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10/21/2002

Metastatic Cancer Succumbs to Immunotherapy

Cheryl A. Thompson

By replacing nearly all of the immune system with cells known to attack a tumor, scientists at the National Institutes of Health have shown that immunotherapy can repel aggressive metastatic cancer. The study was reported online in Science Express.1

Thirteen adults with metastatic melanoma that was unresponsive to standard therapies underwent the experimental treatment. A biopsy of each patient’s melanoma was examined in the laboratory. The tumor-infiltrating lymphocytes were isolated and compared for their propensity to attack a cell line from the patient’s tumor or a human leukocyte antigen-A2+ melanoma. Large populations of T cells were then grown from the most active tumor-infiltrating lymphocytes.

Because previous studies with highly reactive T cells had found that the transferred lymphocytes failed to persist in patients’ immune systems, this time the researchers destroyed nearly all of the original immune system by administering cyclophosphamide 60 mg/kg for two days and then fludarabine 25 mg/m2 for five days. The nonmyeloablative regimen reduced each patient’s peripheral lymphocyte and neutrophil count to less than 20/mm3. With little of their original immune system remaining, the patients received upward of 20 billion tumorspecific T cells, followed by 720,000 U/kg of interleukin-2 every eight hours for 5–12 doses, all by i.v. infusion.

The treatment produced a partial response in six patients. This response has lasted at least 24 months in the youngest patient, an 18-year-old man who entered the study with metastases in his axillary, mesenteric, and pelvic lymph nodes. Four other patients had a mixed response, with substantial shrinkage of at least one metastatic deposit. Three patients did not respond to the treatment at all.

Major adverse effects occurred in six patients. A lymphoproliferative disorder related to Epstein-Barr virus developed in one patient who was initially seronegative for the virus, and a respiratory syn cytial virus infection developed in another patient. Autoimmunity developed in five patients whose highly reactive T cells were specific for a melanocyte differentiation antigen common in melanomas: vitiligo occurred in four, including the patient with the lymphoproliferative disorder, and uveitis developed in another patient, who was treated with a corticosteroid-based ophthalmic product

  1. Dudley ME, Wunderlich JR, Robbins PF et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science [serial online]. 2002 Sept 19. (10.1126/science.1076514).