Lowering upfront transplant toxicity has spun off an encouraging sidestream: using the graft-versus-tumor effect to treat otherwise unresponsive solid tumors.
While various teams of researchers refine low-dose transplants for leukemias and lymphomas, Richard Childs, M.D., and colleagues at the National Heart, Lung, and Blood Institute in Bethesda, Md., report early success using similar transplants for advanced kidney cancer patients.
Primary tumors as well as bone and lung metastases disappeared in three of the first 19 patients treated on Childs study. Seven others had partial remissions, adding up to a 53% response rate, a remarkable achievement against a cancer that has a median survival of 12 to 18 months and has a 5-year-survival rate under 5%.
The first patient treated, a 50-year-old man, is alive and well 2 years after an allogeneic stem cell transplant from a matched sibling. Previous inteferon-alfa therapy did not dent his tumors, leaving the man and his doctors few options. Before the transplant, he received 2 days of cyclophosphamide and 5 days of fludarabine to suppress his immune system and allow the graft to take. After the transplant, which delivered tens of millions of blood stem cells and immune T cells, he received cyclosporine until the threat of graft-versus-host disease had passed.
Slowly building strength over 4 months, the mans new immune system pushed against his cancer. At first, it seemed to be doing nothing. But at day 60 after transplant the tumors began shrinking, at day 110 the CAT scans showed no evidence of tumor, and at day 200 all bone metastasis was gone. The man returned to work 8 months after treatment and continues showing no signs of recurrence.
The other patients who did well had similar response patterns: No regressions occurred while donor T cells increased in number; a complete immune system reconstitution to 100% donor T cells occurred at 30 to 60 days; and finally, anti-tumor effects appeared around 4 months post-transplant. With this lag time for the graft-versus-tumor effect to start working, patients with very limited life expectancy are unlikely to benefit from the treatment. In fact, this lag-time liability possibly accounted for the deaths of eight melanoma patients on the study, all of whom had fast-growing disease that outran the graft-versus-tumor effect, Childs said in a presentation to NIH scientists this spring.
Childs chose to test kidney cancer and melanoma because earlier research sketched these tumors as immuno-responsive. A few case reports had described spontaneous remissions of both types of cancer, presumably after the patients own immune system kicked into gear. And both cancers can respond to interferon and interleukin 2, which enhance T cells cell-killing abilities. "The fact that renal tumors spontaneously remit at all is evidence that the immune system is at work here," said Childs.
But exactly what cellular targets the donors T cell home in on remains unclear, a point to be investigated with diligent lab work. Once these antigens are identified, the donors T cells could be supercharged in vaccine-like fashion, a maneuver that Childs hopes would speed response times and increase overall effectiveness.
|
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |