Metastatic Melanoma Succumbs to Investigational Immunotherapy

By John Gever
SEATTLE, 19 june 2008An investigational T-cell therapy obliterated all signs of disease in a man with metastatic melanoma, researchers here said. The patient appeared to be disease-free two months after infusion with an autologous CD4-positive T-cell clone, specific for the NY-ESO-1 tumor antigen, with no sign of recurrence nearly two years later, reported Cassian Yee, M.D., of the University of Washington, and colleagues in the June 19 issue of the New England Journal of Medicine. Before receiving the immunotherapy, the man had recurrent melanoma with lung and abdominal metastases. His disease had not responded to high-dose interferon-alpha, interleukin-2, and local excision, the researchers said.
The case was part of an ongoing, nine-patient clinical trial, and Dr. Yee said in an interview that results in other patients have not all been so dramatic. The effect in some of them has been limited to disease stabilization, he said.
"I don't want to overstate the significance [of the successful case]," he said.
Nevertheless, he and his colleagues said the case reflects a major advance in T-cell cancer immunotherapy.
It is the first time that a single, tumor-specific, autologous CD4 T-cell clone has been expanded in vitro into the billions of cells needed for therapeutic purposes.
That means that CD4 cell-based immunotherapies can be developed and tested more widely than was previously possible.
Because only 50% to 75% of tumor cells in the case they reported carried the NY-ESO-1 antigen, the researchers did not expect that the therapy could eliminate the entire tumor burden.
They believe the autologous T cells helped mobilize other components of the immune system to target other tumor antigens.
The researchers demonstrated that the patient also developed specific T-cell responses to the MART-1 and MAGE-3 tumor antigens, which they had not engineered into the autologous T-cell clone. These responses were not present before the treatment.
The procedure began by extracting T cells from the patient's blood and co-culturing them in vitro with autologous dendritic cells primed to recognize NY-ESO-1.
A CD4-positive T-cell clone specific for the tumor antigen was then isolated from the culture and grown until the researchers had about 5 billion identical cells.
The expansion involved restimulating and culturing the cells in a standard medium with anti-CD3 monoclonal antibodies, interleukin-2, and irradiated allogeneic lymphocytes and lymphoblastoid cells added as feeder cells.
A similar approach had previously been taken with CD8-positive T cells, for which in vitro expansion recipes are well established. But these cells do not survive more than three weeks after infusing them into patients, limiting their effectiveness, the researchers said.
In addition, CD8 cells depend on the presence of CD4 cells for their anti-tumor effect. The latter release interleukin-2 and other growth factors to create a positive feedback loop that quickly boosts the immune response.
Dr. Yee and colleagues found that the NY-ESO-1 specific T cells survived in large numbers for at least three months in the successful case, constituting about 3% of the patient's entire population of peripheral blood mononuclear cells at the last measurement.
NY-ESO-1 is a well-recognized tumor antigen found in many malignancies, including breast, ovarian, and prostate cancer.
Dr. Yee said the same treatment may be effective in these other cancers. It should also be adaptable to other tumor antigens, he said.
On the other hand, he said, developing the antigen-specific T-cell clones is currently very labor-intensive and time-consuming. It will be difficult to make the treatment available to large numbers of patients unless the process can be simplified, he said.
In an accompanying editorial, Louis M. Weiner, M.D., of Georgetown University, said the report "underscores the remarkable potential of the immune system to eradicate cancer, even when the disease is widespread."
That the study reported only a single case did not bother Dr. Weiner. "In an era when huge, randomized clinical trials are frequently required to demonstrate the efficacy of new treatments, there is still a role for an illuminating, carefully performed, and thoughtfully analyzed pilot study or case report," he wrote.
Dr. Weiner said that Dr. Yee and colleagues had laid out the principles of their immunotherapy and demonstrated clear immune-related mechanisms of action. These, he said, "point to a feasible new direction for adoptive cellular therapy of cancer."
But he cautioned that not all patients are likely to respond as well, as Dr. Yee confirmed.
"Cancers use a variety of immunosuppressive mechanisms to defeat potentially effective immune responses," Dr. Weiner wrote. "It may prove necessary to therapeutically target immune-suppression mechanisms on an individualized basis."
The study was funded by the National Institutes of Health, the General Clinical Research Center, the Edson Foundation, and the Damon Runyon Cancer Research Foundation. Dr. Yee has received support from the Burroughs Wellcome Fund. Dr. Weiner reported relationships with Amgen and Eisai.
Primary source: New England Journal of MedicineSource reference:Hunder N, et al "Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1" N Engl J Med 2008; 358: 2698-703. Additional source: New England Journal of MedicineSource reference: Weiner L, et al "Cancer immunotherapy -- the endgame begins" N Engl J Med 2008; 358: 2664-65.