Chemoimmunotherapy in mice carrying HPV16-associated, MHC class I+ and class I- tumours: Effects of CBM-4A potentiated with IL-2, IL-12, GM-CSF and genetically modified tumour vaccines.

Abstract

The effectiveness of chemoimmunotherapy with ifosfamide derivative CBM-4A and recombinant IL-2, IL-12, GM-CSF, or genetically modified, cytokine-producing tumour vaccines was examined in mice carrying HPV16-associated, MHC class I+ (TC-1), and MHC class I- (MK16) tumours. Intraperitoneal treatment of TC-1 or MK16 tumour-bearing mice with CBM-4A produced a significant tumour-inhibitory effect. When the i.p. treatment of the MHC class I+ TC-1 tumour-bearing mice with CBM-4A was followed by peritumoral s.c. administration of IL-2, IL-12, or both cytokines, the growth of TC1 tumours was inhibited more vigorously than after the chemotherapy alone. In contrast, when the i.p. treatment ofEthe MHC class I- MK16 tumour-bearing mice with CBM-4A was followed by peritumoral s.c. administration of IL-2 or IL-12, the cytokine therapy had no potentiating effect. The only potentiating effect of the MK16 tumour immunotherapy was obtained when the i.p. CBM-4A pretreatment was followed by peritumoral s.c. administration of IL-2 plus IL-12. InEfurther experiments, the TC-1 and MK16 tumour-bearing mice were i.p. pretreated with CBM-4A and then injected s.c., peritumorally, with genetically modified, IL-2 or GM-CSF-producing MK16 tumour vaccines. Whereas both genetically modified tumour vaccines produced a substantial tumour-inhibitory effect in mice carrying TC-1 tumours, no effect of the vaccines was observed in mice carrying MK16 tumour inocula. The systemic effects of local cytokine treatment were examined in mice carrying s.c. MK16 neoplasms, which were pretreated i.p. with CBM-4A, and then injected peritumorally with IL-2 or GM-CSF. Peritumoral administration of GM-CSF had no antimetastatic effect, whereas peritumoral IL-2 administration produced substantial reduction of lung metastases. The systemic antimetastatic effect of IL-2 contrasted with the negligible effect of IL-2 on the s.c. MK16 tumour inoculum. Taken collectively, the results indicate that in mice carrying the MK16 (MHC class I-) tumour, the effects of the adjuvant cytokine therapy were substantially weaker than in mice carrying the TC-1 (MHC class I+) tumour inoculum.