CAR T-cell Therapy Shows Early Promise in Mesothelioma

Mesothelin-target chimeric antigen receptor (CAR) T-cell therapy is being developed for the treatment of Mesothelioma.

by Dr. C.H. Weaver

About CAR T cell therapy

CAR therapies utilize T-cells (CAR T) which are a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes these T cells are re-programmed to identify a patient’s cancer cells.

Once the T cells have been programmed to identify a patient’s cancer cells, they are replicated in the laboratory in very large numbers and infused back into the patient. The re-programmed T cells circulate throughout the body where the identify cancer cells and facilitate an immune attack against them. Simultaneously, the T cells are also replicating within the body, so that more of the immune cells can identify and attack the cancer cells.

Mesothelin is a cell-surface tumor-differentiation antigen that is frequently highly expressed in several cancers, including mesothelioma, lung, pancreas, breast, and ovarian. The mesothelin protein has been found to be expressed in 85% to 90% of mesotheliomas, 80% to 85% of pancreatic cancers, and 60% to 65% of lung cancers, ovarian cancers, and cholangiocarcinomas.2 Importantly, mesothelin is not commonly expressed on normal mesothelial cells which makes it an attractive therapeutic target. Overall mesothelin-expressing solid tumors account for 371,977 tumors in the United States.

In the current clinical study researchers evaluated the safety and maximum tolerated dose of CAR T cells designed to attack the cell-surface protein mesothelin, which is expressed in the majority of cancer cells in mesothelioma and many individuals with NSCLC.

Currently 21 patients with heavily pretreated biopsy-proven malignant pleural disease expressing mesothelin, including 19 patients with malignant pleural mesothelioma and one each with lung and breast cancer have been evaluated following the injection of “IcasM28z” CAR T cells directly into the pleural cavity.

No significant CAR T-cell therapy-related side effects were observed and there were no cases of neurotoxicity or cytokine release syndrome which have been reported to occur with some CAR T cell treatments. Researchers specifically monitored patients for on-targeted, off-tumor side effects but found no evidence of toxicity.

Thirteen patients had detectable CAR T cells in their peripheral blood from day 1 to 38 weeks after infusion. T-cell persistence appeared associated with a 50% or greater serial serum soluble mesothelin-related peptide levels and evidence of tumor regression. One patient with mesothelioma underwent successful curative-intent surgical resection 6 weeks after CAR T-cell infusion.

References:

  1. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6(2):133-146. doi: 10.1158/2159-8290.CD-15-0583.
  1. Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.
  1. Adusumilli PS, Zauderer M, Rusch V, et al: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR-T cells. 2019 AACR Annual Meeting. Abstract CT036. Presented March 31, 2019.
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