CAR-T against myeloma
GM lymphocytes helped half of the subjects with multiple myeloma
Vera Mukhina, N+1
Chinese researchers have published in the journal Proceedings of the National Academy of Sciences the results of a preliminary clinical trial of GM lymphocyte therapy for multiple myeloma (Xu et al., Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma). Of the seventeen subjects, eight achieved complete remission or significant tumor reduction, and one patient died from a cytokine storm.
With recurrent multiple myeloma, a malignant transformation of B cells localized in the bone marrow occurs. GM lymphocytes (CAR-T) have performed well in the treatment of other blood tumors, but so far only two types of therapy are approved by the FDA and both are used for the treatment of acute lymphoblastic leukemia. CART treatment involves modification of the patient's T cells, into which chimeric receptors are embedded. The DNA sequences of these receptors are constructed in the laboratory and when they are inserted, the patient's cells are able to quite accurately recognize tumor cells and destroy them in the same way as they usually do with foreign pathogens.
In order for the receptor to be able to recognize a cancer cell, it is necessary to first determine the target that it will bind: ideally, it should be a protein that is present on the surface of all malignant cells and is absent in healthy ones. In acute leukemia, it is usually CD19 protein, and in this case it was decided to choose BCMA protein. It is necessary for the survival of plasma B cells and its gene is usually quite active in myeloma. LCAR-B38M cells are able to recognize it from two sites at once and have proven themselves well in previous studies, so they were selected for clinical trials by a group led by Jie Xu.
The trials involved 17 patients with a recurrent form of multiple myeloma, in which the prognosis is particularly unfavorable. Two therapy options were tested, in which the dose of LCAR-B38M enters the body immediately or is divided into three parts and administered in stages, but the researchers did not notice any difference between these methods. The therapy initially had a positive effect on 15 people, but by the end of the observations, which lasted an average of 417 days, seven of them had myeloma relapsed.
Dynamics of patients' condition. A drawing from an article in PNAS.
Therapy did not work on one of the two remaining patients, and the other died from a cytokine storm — this is the name given to a situation in which the immune system's reaction to tumor cells turns out to be so strong and sharp that the body does not have time to prepare and the inflammation gets out of control, covering the entire body. This is a common side effect of GM lymphocyte therapy and is not the first case of death of patients during clinical trials. All the other patients in this study also experienced this side effect of therapy to varying degrees, but it was possible to compensate for it.
In a recent study, scientists managed to find a remedy that helps with cytokine storm. They suggest blocking receptors to cytokine molecules with the help of inhibitors injected from the outside or already embedded in the GM lymphocyte.
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