2), Zhejiang public welfare foundation (GF18H180002).