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

October 1, 2018, Perelman School of Medicine at the University of Pennsylvania
CAR T Cells ready for infusion. Credit: Penn Medicine

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' . 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 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 (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, Ph.D., 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."

Explore further: Clinical trial suggests new cell therapy for relapsed leukemia patients

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

Related Stories

Clinical trial suggests new cell therapy for relapsed leukemia patients

November 20, 2017
A significant proportion of children and young adults with treatment-resistant B-cell leukemia who participated in a small study achieved remission with the help of a new form of gene therapy, according to researchers at ...

Chronic lymphocytic leukemia patient goes into remission thanks to single CAR T cell

May 30, 2018
The doctors who have spent years studying the case call it "a series of fortunate events." What began as a remarkable response to chimeric antigen receptor (CAR) T cell therapy is now providing evidence about the human genome ...

New CAR T case study shows promise in acute myeloid leukemia

May 9, 2018
Chimeric Antigen Receptor T-cell therapy, also known as CAR T therapy, was named the biggest research breakthrough of 2017 by the American Society of Clinical Oncology. The personal gene therapy utilizes a patient's own immune ...

T cell biomarker predicts which CLL patients will respond to CAR T cell therapy

April 30, 2018
Penn Medicine researchers may have found the reason why some patients with advanced chronic lymphocytic leukemia (CLL) don't respond to chimeric antigen receptor (CAR) T cell therapy, and the answer is tied to how primed ...

Seattle Children's opens CD22 CAR T-cell immunotherapy trial for children and young adults

July 27, 2017
After seeing promising results in phase 1 of the Pediatric Leukemia Adoptive Therapy (PLAT-02) trial with 93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) achieving complete initial remission, ...

For first time in 40 years, cure for acute leukemia within reach

August 24, 2018
Acute myeloid leukemia is one of the most aggressive cancers. While other cancers have benefitted from new treatments, there has been no encouraging news for most leukemia patients for the past 40 years. Until now.

Recommended for you

Combining three treatment strategies may significantly improve melanoma treatment

December 12, 2018
A study by a team led by a Massachusetts General Hospital (MGH) investigator finds evidence that combining three advanced treatment strategies for malignant melanoma—molecular targeted therapy, immune checkpoint blockade ...

Lethal combination: Drug cocktail turns off the juice to cancer cells

December 12, 2018
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth—this was discovered by researchers from the University of Basel's Biozentrum two years ago. In a follow-up study, ...

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

Researchers use computer model to predict prostate cancer progression

December 12, 2018
An international team of cancer researchers from Denmark and Germany have used cancer patient data to develop a computer model that can predict the progression of prostate cancer. The model is currently being implemented ...

An integrated approach to finding new treatments for breast cancer

December 12, 2018
Unraveling the complexity of cancer biology can lead to the identification new molecules involved in breast cancer and prompt new avenues for drug development. And proteogenomics, an integrated, multipronged approach, seems ...

New insight into stem cell behaviour highlights therapeutic target for cancer treatment

December 12, 2018
Research led by the University of Plymouth and Technische Universität Dresden has identified a new therapeutic target for cancer treatment and tissue regeneration – a protein called Prominin-1.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.