Penn discovers new, rare mechanism for ALL to relapse after CAR T cell therapy

CAR T cells ready for infusion. Credit: Penn Medicine

A single leukemic cell, unknowingly constructed with the leukemia-directed chimeric antigen receptor (CAR) lentivirus and backfused in a patient, was able to reproduce and cause a fatal recurrence of B-cell acute lymphoblastic leukemia (ALL). New research from the Abramson Cancer Center at the University of Pennsylvania found that in one patient the CAR-lentivirus that would usually enter a T-cell to teach it to hunt cancer eventually also binds with a leukemic cell. The presence of the CAR on the leukemia cell can give that cell the ability to hide from the therapy by masking CD19, the protein that CARs targets to kill cancer. Leukemic cells without CD19 are resistant to CART therapy, so this single cell led to the relapse of the patient. Naturopathy today published the findings.

The treatment, developed by researchers at Penn's Perelman School of Medicine and at Children's Hospital of Philadelphia (CHOP), modifies the patient's own immune T-cells, which are collected and reprogrammed to treat the cancer cells of the patient to seek and destroy. Once infused into the bodies of patients, these cells multiply and attack, targeting cells expressing CD19.

"In this case, we discovered that 100 percent of recurrent leukemic cells carried the CAR we use to genetically engineer T-cells," said lead author Marco Ruella, MD, assistant professor of Hematology-Oncology at Penn. "This is the first time in hundreds of patients treated at Penn and other institutions that we have observed this mechanism of relapse and it provides important evidence that due to the delicate and complex production process every small variation can have an impact on the patient's results. . "

The patient, a 20-year-old who received CAR-T cell therapy and was manufactured by Penn as part of a Penn-sponsored clinical trial that was completed in 2016, began the highly advanced leukemia trial that had been relapsed three times before. After receipt of the modified T cells, the patient had complete remission for relapse for nine months. In about 60 percent of ALL relapses, tests show cancer cells that do not express CD19. CD19 was also undetectable in relapse in this patient. But in this case the analysis showed that the leukemic cells were positive for the CAR protein.

This study comes on the heels of another case that essentially showed the opposite situation – a patient was in remission thanks to a single CAR T cell that reproduced and controlled chronic lymphocytic leukemia (CLL).

"We learn so much from every patient, both in the success and failure of this new therapy, which helps us improve these still developing treatments so that they can benefit more patients," said J. Joseph Melenhorst, Ph.D. ., associate professor of Pathology and Laboratory Medicine and a member of Penn's Center for Cellular Immunotherapies. Melenhorst was the oldest author of this research, as well as the research that showed remission of a single cell. "This is a single case, but it is still incredibly important and can help us refine the complex processes for the production of CAR-T cell therapy to ensure the best chance of long-term remissions."

Explore further:
Clinical research suggests new cell therapy for patients with recurrent leukemia

More information:
Marco Ruella et al, Induction of resistance to chimeric antigen receptor T-cell therapy by transduction of a single leukemic B-cell, Naturopathy (2018). DOI: 10.1038 / s41591-018-0201-9

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Perelman School of Medicine at the University of Pennsylvania

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