BETHESDA, MdIn a pilot study, 10 of 19 patients with advanced renal cell cancer had a response to nonmye-loablative allogeneic peripheral blood stem cell transplantation, reported Richard Childs, MD, of the National Heart, Lung, and Blood Institute.
The regressions of metastases were often striking, occurring at multiple sites in patients who had had no response to prior therapy with interleukin-2, interferon-alfa, or both, Dr. Childs said. Remarkably, all disease completely regressed in three patients, and they remained in remission 27, 25, and 16 months after transplantation.
The rationale for the approach lies in the immunogenic properties of renal cell carcinoma. Systemic cytotoxic chemotherapy is generally ineffective, but about 20% of renal cell carcinoma patients respond to immunomodulatory cytokines.
Because renal cell carcinoma appears to be susceptible to immunomodulation, we postulated that a graft-vs-tumor effect, analogous to the graft-vs-leukemia effect in hematologic cancers, might be generated after the transplantation of allogeneic lymphocytes from a healthy donor, Dr. Childs commented.
A low-intensity but highly immunosuppressive preparative regimen of cyclophosphamide(Drug information on cyclophosphamide) and fludarabine was se-lected to reduce transplant-related complications. Cyclosporine was started four days before transplant to prevent graft rejection and graft-vs-host disease (GVHD).
Between February 1998 and August 1999, the researchers, all from the National Institutes of Health, treated 19 patients with metastatic renal cell carcinoma who had suitable sibling donors (HLA identical or a mismatch at a single HLA locus). Median patient age was 48 (range, 37 to 65). All had progressive disease despite previous therapy.
The patients received a median of 8 × 106 CD34 cells/kg and 4.2 × 108 CD3 T cells/kg. All 19 patients had sustained engraftment of both donor T cell and myeloid lineages.
Three of the 19 patients had a complete response to treatment, and seven had a partial response, for an overall response rate of 53%. Regression of metastases occurred at multiple sites, including the liver, bones, and lungs (N Engl J Med 343:750-758, 2000).
Tumor regression did not occur until a median of 4 months after transplant and was seen only after all of the recipients T cells were of donor origin. In 8 of the 10 responders, metastatic regression did not occur until after cyclosporine was withdrawn.
Remarkably, in two patients the interval from transplantation to regression of metastatic disease was more than 200 days, Dr. Childs said.
Tumor regression was associated with severe acute graft-vs-host disease, occurring in 9 of 10 patients with graft-vs-host disease (grade 2-4) vs only 1 of 9 patients without severe graft-vs-host disease.
At the time of the report, nine patients were alive a median of 402 days after transplantation (range, 287 to 831 days). The three complete responders remain in remission at 16 to 27 months after transplant. Four of seven partial responders were in remission 9 to 19 months after their transplant.
The most serious complication was acute graft-vs-host disease (grade 2-4), which developed in 10 patients a median of 55 days (range, 21 to 113 days) after the transplant. The graft-vs-host disease responded to treatment in nine patients. Two patients died of transplant-related complicationsone of graft-vs-host disease and another of bacterial sepsis.
Dr. Childs and his NIH colleagues noted that although the presence of acute graft-vs-host disease (grade 2-4) was significantly associated with tumor response, it was not essential for a graft-vs-tumor effect; two patients did not have acute graft-vs-host disease when their disease regressed.
Further, some tumors regressed months after the onset of graft-vs-host disease, suggesting that the T-cell population that caused tumor regression was distinct from the population that induced graft-vs-host disease, the researchers said.
Dr. Childs stressed that the study was small with relatively short follow-up. Additional patients and more time will be required to determine the frequency and durability of the responses to allogeneic T cells, he said.
He also pointed out several limitations of the therapy, including the risk of fatal complications and the prolonged time required for tumor regression. Patients with rapidly advancing metastatic disease, who would be unlikely to live long enough for the generation of a graft-vs-tumor effect, would not benefit from such therapy, he said.