CAR-Cell Therapy for Solid Tumors

Molecular Cancer. 2023 Jan; 22 (1), 20.

Authors: Maalej KM, Merhi M, Inchakalody VP, Mestiri S, Alam M, Maccalli C, Cherif H, Uddin S, Steinhoff M, Marincola FM, Dermime S.

Cancer presents a paramount health issue with increasing annual incidence and mortality rates. Conventional therapeutic approaches involving surgery, radiation therapy, and chemotherapy have major drawbacks and many patients with metastatic or recurrent disease still face dismal outcomes.
Currently, there are several ongoing clinical trials utilizing CAR-T cell therapy for solid tumors including glioblastoma, lung cancer, liver cancer, gastric cancer, renal cancer, prostate cancer, osteosarcoma, peritoneal carcinomatosis, pleural cancer, central nervous system tumors and neuroblastoma.

Encouraging outcomes were demonstrated in phase I/II clinical study (NCT00902044) using human epidermal growth factor receptor-2 (HER2)-CAR-T cells in the treatment of 19 patients with HER2-positive sarcomas (16 osteosarcomas, 1 primitive neuroectodermal, 1 Ewing sarcoma, and 1 proto fibroblastic small round cell tumor).
In the study, out of 17 evaluable patients, 4 experienced stable diseases for 3 to 14 months, 3 of these patients received no additional therapy and had their tumor removed, with 1 showing≥90% tumor necrosis.

IL-13Rα2 is highly expressed in glioblastoma (GBM) tumor cells but is rarely expressed in normal brain cells, making it an interesting target for CAR-T cell therapy in glioblastoma cancer.
In the study (NCT02208362), multi-dose treatment with IL-13Rα2-CAR-T cells induced a complete tumor regression for nearly 8 months in a patient with disseminated glioblastoma. For the same targeted tumor antigen, another clinical trial (NCT00730613) used anti-IL-13Rα2-CAR-T cells for the treatment of 3 patients with recurrent GBM. The therapy was well tolerated with controlled brain inflammation in all patients with recurrent disease.

In neuroblastoma cells, disialoganglioside (GD2) is highly expressed and might be considered another interesting target for CAR-T cells in GBM.
A phase-I clinical trial (NCT00085930) evaluating GD2 CAR-T cells effect on 11 patients with neuroblastoma, showed complete remission in 3 patients. GD2 was also targeted in a phase-I trial (ACTRN12613000198729) for GD2-positive metastatic melanoma patients treated with CAR-T cell therapy.

The orphan tyrosine kinase receptor ROR1 is a candidate target for CAR-T cell therapy because it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival.
A phase I trial (NCT02706392) examined the efficacy and safety of CAR-T cells targeting the transmembrane tyrosine kinase receptor (ROR1) expressed in lung and breast cancers. In this study, 4 out of 5 patients with lung and breast cancer experienced a mixed response with a lower tumor burden at some metastatic sites.

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.
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 a partial response and 5 had stable disease for 2 to 8 months without severe toxicity. Moreover, in a phase-I clinical trial, 10 patients with recurrent EGFRvIII+ glioblastoma (GBM) were treated with EGFRvIII-engineered CAR-T cells (NCT02209376).