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Engineered T-Cells Show Extended Leukemia Remission

Acute lymphoblastic leukemia cells

Acute lymphoblastic leukemia cells (Christaras A, Wikimedia Commons)

1 February 2018. A clinical trial shows a patient’s immune system cells, modified to add cancer-fighting proteins, can extend high remission among children with a type of leukemia for as long as 12 months, but also with high rates of adverse effects. Results of the trial testing the therapy tisagenlecleucel, made by pharmaceutical company Novartis, appear in today’s issue of New England Journal of Medicine (paid subscription required).

The intermediate-stage clinical trial is testing tisagenlecleucel — marketed as Kymirah by Novartis and approved by FDA — among children and young adults up to age 25, with relapsed or recurring B-cell acute lymphoblastic leukemia. This type of leukemia is a cancer of blood and bone marrow that progresses quickly, making an overabundance of immature lymphocytes, a type of white blood cell. It is also the most common type of cancer among children, although it can affect adults as well. The patients’ leukemia in this case also expresses a characteristic protein known as CD19 that acts as a target for the treatments.

Tisagenlecleucel treatments start with a sample of an individual’s blood cells, where T-cells from the immune system are separated out, then reprogrammed with genetic engineering to find and kill cancer cells. The engineered T-cells become hunter cells, containing a protein known as chimeric antigen receptor that acts like an antibody.

These modified chimeric antigen receptor or CAR T-cells are infused back into the patient, seeking out and binding to CD19 found on the surface of B cells — another immune-system blood cell — associated with several types of blood-related cancers. Among the properties programmed into tisagenlecleucel is the ability of hunter cells to quickly multiply and accumulate to battle the cancer cells.

The trial enrolled 92 patients at 25 sites in North America, Europe, Japan, and Australia, of which 75 completed the trial. Some 17 participants had to discontinue the trial before infusion of the modified T-cells because of the rapid progression of their disease, while the T-cells from another 7 patients failed to generate due to poor cell growth. In December 2016, Science & Enterprise reported on early results from 29 participants, showing an 83 percent with complete remission, but also high rates of adverse effects.

The new study, led by Stephan Grupp, director of cancer immunotherapy at Children’s Hospital of Philadelphia, continues to show high rates of remission for the 75 participants. After 3 months, 61 of the 75 participants, or 81 percent, show complete remission of their leukemia. Among these 61 participants, 80 percent were relapse-free after 6 months, and 59 percent after 12 months. Overall survival rates among all participants were 90 percent after 6 months and 76 percent after 12 months. Blood tests show tisagenlecleucel still present in participants as long as 20 months following infusion.

As seen in earlier trials of CAR T-cell treatments, however, large percentages of participants in this study report adverse effects, most of them severe. Nearly 3 in 4 (73%) participants reported adverse effects considered severe or life-threatening. The most common adverse effect (77%) was cytokine release syndrome that occurs when enzymes are emitted from cells targeted by treatments, causing flu-like symptoms such as fevers, nausea, and muscle pain, with nearly half (47%) requiring intensive care. Neurological effects were also reported in 40 percent of participants, which occurred within 8 weeks of infusion and the authors say were managed with supportive care.

Also reported in Science & Enterprise, Novartis licensed the technology behind the treatments in 2012 from University of Pennsylvania, which conducted the original research. Children’s Hospital of Philadelphia is affiliated with UPenn’s medical school.

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