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Engineered T-Cells Get Leukemia Response

Human T-cell lymphocyte

Scanning electron micrograph of a human T-cell lymphocyte (National Institute of Allergy and Infectious Diseases, NIH)

(6 June 2016) An early-stage clinical trial testing genetically engineered T-cells from the immune system, shows the treatments are effective against a form of leukemia when combined with chemotherapy drugs. Results of the trial were reported by study leader Jae Hong Park of Memorial Sloan Kettering Cancer Center on 4 June at a meeting of American Society for Clinical Oncology in Chicago.

The study tested treatments by the company Juno Therapeutics in Seattle, for persistent B cell acute lymphoblastic leukemia, a cancer of blood and bone marrow that progresses quickly, making an overabundance of immature lymphocytes, a type of white blood cell. It is the most common type of cancer among children, although it can also affect adults.

The treatments, code-named JCAR015 by Juno, harness the cancer-fighting ability of a patient’s own T-cells, white blood cells in the immune system, engineered with a gene adding molecules known as chimeric antigen receptors to their DNA. Without these added weapons, cancerous cells evade the immune system, allowing tumors to grow unchecked.

The chimeric antigen receptors added to T-cells, called CAR-Ts, are designed in this case to attack cancer cells identified with specific CD19 proteins. These CD19 molecules act as indicators of weakened B-cells in the immune system found with blood-related cancers. The modified T-cells are then infused back into the patient.

In the clinical trial, 51 adults with refractory or relapsed acute lymphoblastic leukemia at Memorial Sloan Kettering took part, 31 individuals with a morphological condition (observable changes in cells), and 20 with a minimal level of the disease. Participants first received chemotherapy with the standard leukemia drug cyclophosphamide or a combination of cyclophosphamide and another drug, fludarabine to improve the reception to T-cell treatments. The study looked primarily at the safety of the treatments, but also tracked evidence of treating the disease.

The results show 23 of the 31 participants with a morphological condition and 18 of 20 individuals with a minimal disease condition experienced a complete response, or disappearance of all signs of the leukemia, after a median follow-up time of 8.5 months. Of the patients achieving a complete response, complete molecular remission occurred in 19 patients with morphological conditions and 14 patients with minimal disease.

The median overall survival time for all participants was 13 months, with 9 months median overall survival for those with a morphological condition. Survival times and responses to the treatments were about the same for people in the study who later received stem cell transplants, as those who did not get transplants.

Sizeable numbers of participants, however, experienced adverse reactions. About a quarter (27%) experienced severe cytokine release syndrome that occurs when enzymes are emitted from cells targeted by treatments, which can cause flu-like symptoms such as fevers, nausea, and muscle pain, as well as neurological symptoms including hallucinations and delirium. In addition, 29 percent reported severe or disabling neurological toxicity reactions of grade 3 or higher, such as sensory loss, motor weakness, or paralysis.

Juno Therapeutics is a spin-off company from from Fred Hutchinson Cancer Research Center in Seattle, Memorial Sloan-Kettering Cancer Center in New York, and Seattle Children’s Research Institute. The company is now recruiting participants for an intermediate-stage trial of JCAR015 with refractory or relapsed acute lymphoblastic leukemia.

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