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Melanoma Mets Regress After Gene Therapy

Melanoma Mets Regress After Gene Therapy

BETHESDA, Maryland—Two of 15 patients with metastatic melanoma had tumor regression after treatment with genetically modified peripheral blood lymphocytes (PBLs), Richard A. Morgan, PhD, and his colleagues from the NCI's Surgery Branch, Center for Cancer Research, reported in Science Express (published online 31 August 2006; 10.1126/science.1129003). "These results represent the first time gene therapy has been used successfully to treat cancer," said Elias Zerhouni, MD, NIH director. "Moreover, we hope it will be applicable not only to melanoma but also for a broad range of common cancers, such as breast and lung cancer."

The researchers, led by Steven A. Rosenberg, MD, PhD, had previously shown that adoptive transfer of autologous tumor-specific T cells, expanded ex vivo and given after host immunodepletion, led to responses in metastatic melanoma patients, but this approach is limited because many cancer patients do not have pre-existing tumor-specific T cells. To overcome this, the researchers set out to genetically modify normal peripheral blood lymphocytes (PBLs).

PBLs were transduced with the genes encoding the alpha and beta chains of the anti-MART-1 T cell receptor (TCR). These genes were cloned from a tumor-infiltrating lymphocyte (TIL) clone obtained from a metastatic melanoma patient who had a near-complete regression after adoptive TIL transfer. A retroviral vector was constructed to express the MART-1 TCR alpha and beta chains.

The engineered T cells were tested in 17 patients with progressive metastatic melanoma refractory to prior therapy with IL-2. All patients treated in the second and third of three cohorts (all with slightly different protocols) showed persistence of the transduced cells at more than 9% at 1 and 4 weeks after treatment. There were no toxicities attributed to the treatment. "Most importantly, two patients demonstrated a sustained objective regression of their metastatic melanoma assessed by standard RECIST criteria," Dr. Morgan said. One patient had a complete regression of the axillary mass and an 89% reduction of a liver mass, which was resected. "He remains clinically disease free at 19 months after treatment," he said. The second patient had a regression of a hilar mass and is clinically disease free 18 months later.

 
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