A team of researchers, led by Steven A. Rosenberg, M.D., at the National Cancer Institute, part of the National Institutes of Health, have found that patients with advanced melanoma who had not responded to previous therapies experienced a significant reduction in the size of their cancers as a result of receiving a new immunotherapy. This immunotherapy consisted of a combination of chemotherapy and reintroduction of their own (autologous) activated lymphocytes. Autologous lymphocytes are white blood cells that have been removed from the patient, activated or re-educated to attack the tumor, then reintroduced into the patient. The promise of this therapy is that a patient's own immune system can be used to effectively treat existing tumors. Results are reported in the April 2005 issue of the Journal of Clinical Oncology.*
"These results represent confirmation of our original findings that were published in Science in 2002," said Rosenberg. The findings published in 2002** were in an initial patient population of 13 and these new findings represent almost a three-fold increase in patient numbers.
Thirty-five patients with melanoma that had progressed throughout the body were chosen for the study. The patients had not responded successfully when treated with standard therapies and had developed growing tumors. Blood was drawn from the patients, and then lymphocytes, a type of white blood cell in the blood that can attack tumors, were separated from other parts of the blood. Next, patients were treated for two days with the chemotherapy agent cyclophosphamide followed by five days of fludarabine. The chemotherapy drugs were used to reduce the number of lymphocytes circulating in the blood, therefore reducing competition for the newly activated tumor-fighting lymphocytes being reintroduced in to the blood stream.
After the seven days of chemotherapy, the patients received their own lymphocytes that had been renewed with increased tumor-fighting capacity. They also received a high dose of Interleukin-2 (IL-2), a protein made by the body that makes the tumor-fighting cells mature and multiply.
Of the 35 patients in this study, 18 (51 percent) experienced an improvement in the amount of tumor present at diverse sites in the body: lung, liver, lymph nodes, brain and skin. Eight other patients demonstrated a mixed or minor response. Of the 18 patients showing improvement, 15 had a partial response that lasted from two months to more than two years. It is noteworthy that there were three (9 percent) patients who continued to experience complete disappearance of tumors. This result is particularly significant because these patients had not responded to standard treatments or chemotherapies used in treating patients with melanoma.
Thirteen patients relapsed after positive response to therapy and developed tumors at pre-existing or new sites within the body. There were no treatment-related deaths in this study. The loss of white blood cells, which fight infections, led to the development of infections in seven patients. Toxicities related to the chemotherapy and administration of a high dose of IL-2 were easily managed.
The results of this study prove that a combination of chemotherapy and infusion of autologous, stimulated, white blood cells can have an impact on metastatic melanoma tumors in patients who do not respond to other therapies. "The results of this study are encouraging, and suggest that some patients with melanoma who do not respond to conventional treatments may get a durable benefit from treatments based on using their own immune cells" said Mark Dudley, Ph.D., coauthor of the study.
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*Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastic melanoma. Journal of Clinical Oncology April 1, 2005; 23(10).
**Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850-854.
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