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.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
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.
- 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.
- 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.
- 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.