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Engineered T-Cells Get High Leukemia Remission in Trial

Acute myeloid leukemia cells

Acute myeloid leukemia cells (Cancer Genome Atlas, NIH)

28 April 2016. A clinical trial shows engineered immune-system cells transplanted in patients with one form of leukemia achieves a 93 percent remission rate. Results of the trial, at the Fred Hutchinson Cancer Research Center in Seattle, were reported in the 25 April issue of The Journal of Clinical Investigation.

Fred Hutchinson Center researchers were testing the cancer-fighting ability of T-cells, white blood cells in the immune system, engineered with added synthetic molecules known as chimeric antigen receptors. 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, were 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 CAR-T technology developed at the Fred Hutchinson Center is licensed to a spin-off company Juno Therapeutics, founded in 2013 with researchers at Memorial Sloan-Kettering Cancer Center in New York, and Seattle Children’s Research Institute. Juno is a sponsor of this clinical trial, with several of the authors supported by or with equity stakes in the company.

In the CAR-T process, blood cells are extracted from cancer patients and their T-cells with the required genetic sequences in the cells’ DNA are separated for enrichment. The T-cells are then grown in the lab into dosage quantities for infusion back into the patient. In the body, the engineered T-cells multiply in the presence of targeted proteins, in this case CD19 proteins, and attack their corresponding tumor cells.

The clinical trial recruited 32 patients with relapsing or 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 also the most common type of cancer among children, although it can also affect adults. Two of the individuals developed complications from prior treatments, leading to one death. The 30 remaining participants received a form of chemotherapy that enhances immune-system response against cancerous cells, before receiving the engineered T-cells.

Of the 30 individuals, 29 still had leukemia cells in their bone marrow following the chemotherapy and CAR-T treatments. After 3 weeks, 27 of these 29 participants had no detectable leukemia in their bone marrow, according to flow cytometry tests that use lasers to identify fluorescent-labeled cells. This remission of leukemia occurred at all dosage levels tested. The treatments also removed cancer that spread to other parts of the participants’ bodies.

The results, however, were not uniformly favorable. Five of the 27 remission patients later relapsed, some of which did not respond to a second CAR-T therapy. In addition, many of the participants experienced 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.

The research team plans to follow-up with the patients over a 15-year period, as required by FDA for gene therapies. Further trials testing CAR-T therapies with other forms of acute lymphoblastic leukemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia are also recruiting patients.

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