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

We have previously shown that A-NIC cells when locoregionally administered accumulate within established cancer metastases and establish direct contac t with both tumor cells and microvascular endothelial cells. Nevertheless, the accumulation of adoptively transferred A-NK cells into established canc er metastases is not sufficient for therapeutic efficacy in the B16 melanom a model. We have therefore attempted to enhance the anti-metastatic therape utic efficacy of adoptively transferred A-NK cells with standard anticancer chemotherapeutic agents. We have found that chemoimmunotherapy with A-NK c ells plus cyclophosphamide to be more effective than A-NK cell adoptive imm unotherapy alone. We have now built on these findings, by examining the abi lity of novel biologic response modifiers (low molecular weight benzothiazo le compounds) to augment adoptive immunotherapy with A-NK cells. Two compou nds KB-R4107 (4-methoxy-2- (4-t-butylphenyl)benzothiazole) and KB-R4250 (4- methoxy-2- (4-trifluoromethylphenyl)benzothiazole) enhanced reduction of B1 6 melanoma pulmonary metastases mediated by A-NK eel! adoptive immunotherap y. Both compounds were administered for 5 days prior to administration of A -NI : cells at 100 mg/kg p.o. An experimental groups initially contained at least 7 animals and were examined for tumor burden on day 10. With B16 mel anoma 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 weig ht, heterocyclic, biological response modifiers which can augment the anti- metastatic therapeutic effect of adoptively transferred A-NK cells.