Preclinical and early clinical trial with mafosfamide as immune modulator.
Low doses of cyclophosphamide (CPA) modulate immune responses and induce complete tumor regression and cures in mice. The mechanism of action is related to the development of a T-cell-dependent immune reaction. We started a trial with mafosfamide (MAF), the active metabolite of CPA and found that the response of Ehrlich ascites-tumor (EAT) cells in vivo to this compound is biphasic. The highest cure rate (70%) is obtained with a low i.p. dose of 7 mg/kg/d. Hematologic side effects were not observed. Arguments for an immune mechanism involved are that (1) mice treated with MAF showed a statistically significant increase in spleen weight compared with untreated controls, (2) after treatment large numbers of mononuclear cells appeared in the ascites, and (3) long-term surviving mice were resistant to further challenge with large inocula of EAT. We started a pilot trial in patients with metastasizing and advanced renal cell carcinoma - a disease which can be considered to be influenced by the immunologic response of the tumor host. The starting dose of MAF was 24 mg/m2/d administered i.v. Therapy was repeated at 14 days interval on an out-patient basis. Monitoring of mononuclear cells in the peripheral blood with monoclonal antibodies using a FACS IV were performed two times a week. There are eleven patients on study. Up to now, four out of them have been fully evaluated with respect to toxicity, immune modulation and tumor response. With respect to response to treatment, 2 patients had no change of disease, 1 patient had a mixed and 1 patient a partial response. No hematological or other toxicities could be observed. All patients showed an increase in monocytes/macrophages as well as NK-cells--clearly related to therapy.
Klein
H O
HO
I. Medical Clinic, University of Cologne, Köln, F.R.G.
Kreysch
H G
HG
Coerper
C
C
Voigt
P
P
Ruff
I
I
D000276:Adjuvants, Immunologic; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal; D001202:Ascitic Fluid / Q000166:cytology; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D004341:Drug Evaluation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008970:Molecular Weight; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; C048341:mafosfamide; D003520:Cyclophosphamide