Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

Abstract

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies’ clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.

CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

“…CAR-T cell clinical trials, targeting several antigens expressed in tumors of different organs, are registered on clinicaltrials.gov and summarized in Table 1 . The common CAR-T cell targets in solid tumors have been recently reviewed [ 45 , 46 ]. Promising clinical outcomes of CAR-T cell therapy in solid tumors are reported in this section according to the targeted tumor antigens.…”

“…The epidermal growth factor receptor (EGFR) plays an important role in the development and progression of solid tumors and has emerged as an important therapeutic target in different types of cancer such as non-small-cell lung carcinoma, breast, gastroesophageal and colorectal cancers [ 57 ]. In addition, many clinical trials have been conducted on CAR-T cells targeting EGFR for the treatment of EGFR-positive solid tumors [ 45 ]. A phase-I clinical trial (NCT01869166) of EGFR CAR-T cell therapy in 11 patients with EGFR+ refractory/ relapsed non-small cell lung cancer (NSCLC) showed that 2 patients achieved partial response and 5 had stable disease for 2 to 8 months without severe toxicity [ 58 ].…”

The potential role of the thymus in immunotherapies for acute myeloid leukemia

“…While the application of genetically engineered CAR-T-cell therapies have been successful for lymphoid malignancies, its use for the treatment of heterogeneous AML faces several unmet challenges ( 166 ). This includes the lack of AML-specific cell-surface antigen that minimizes off target toxicity and the suppression of T cell activity and proliferation by AML blasts ( 167 ).…”

The immunotherapy advancement targeting malignant blastomas in early childhood

“…CAR T-cell therapy principally employs gene editing that facilitates T cells to target tumor cell-specific antigens through gene modification intended to kill target-specific tumor cells. For the CAR T-cell therapy, the T cells from patients’ site-specific tumor tissues will be derived and then injected back into the patients’ bodies after in vitro gene editing and amplification to produce pronounced anti-tumor effects ( 15 ). CAR T-cell therapy has shown promising clinical outcomes in patients diagnosed with acute lymphoblastic leukemia ( 16 ).…”

“…However, due to side effects, antigen escape, and immune suppressive tumor microenvironment (TME), the CAR T-cell therapeutic effect on solid tumors is not satisfactory. Although CAR T-cell therapy has found many alternative targets in the treatment of solid tumors, most of them show limited anti-tumor effects in clinical trials ( 15 , 17 , 18 ). The application of CAR T-cell therapy in attenuating solid tumors demands more clinical studies.…”