Recurrence After CAR-T Treatment? The Nature Medicine Reveals the Unexpected Behind

As a star product of immunotherapy, CAR-T therapy has shown tremendous strength in blood cancer and has been approved by FDA for the treatment of some acute lymphoblastic leukemia (ALL) and specific types of non-Hodgkin's lymphoma. Recently, however, a research team found a special case of CAR-T treatment: ALL leukemia patients reappealed after CAR-T treatment! Moreover, they confirmed that the culprit for recurrence was a special cell, leukemia cells carrying CARs (chimeric antigen receptors). 

Recurrence After CAR-T Treatment? The Nature Medicine Reveals the Unexpected Behind

The study was led by Professor Carl H. June of the University of Pennsylvania, a "bull" in the CAR-T field, and published in the Journal Nature Medicine. 

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

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

They analyzed that CAR on leukemia cells might enable cancer cells to hide CD19 proteins, thereby avoiding treatment. Moreover, leukemia cells lacking CD19 protein are resistant to CAR-T treatment. 

1. Special cases: recurrence after CAR-T treatment
The 20-year-old patient underwent a study of CAR-T cell therapy in Pennsylvania in 2016 and was completely relieved after injection of CAR-T cells. Unfortunately, nine months after treatment, the patient relapsed and eventually died of complications associated with leukemia. 

Typically, 60% of ALL recurrences show that cancer cells do not express CD19. Now, in this case, the researchers found that CD19 was also undetectable in patients. However, leukemia cells were positive for CAR protein. 

"We found that 100% of recurrent leukemia cells carry CAR." Marco Ruella, assistant professor of Hematology and oncology at the University of Pennsylvania, said. They further found that the carcinogenic cells carrying CAR originated from a "CAR-cancer cell", which was accidental in the production of CAR-T cells. 

"We found this relapse mechanism for the first time among hundreds of patients treated at the University of Pennsylvania and other institutions, which reminds us that any small variation may have an impact on the prognosis of patients." Marco Ruella emphasized. 

2. Another special case
In May, Professor Carl H. June's team also found a rare case: a patient with chronic lymphoblastic leukemia who had received CAR-T therapy had been cancer-free for five years. 

Specifically, the patient maintained a "cancer-free" state for five years after the treatment of a special CAR-T cell, and the offspring produced by the proliferation of this special T cell 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 their growth. When the TET2 gene is destroyed (i.e. when the CAR gene is inserted into it), the corresponding CAR-T cells will expand on a large scale and eventually "eradicate" the patient's leukemia. 

Scientists believe that both success and failure cases deserve our in-depth study and experience, so as to benefit more patients. A single case will help us improve the complex process of manufacturing CAR-T cells to ensure long-term remission. 

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