In vivo biological results of the association between interleukin-2 and interleukin-3 in the immunotherapy of cancer.
The concomitant generation of macrophage-mediated suppressive events, as documented by the increase in neopterin and soluble interleukin-2 (IL-2) receptor (SIL-2R), and the enhanced production of cortisol, would represent the most investigated phenomena responsible for the reduced anticancer efficacy of IL-2 immunotherapy in humans. Based on our preliminary experimental studies suggesting a modulatory role of IL-3 on immune and endocrine effects induced by IL-2, a study was performed to evaluate the influence of IL-3 on biological effects of IL-2 cancer immunotherapy. We have evaluated 12 immunotherapeutic courses with IL-3 plus IL-2, which were performed in 6 patients with metastatic non-small cell lung cancer. The results were compared to those seen in 22 courses with IL-2 alone, carried out in 12 patients with metastatic non-small cell lung cancer. IL-3 was given intravenously at a daily dose of 1 microgram/kg/b.w. at 6 p.m. for 14 consecutive days, starting 7 days before IL-2. IL-2 was given subcutaneously at a dose of 3 million IU twice/daily for 5 days/week for 3 weeks. The increase in serum levels of the specific macrophage marker neopterin, induced by IL-2, was completely blocked by IL-3. The IL-2-induced SIL-2R rise was significantly lower during IL-3 plus IL-2 than under IL-2 alone. The increase in cortisol levels in response to IL-2 was neutralised by IL-3. The increase in lymphocyte, T lymphocyte, natural killer (NK) cell, activated T lymphocyte and eosinophil mean number was significantly higher during IL-3 plus IL-2 than during IL-2 alone. Episodes of fever, asthenia, anorexia, vomiting, anaemia and thrombocytopenia were significantly more frequent in patients receiving IL-2 alone than in those treated with IL-3 and IL-2. This preliminary study would suggest that IL-3 may improve the tolerability of IL-2 immunotherapy and enhance the biological antitumour properties of IL-2 by neutralising cortisol increase and macrophage-mediated suppressive events, with a following potential amplification of Il-2 anticancer efficacy.
Division of Radiation Oncology, San Gerardo Hospital, Monza, Milan, Italy.
P
P
Lissoni
S
S
Barni
E
E
Tisi
F
F
Rovelli
S
S
Pittalis
R
R
Rescaldani
L
L
Vigoré
A
A
Biondi
A
A
Ardizzoia
G
G
Tancini
D000368:Aged; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000628:therapy*; D004804:Eosinophils; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D007377:Interleukin-3 / Q000627:therapeutic use*; D007958:Leukocyte Count; D008175:Lung Neoplasms / Q000097:blood / Q000628:therapy*; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D019798:Neopterin; D015375:Receptors, Interleukin-2 / Q000378:metabolism
D007376:Interleukin-2; D007377:Interleukin-3; D015375:Receptors, Interleukin-2; D001708:Biopterins; D019798:Neopterin; D006854:Hydrocortisone