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


Credit: Penn Medicine

PHILADELPHIA – A single leukemia cell, unknowingly engineered with the leukemia-targeting chimeric antigen receptor (CAR) lentivirus and infused back into a patient, was able to reproduce and cause a deadly recurrence of B-cell acute lymphoblastic leukemia (ALL). New research from the Abramson Cancer Center of 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 also ended up binding with a leukemic cell. The presence of the CAR on the leukemic cell may have given that cell the ability to hide from the therapy by masking CD19, the protein that CARs target to kill cancer. Leukemic cells without CD19 are resistant to CAR T therapy, so this single cell led to the patient's relapse. Nature Medicine published the findings today.

The treatment, developed by researchers in Penn's Perelman School of Medicine and at Children's Hospital of Philadelphia (CHOP), modifies patients' own immune T cells, which are collected and reprogrammed to potentially seek and destroy the patients' cancer cells. Once they are infused back into patients' bodies, these newly built cells both multiply and attack, targeting cells that express CD19.

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

The patient, a 20-year-old who received CAR-T cell therapy manufactured by Penn as part of a Penn-sponsored clinical trial which was completed in 2016, entered the trial with very advanced leukemia that had relapsed three times previously. After receiving the modified T cells, the patient had a complete remission for nine months before relapsing. In about 60 percent of ALL relapses, testing shows cancer cells that do not express CD19. CD19 was also not detectable at relapse in this patient. But in this case, analysis showed the leukemia cells were positive for the CAR protein.

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

"We learn so much from each patient, in both success or failure of this new therapy, that helps us improve these still-developing treatments so they can benefit more patients," said J. Joseph Melenhorst, PhD, an associate professor of Pathology and Laboratory Medicine and a member of Penn's Center for Cellular Immunotherapies. Melenhorst was the senior author on this study as well as the research showing remission from a single cell. "This is a single case, but is still incredibly important and can help us refine the intricate processes required for manufacturing CAR-T cell therapy to ensure the best chance of long-term remissions."


Penn co-authors of this study include Jun Xu, Joseph A. Fraietta, Tyler J. Reich, David E. Ambrose, Michael Klichinsky, Olga Shestova, Prachi R. Patel, Irina Kulikovskaya, Farzana Nazimuddin, Vijay G. Bhoj, Bruce L. Levine, Christopher L. Nobles, Frederic D. Bushman, Regina M. Young, John Scholler, Saar I. Gill, Carl H. June, and Simon F. Lacey. CHOP co-authors include David M. Barrett, Shannon L. Maude, and Stephan A. Grupp. Novartis co-authors include Elena J. Orlando and Hans Bitter.

Further development of this type of T-cell therapy led to the approval of Kymriah (tisagenlecleucel, formerly CTL 019), the first therapy based on gene transfer approved by the U.S. Food and Drug Administration, in August 2017 for the treatment of relapsed or refractory pediatric and young adult patients with B-cell precursor ALL. It is also approved for treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) – the most common form of non-Hodgkin's lymphoma – as well as high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

This study was supported by research funding from the Novartis Institute for Biomedical Research, the National Institutes of Health (5R01CA120409), the Society for Immunotherapy of Cancer, the American Association for Cancer Research, the Gabrielle's Angel Foundation, the Italian Society for Experimental Hematology and the Italian Leukemia Association, the ASH Scholar Award, the National Cancer Institute (1K99CA212302-01A1, P01CA214278-01, T32CA009140), and the St. Baldrick's Foundation Scholar Award.

Editor's Note: The University of Pennsylvania has licensed some technologies involved in these studies to Novartis. Some of the scientists involved in these trials are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and some of these inventors have benefitted financially and/or may benefit financially in the future. Some CHOP investigators serve or have served as consultants to Novartis to support the company's continued development of CAR T therapies. In addition, Dr. Grupp is an inventor of a process for treating toxic reactions to CAR T-cell therapy.

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