Recurrence after CAR-T treatment? Nature Medicine Reveals the Accident Behind

Recurrence after CAR-T treatment? Nature Medicine Reveals the Accident Behind As a star product of immunotherapy, CAR-T therapy has shown great strength in blood cancer and has been approved by the FDA for the treatment of certain acute lymphoblastic leukemia (ALL) and certain types of non-Hodgkin Lymphoma. Recently, however, a research team has discovered a special case of CAR-T treatment: patients with ALL leukemia have relapsed after receiving CAR-T treatment! Moreover, they confirmed that the main cause of recurrence is a special cell, a leukemia cell carrying CARs (chimeric antigen receptor).

The study was conducted by a team led by Professor Carl H. June of the University of Pennsylvania, and the results were published in the journal Nature Medicine.

The CAR-T strategy adopted by the Carl H. June team is to alter the patient's own immune T cells, which are collected and modified in vitro using chimeric antigen receptors (CARs) to specifically recognize cancer cells. Once reinfused into the patient, these engineered T cells can target cancerous cells expressing the CD19 protein.

However, for this particular case, when manufacturing CAR-T cells, the CAR that should have modified T cells actually combined with leukemia cells! This "CAR-cancer cell" replicates in the patient and eventually causes ALL to relapse.

They analyzed that CAR on leukemia cells may allow cancer cells to mask the CD19 protein and evade immunotherapy. Moreover, leukemia cells lacking the CD19 protein are resistant to CAR-T treatment.

1. Special case: recurrence after CAR-T treatment The 20-year-old patient received a CAR-T cell therapy study from Penn in 2016 and achieved complete remission after injection of CAR-T cells. Unfortunately, 9 months after treatment, the patient relapsed and eventually died of complications associated with leukemia.

Typically, 60% of ALL recurrences show a condition in which cancer cells do not express CD19.

Now, in this case, the researchers found that CD19 was not detected in patients. However, leukemia cells are positive for CAR protein.

"We found that 100% of relapsed leukemia cells carry CAR," said Marco Ruella, assistant professor of hematology oncology at the University of Pennsylvania. Their further study found that these CAR-bearing cancerous cells are derived from a "CAR-cancer cell" that is accidentally occurring in the manufacture of CAR-T cells.

"We found this recurrence mechanism for the first time in hundreds of patients treated at the University of Pennsylvania and other institutions. It reminds us that any minor variation may have an impact on the patient's prognosis," Marco Ruella stressed.

2. Another special case In May of this year, Professor Carl H. June team also found a rare case: a patient with chronic lymphocytic leukemia treated with CAR-T therapy has been cancer free for 5 years.

Specifically, this patient has maintained a "no cancer" status for a particular CAR-T cell for 5 years after treatment, and the offspring produced by this particular T cell proliferation have been present in the patient's immune system.

They found that in this particular case, the CAR sequence (gene) was inserted into a gene called TET2. TET2 is usually responsible for regulating the formation of blood cells and controlling the growth of these cells. When the TET2 gene is destroyed (that is, after the CAR gene is inserted), the corresponding CAR-T cell will be expanded on a large scale, eventually "destroying" the patient's leukemia.

Scientists believe that both successful and failed cases deserve our in-depth study to gain experience and to benefit more patients. A single case helps us to refine the complex process of making CAR-T cells to ensure long-term relief.