PHASE-I TRIAL OF ANTI-CD3-STIMULATED CD4(-CELLS INFUSIONAL INTERLEUKIN-2, AND CYCLOPHOSPHAMIDE IN PATIENTS WITH ADVANCED CANCER() T)

Purpose: We performed a phase I trial to determine whether in vivo exp ansion of activated CD4(+) T cells was possible in cancer patients. (1 11)Indium labeling was used to observe trafficking patterns of the inf used stimulated CD4(+) T cells. The influence of cyclophosphamide (CTX ) dosing on immunologic outcome was also examined. Patients and Method s: patients with advanced solid tumors or non-Hodgkin's lymphoma recei ved CTX at 300 or 1,000 mg/m(2) intravenously (IV). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched popula tion of CD4(+) T cells was obtained by negative selection. The CD4(+) T cells were activated ex vivo with anti-CD3, cultured with interleuki n-2 (IL-2) for 4 days, and adoptively transferred. After adoptive tran sfer, patients received IL-2 (9.0 x 10(6) IU/m(2)/d) by continuous inf usion for 7 days. Results: The absolute number of CD4(+), CD4(+)/DR+, and CD4(+)/CD45RO(+) T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree o f CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients ente red the CTX-induced nadir. One complete response (CR), two partial res ponses (PRs), and eight minor responses were observed. Trafficking of (111)Indium-labeled CD4 cells to subcutaneous melanoma deposits was al so documented, Conclusion: CD4(+) T cells can be expanded in vivo in c ancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a v ariety of tumors, including melanoma and non-Hodgkin's lymphoma; a hig h percentage of patients had at least some tumor regression from the r egimen that produced the greatest CD4(+) T-cell expansion.