Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma.
OBJECTIVE
CD4(+)CD25(+) regulatory T (T(reg)) cells are present in increased numbers in patients with advanced cancer and CD25(+) T cell depletion potentiates tumour immunity in animal models. The aim of this study was to assess the feasibility and safety of adoptive transfer of CD25(+) depleted autologous T cells in patients with advanced renal cell carcinoma and to examine resulting changes in lymphocyte subsets.


METHODS
Six patients with advanced renal cell carcinoma underwent leukapheresis followed by conditioning chemotherapy with cyclophosphamide and fludarabine. The autologous leukapheresis product was depleted of CD25(+) cells using CliniMACS System then re-infused into the patient.


RESULTS
Efficient CD25(+) depletion from all leukapheresis products was achieved and 0.55-5.87 x 10(7)/kg CD3(+) cells were re-infused. Chemotherapy related haematological toxicity was observed, but blood counts recovered in all patients allowing discharge after a mean inpatient stay of 21 days. One patient subsequently developed a rapidly progressive neurological syndrome. A transient reduction in CD25(+) subset was noted in the peripheral blood of 5 out of 6 patients with evidence of increased T cell responses to PHA in 4 out of 6 patients. One patient showed increased specific proliferative responses to the tumour associated antigen h5T4 coinciding with the nadir of T(reg) cells.


CONCLUSIONS
Given the transient nature of the reduction in CD25(+) subset and the observed toxicity there is a need to explore further strategies to improve the safety and efficacy of this approach. Nevertheless, the results provide proof of concept in potentiation of tumour antigen T cell responses when T(reg) cell levels are depleted.
Thistlethwaite
Fiona C
FC
Cancer Research UK Department of Medical Oncology, University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK. fthistlethwaite@PICR.man.ac.uk
Elkord
Eyad
E
Griffiths
Richard W
RW
Burt
Deborah J
DJ
Shablak
Alaaeldin M
AM
Campbell
John D M
JD
Gilham
David E
DE
Austin
Eric B
EB
Stern
Peter L
PL
Hawkins
Robert E
RE
D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007680:Kidney Neoplasms / Q000628:therapy*; D007937:Leukapheresis; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory; D014182:Transplantation, Autologous
D017252:CD3 Complex