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CAR T-cell therapy: A "revolutionary" living therapy



Currently, two chimeric antigen receptor T-cell (CAR T-cell) therapies are approved for use in the United States: Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel). Both therapies were designed to treat different forms of blood cancer, with Kyrmiah targeting B-cell acute lymphoblastic leukemia (B-ALL) in people ages >25 years whose malignancies have not responded to other forms of treatment, and Yescarta® for adults with B-cell cancers that have also not responded to conventional treatment.



CAR T-cell therapies are a subgroup of immunotherapy, known as a "living therapy".



Blood is obtained from the patient and is then sent to a laboratory. Here, scientists genetically modify the patient's T cells to produce a chimeric antigen receptor (CAR) on their surface. The receptors are synthetic, meaning they don't exist naturally. The receptors enable the T cells to recognize and attach to an antigen on tumor cells, initiating the destruction of the cancerous cell.



Currently available CAR T-cell therapies, target an antigen known as CD19. These genetically modified T cells are then replicated and "expanded" to create hundreds of millions of cells, before being infused back into the patient's body.





Video credit: Hope City.﻿



"The whole idea of harnessing the immune system to fight cancer is a revolutionary idea that has finally come to fruition," says Larry W. Kwak, M.D., Ph.D.at City of Hope.



Lacking the prototypical target for CAR T-cell therapy



Whilst some patients show a robust response to CAR T-cell therapy, some patients can experience relapses. Particularly in B-cell malignancies, up to 30% of patients experience relapse.



This can occur when a patient's cancer cells stop expressing the CD19 target. "Immune therapies, such as CAR T cells, exert immunologic pressure on the tumor cells. If the target is dispensable for survival, the tumor will eventually escape the therapy by downregulating surface expression of the target so that it is no longer visible to the CAR T cells. This happens after CD19 CAR T therapy, because CD19 is not required for tumor survival," says Kwak.



Today, Hon Qin and colleagues, including Kwak, at City of Hope have published a new study in which they have developed CAR T cells that target an alternative B cell-specific surface marker – B-cell activating factor receptor (BAFF-R). Their findings are published in the journal Science Translational Medicine.



BAFF-R: An alternative approach



BAFF-R is a membrane protein that recognizes B-cell activating factor (BAFF), which enhances B cell survival and is essential for B cell maturation. The BAFF-R mechanism has been targeted successfully for autoimmune diseases with monoclonal antibodies against the BAFF ligand, however it's promise in cancer therapy has not yet been investigated.



In this study, the researchers tested BAFF-R directed CAR T cells against human lymphoma and acute lymphocytic leukaemia cell lines in vitro and in mouse models. They compared this approach with the CD19-directed CAR T cells, and particularly focused on the effect of BAFF-R-CAR T-cell therapy against CD19 negative targets. The authors found that BAFF-R-directed CAR T cells applied in mice with human lymphoma cells resulted in complete tumor regression and 100% long-term survival in the animals.



"BAFF-R CAR T-cell therapy was extremely potent. A single treatment of human tumors growing in mice cured the majority of tumor-bearing mice," Kwak comments. In CRISPR-modified human leukemia cells that lacked CD19, they found BAFF-R-directed cell therapy worked effectively. Furthermore, CD19 negative tumor cells, isolated from four patients with leukemia that had experienced relapse, were also killed by the therapy.



"We observed that relapsed leukemia cells lacking CD19 still expressed the BAFF-R target. While these leukemias could no longer be killed by CD19 CAR T cells, they could be recognized by BAFF-R CAR T cells (rescue)," says Kwak.



He continues: "The major potential advantage of the BAFF-R target over CD19 is that we believe BAFF-R is required for tumor survival, making it less likely that the tumor can escape by no longer expressing this target. The only way to know for sure is clinical trials in human patients."



Clinical trials



The authors are enthusiastic about these findings and intend to translate the results from the laboratory to the clinic to help patients with blood cancer.



"Based on these exciting results, plans for a Phase I clinical trial are moving rapidly forward. We anticipate the trial will begin at City of Hope within six months. The trial will offer this novel therapy to patients with leukemia whose tumors have relapsed after initial CD19 CAR T-cell therapy," Kwak concludes.



Larry Kwak was speaking with Molly Campbell, Science Writer, Technology Networks.



Reference:

Qin et al. 2019. CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Science Translational Medicine. DOI: http://dx.doi.org/10.1126/scitranslmed.aaw9414.

