Synergistic antitumour effects of chemo-immunotherapy with an oxazaphosphorine drug and IL-2-secreting cells in a mouse colon cancer model.
The therapeutic efficacies of two chemical agents-cyclophosphamide (CY) and compound CBM-11-were compared in a chemo-immunotherapy protocol combining a single injection of a cytotoxic agent with a series of weekly peritumoural (p.t.) administrations of non-tumourigenic plasmocytoma cells engineered to produce interleukin-2 (IL-2). Compound CBM-11, an optically active S(-) isomeric form of a bromine-substituted analogue of ifosfamide, is currently used in Phase I clinical trials in Poland. The treatment was applied to mice bearing well-established subcutaneous (s.c.) MC-38 colon tumours. Single intraperitoneal injection of 200 mg/kg of CY or of an equitoxic dose of 140 mg/kg of CBM-11 alone resulted in a tumour growth delay (TGD) of 10-13 and 17-21 d, respectively. This effect was accompanied by an increase in life-span (ILS) of at most 42 and 62% over control. Complete responses (CR) were not observed. Combination of CY or CBM-11 with 6-7 p.t. injections of IL-2-secreting cells resulted in potentiation of the therapeutic effects: TGD and ILS values were considerably increased and long-lasting CRs were observed. The overall incidence of CR after combined treatment was ca 16% and 42% for CY and CBM-11, respectively (P=0.049). A specific anti-MC-38 immunity was induced by the treatment, as verified by rechallenge of cured mice with MC-38 tumour cells 3-4 months post therapy cessation. Our results indicate that tumour destruction by chemotherapy (even if not complete) and prolonged local delivery of IL-2 secreted by allogeneic cells of an easy to culture line are sufficient to secure long-lasting specific antitumour immunity in cured mice.
Kusnierczyk
H
H
Department of Tumour Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. hkusnier@immuno.iitd.pan.wroc.pl
Pajtasz-Piasecka
E
E
Radzikowski
C
C
D000230:Adenocarcinoma / Q000188:drug therapy / Q000628:therapy*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D007376:Interleukin-2; D003520:Cyclophosphamide; C073801:bromofosfamide; D007069:Ifosfamide