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 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
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regression did not occur until after cyclosporine was withdrawn.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.
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
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