Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens.
OBJECTIVE
This phase I trial assessed the safety, efficacy, and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma.


METHODS
Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for donor engraftment of myeloid and lymphoid cells, for clinical response by serial imaging, and for immunologic response by in vitro isolation of donor-derived CD8(+) CTLs recognizing recipient minor histocompatibility (H) antigens.


RESULTS
All patients achieved initial mixed hematopoietic chimerism with two patients rejecting their graft and recovering host hematopoiesis. Four patients developed acute, grade 2 to 3, graft-versus-host disease and four patients developed extensive chronic graft-versus-host disease. Five patients had progressive disease, two patients had stable disease, and one patient experienced a partial response after receiving donor lymphocyte infusions and IFN-alpha. CD8(+) CTL clones recognizing minor H antigens were isolated from five patients studied. Clones from three patients with a partial response or stable disease recognized antigens expressed on renal cell carcinoma tumor cells.


CONCLUSIONS
Treatment of metastatic renal cell carcinoma with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning with fludarabine/total body irradiation is feasible and may induce tumor regression or stabilization in some patients. CD8(+) CTL-recognizing minor H antigens on tumor cells can be isolated posttransplant and could contribute to the graft-versus-tumor effect. Such antigens may represent therapeutic targets for posttransplant vaccination or adoptive T-cell therapy to augment the antitumor effects of allogeneic hematopoietic cell transplantation.
Tykodi
Scott S
SS
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA.
Warren
Edus H
EH
Thompson
John A
JA
Riddell
Stanley R
SR
Childs
Richard W
RW
Otterud
Brith E
BE
Leppert
Mark F
MF
Storb
Rainer
R
Sandmaier
Brenda M
BM
D018262:Adenocarcinoma, Clear Cell / Q000276:immunology / Q000556:secondary / Q000628:therapy; D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002291:Carcinoma, Papillary / Q000276:immunology / Q000556:secondary / Q000628:therapy; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D020350:Graft vs Tumor Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000276:immunology*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014916:Whole-Body Irradiation / Q000009:adverse effects
D000951:Antigens, Neoplasm; D015778:Minor Histocompatibility Antigens; D016572:Cyclosporine; D014740:Vidarabine; D009173:Mycophenolic Acid; C024352:fludarabine