Treatment of human solid malignancies with autologous activated lymphocytes and cimetidine: a phase II trial of the cancer biotherapy research group.
OBJECTIVE
The Cancer Biotherapy Research Group conducted a clinical trial to verify encouraging reports of antitumor activity of autolymphocyte therapy.


METHODS
Patients with a variety of advanced solid malignancies underwent an initial leukapheresis procedure to collect about 5 x 10(9) autologous lymphocytes that were stimulated in vitro for 3 days with anti-CD3 monoclonal antibody in the presence of indomethicin and cis-retinoic acid to obtain media that was frozen in aliquots. This media contained significant amounts of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon-gamma, and IL6, but no IL-2. Subsequently patients underwent up to 6 monthly leukaphereses to collect 2-5 x 10(9) autologous lymphocytes that were incubated in vitro for 6 days in the cryopreserved media containing autologous lymphokines, resulting in a cell population enriched for noncytotoxic T-helper lymphocytes. These were administered intravenously monthly for up to 6 months with daily oral cimetidine at a dose of 600 mg po qid, which was given throughout the treatment period. Tumor response was assessed every 2 months.


RESULTS
There were 47 patients (25 women and 22 men) with a median age of 55 years (range 31-79). One hundred seventy four treatments were delivered and were well tolerated. A mean of 2.05 +/- 1.46 (range 0.82-12.8 x 10(9)) cells were infused. Eighty-five percent received two or more doses; 19% received six doses. Objective tumor responses were observed in 1/15 renal cell, 1/13 colorectal, 0/6 breast, 0/5 lung, 0/2 gastric, 0/2 sarcoma, 0/1 pancreas, 0/1 prostate, 0/1 melanoma, and 0/1 eccrine. Forty-three patients have died. Median survival was 8.8 months, 1-year survival 35%, and 2-year survival 15%.


CONCLUSIONS
This complex treatment program was feasible. Infusion of these cells was well tolerated. Some antitumor activity was seen in patients with renal cell cancer and colorectal cancer.
Dillman
Robert O
RO
Hoag Cancer Center, Newport Beach CA 92658, USA. rdillman@hoaghospital.org
Soori
Gamini
G
DePriest
Carol
C
Nayak
Shankar K
SK
Beutel
Linda D
LD
Schiltz
Patric M
PM
de Leon
Cristina
C
O'Connor
Audrey A
AA
D019264:Adoptive Transfer / Q000009:adverse effects; D000328:Adult; D000368:Aged; D064987:Cell- and Tissue-Based Therapy; D002927:Cimetidine / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D016896:Treatment Outcome
D002927:Cimetidine