Enhanced anti-metastatic efficacy of IL-2 activated NK (A-NK) cells with novel benzothiazoles.

We have previously shown that A-NK cells when locoregionally administered accumulate within established cancer metastases and establish direct contact with both tumor cells and microvascular endothelial cells. Nevertheless, the accumulation of adoptively transferred A-NK cells into established cancer metastases is not sufficient for therapeutic efficacy in the B16 melanoma model. We have therefore attempted to enhance the anti-metastatic therapeutic efficacy of adoptively transferred A-NK cells with standard anticancer chemotherapeutic agents. We have found that chemoimmunotherapy with A-NK cells plus cyclophosphamide to be more effective than A-NK cell adoptive immunotherapy alone. We have now built on these findings, by examining the ability of novel biologic response modifiers (low molecular weight benzothiazole compounds) to augment adoptive immunotherapy with A-NK cells. Two compounds KB-R4107 (4-methoxy-2-(4-t-butylphenyl)benzothiazole) and KB-R4250 (4-methoxy-2-(4-trifluoromethylphenyl)benzothiazole) enhanced reduction of B16 melanoma pulmonary metastases mediated by A-NK cell adoptive immunotherapy. Both compounds were administered for 5 days prior to administration of A-NK cells at 100 mg/kg p.o. All experimental groups initially contained at least 7 animals and were examined for tumor burden on day 10. With B16 melanoma cells administered on day 0 and A-NK cells administered on Day 4, KB-R4107 and KB-R4250 yielded on average a 64% and 52% reduction in metastatic burden, respectively compared to an average 17% reduction using A-NK cells alone. In contrast these compounds did not diminish metastatic burden when administered alone. KB-R4107 and KB-R4250 are therefore low molecular weight, heterocyclic, biological response modifiers which can augment the anti-metastatic therapeutic effect of adoptively transferred A-NK cells.