Intraperitoneal adoptive immunotherapy of ovarian carcinoma with tumor-infiltrating lymphocytes and low-dose recombinant interleukin-2: a pilot trial.
A pilot study was conducted in patients who had advanced epithelial ovarian carcinoma, and who were refractory to platinum-based chemotherapy, to determine the feasibility and clinical effects of a schedule of intraperitoneal (IP) tumor-infiltrating lymphocytes (TIL) expanded in recombinant interleukin-2 (rIL-2), and low-dose rIL-2 IP. TIL were expanded from solid metastases or malignant effusions in serum-free AIM V medium supplemented with low concentrations (600 IU/ml) or rIL-2 using a four-step method of expansion that included a hollow fiber bioreactor (artificial capillary culture system). Patients received IP TIL suspended in dextrose 5% in sodium chloride 0.2% containing 0.1% human albumin and 6 x 10(5) IU rIL-2 on day 1, followed by 6 x 10(5) IU rIL-2/m2 body surface area, administered daily by bolus IP injection, on days 2-4, 8-11, and 15-18. In the absence of disease progression, two additional 4-day cycles of IP rIL-2 were administered. Patients (n = 3) whose TIL failed to grow in vitro received IP IL-2 alone. Eight patients received rIL-2 expanded TIL (10(10)-10(11) range) plus rIL-2 followed by several cycles of rIL-2 alone. One of these patients was treated twice with TIL plus rIL-2. Expanded TIL were primarily CD3+CD4+TCR alpha beta+ (eight TIL-derived T-cell lines). One TIL-derived T-cell line was comprised mostly of CD3+CD8+TCR alpha beta+ cells. Eleven patients (eight treated with TIL plus rIL-2 and three patients treated with rIL-2 alone) received a total of 38 cycles of rIL-2 without TIL. Grade 3 clinical toxicity (peritonitis) occurred in 1 of 9 cycles of TIL plus rIL-2 and 1 of 38 cycles of rIL-2 alone. Each cycle was 4 days long. Grade 3 anemia occurred in 1 of 9 TIL plus rIL-2 cycles and 3 of 38 cycles of rIL-2 alone. There were no measurable responses; however, four of eight patients treated with IP TIL plus rIL-2 had some indication of clinical activity: ascites regression (two patients), tumor and CA-125 reduction (one patient), and surgically confirmed stable tumor and CA-125 values (one patient). The schedule of IP TIL plus low-dose rIL-2 shows manageable toxicity and is worthy of further evaluation in patients with epithelial ovarian cancer who have less tumor burden.
Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston.
R S
RS
Freedman
C L
CL
Edwards
J J
JJ
Kavanagh
A P
AP
Kudelka
R L
RL
Katz
C H
CH
Carrasco
E N
EN
Atkinson
W
W
Scott
B
B
Tomasovic
S
S
Templin
D000328:Adult; D000368:Aged; D002460:Cell Line; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000637:transplantation*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000628:therapy; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
D007376:Interleukin-2; D011994:Recombinant Proteins