SPECIAL ISSUE REVIEW

The toxicity of cell therapy: Mechanism, manifestations, and challenges

Yongjia Jin | Yan Dong | Jin Zhang | Jingwei Sun | Yarong Liu | Yong Chen
Shanghai Electric Power Hospital, Shanghai, China
Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Grit Biotechnology, Shanghai, China

Correspondence

Yong Chen, Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; or Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Abstract

Adoptive cell therapy (ACT), including tumor-infiltrating lymphocytes (TILs), T cell receptor engineered T cell (TCR-T), and chimeric antigen receptor engineered T cell (CAR-T), has shown significant clinical benefits for cancer treatment. However, all of these ACT therapies are associated with toxicities from mild to life threatening in clinic. Common ACT-related toxicities include cytokine release syndrome (CRS), neurological toxicity, on-target/off tumor or off-target toxicities, and toxicities associated with lymphodepletion preconditioning and high dose IL-2 administration. This review summarizes clinical manifestations of adverse events associated with ACT treatment and discusses the underlying pathological mechanisms. Moreover, challenges and opportunities of managing ACT-related toxicities have been discussed to give an indication of how to improve the safety of ACT treatment without dampening the therapeutic effect.

KEYWORDS

adoptive cell therapy, clinical manifestation, cytokine release syndrome, neurological toxicity, pathological mechanism, toxicity

1 | OVERVIEW OF ADOPTIVE CELL THERAPY

Cancer immunotherapy, especially cellular immunotherapy with autologous or allogeneic T cells or other immune cells, has been established as a powerful therapeutic strategy for cancer treatment in the past decades. Currently, adoptive cell therapy (ACT) can be mainly classified into three different categories: (1) ACT with tumor-infiltrating lymphocytes (TILs) isolated from tumor samples of the patient followed by in vitro expansion and reinfusion to the patient, (2) T cells engineered with a T cell receptor (TCR) specific for a given tumor antigen, or (3) the genetic engineering of T cells using chimeric antigen receptors (CARs).

1.1 | ACT with TILs

TILs have been used as cellular immunotherapy for the longest time, and the first study with tumor control was conducted by Rosenberg et al. (1988), with TILs isolated from freshly resected melanomas and infused into patients with IL-2, achieving 60% of objective regression. TIL therapy usually requires preconditioning with lymphodepletion, which has been approved to improve the proliferation and antitumor function of transferred cells. TILs have shown antitumor activity in various cancer types, such as melanoma, lung cancer, and gastrointestinal cancers. Although ACT with TILs is currently the most effective clinical treatment for metastatic melanoma, the challenges are to reproducibly isolate and expand TILs across different patients and various cancer types with standardization.

1.2 | ACT with T cell receptor engineered T cell

To produce large amounts of tumor antigen-specific T cells, another strategy is to genetically introduce natural TCR or CAR to T cells. T cell receptor engineered T cell (TCR-T) therapy targets TCR that recognizes antigen derived from either an intracellular or membrane-associated protein presented by major histocompatibility complex (MHC). The first clinical trial was conducted in treating metastatic melanoma with the MART-1 antigen specific TCR-T cells and resulted in over 10% objective regression.

1.3 | ACT with CAR-T

CARs are synthetic receptors that combine an extracellular single-chain variable fragment (scFv) recognizing tumor antigens and functional intracellular domain. The first generation of CAR contains only ITAM motifs in the intracellular domain, while the second generation includes a costimulatory domain, which offers higher activity and longer persistence. CAR-T cells specific for the B cell antigen CD19 have shown prominent clinical outcomes in patients with relapse refractory malignant hematological tumors.

2 | CELL THERAPY– RELATED TOXICITIES

Compared with traditional cancer therapies, ACT can target tumors more precisely and generally results in reduced toxicity. However, ACT also induces inflammatory-related adverse events that could potentially be life-threatening. The toxicity of conventional therapeutic chemicals usually subsides after treatment cessation. Still, the transferred T cells can exist in patients for years, complicating the management of expected and unexpected ACT-related toxicities.

2.1 | Cytokine release syndrome

2.1.1 | Clinical manifestations

Cytokine release syndrome (CRS) is a common type of toxicity appearing in all three kinds of ACT therapies. The most common symptoms include fevers and chills, usually beginning from several hours after cell infusion. Fatal CRS cases have also occurred in clinics.

2.1.2 | Pathological mechanisms

CRS is induced by the activation of T cells through the recognition of cognate antigens. Multiple cytokines and chemokines are released, including IL-6, IFN-γ, and others, indicating CRS severity, although real-time monitoring of cytokines is challenging.

2.2 | Neurological toxicity

2.2.1 | Clinical manifestations

Neurological toxicity, also known as CAR-T-cell-related encephalopathy syndrome (CRES), manifests in confusion, delirium, and seizures, among others. It can occur concurrently with CRS or independently afterward.

2.2.2 | Pathological mechanisms

The underlying mechanisms may include the diffusion of cytokines into the brain or T cells trafficking into the brain.

2.3 | On-target/off-tumor toxicity

Target antigens may also be expressed on healthy tissues. This toxicity is particularly relevant for both CAR-T and TCR-T therapies, where normal tissues can be damaged along with tumor cells.

2.4 | Off-target toxicity

Antigens expressed on normal tissues can cross-react with tumor antigens targeted by transferred T cells, leading to unexpected toxicities.

2.5 | High dose IL-2–related toxicity

2.5.1 | Clinical manifestations

Administration of high dose IL-2 can lead to systemic toxicities, including the vascular leak syndrome and organ damage. Monitoring during treatment is crucial.

2.5.2 | Pathological mechanisms

The pathogenesis may involve immune cell activation, cytokine release, and abnormal endothelial cell adhesion.

2.6 | Lymphodepletion-related toxicity

2.6.1 | Clinical manifestations

Lymphodepletion preconditioning results in toxicities like prolonged neutropenia and a higher risk of infections.

2.6.2 | Pathological mechanisms

Lymphodepletion enhances ACT by increasing supportive cytokines and removing suppressive Treg cells.

3 | CONCLUSION: CHALLENGES AND OPPORTUNITIES OF MANAGING THE TOXICITY OF ACT

In conclusion, the understanding of pathological mechanisms underlying cell therapy-associated toxicities is essential for improving the safety of ACT therapies. Effective management strategies for CRS and neurological toxicity, including potential new therapeutic agents and minimizing toxicity through novel T cell engineering designs, remain critical areas for future research.