Clinical efficacy of CAR-T cells depends on chemical modifications, says study

One in five cancers affects lymph nodes and blood cells resulting in lymphomas and leukemias, respectively. Treatment with drugs led to major advances in cancer cure; however, there are instances where there is no clinical response or development of drug resistance.

Clinical efficacy of CAR-T cells depends on chemical modifications, says study
Image Credit: Josep Carreras Leukaemia Research Institute.

During recent years, there arose an alternative for these cases—a cell therapy called CAR-T that collects the T-lymphocytes of cancer patients alters them employing genetic engineering in the lab, and delivers them again to the patient so that they can combat cancer more efficiently. This system is anticipated to revolutionize the treatment of hematological malignancies.

This groundbreaking novel cellular medicine, also known as chimeric antigen receptor T-lymphocyte therapy (CAR-T), comes with problems that can be outlined in the emergence of side effects, cases insensitive to the therapy, and its high financial cost. Hence, it is vital to be able to recognize which patients possibly benefit from using CAR-T cells and comprehend how to enhance the healing capabilities of these cells.

Researchers from the team of Dr. Manel Esteller, Director of the Josep Carreras Leukemia Research Institute (IJC), ICREA Research Professor, and Professor of Genetics at the University of Barcelona, demonstrated that the profile of chemical modifications of the DNA of CAR-T cells delivered to the patient ascertains their clinical efficiency.

The research was carried out in association with scientists from the Barcelona Clinic Hospital, the Bambino Gesù Pediatric Hospital in Rome, and the Sheba Medical Center in Israel, pioneering in this unique therapy. The study was published on September 28th, 2021, in The Journal of The National Cancer Institute, an official magazine of the National Cancer Center (NCI) of the United States.

CAR-T cell treatment has restored hope to patients with leukemia and lymphoma where all previous therapies had failed. However, we know very little about the factors that influence the success or not of this treatment.”

Dr Manel Esteller, Director, Josep Carreras Leukemia Research Institute

We decided to look in detail at the molecular characteristics of more than 100 samples of CAR-T cells provided to patients with leukemias and lymphomas. We discovered that there was a genetic regulation profile (epigenome) that was associated with the absence of disease relapse and an improved overall survival of these people,” states Dr. Esteller.

In addition, we observed that this epigenetic pattern is typical of young T lymphocytes that, as they have a long life ahead and a greater capacity to remain in the patient's bloodstream, perhaps for this reason they are more efficient CAR-T cells.”

Dr Manel Esteller, Director, Josep Carreras Leukemia Research Institute

Dr. Esteller further remarks, “It is worth investigating now whether these cell subpopulations would be ideal to be selected and administered, or if we can also enrich them using epigenetic drugs that are already used in the context of other leukemias and lymphomas.”

Source:
Journal reference:

Garcia-Prieto, C. A., et al. (2021) Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies. The Journal of the National Cancer Institute. doi.org/10.1093/jnci/djab194.

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