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Based on our clinical findings that the ability of cancer patients to generate lymphokine-activated killer (LAK) cells was remarkably augmented after mitomycin C (MMC) administration, we designed a treatment regimen that consisted of MMC 12 mg/m2, i.v. on day 1 and recombinant interleukin-2 (IL-2) 700 U/m2, i.v. every 12 hr from day 4 through day 8. Of 29 patients with advanced carcinoma treated with this regimen, 10 had a partial response (PR) and 4 had a minor response. The correlation of hematological and immunological changes associated with this treatment with the antitumor response to this therapy was investigated. Pretreatment values of total white blood cell and lymphocyte counts, and the level of increase of eosinophil counts in responder patients who showed a PR, were significantly greater than those in nonresponder patients. However, there was no correlation between clinical response and cytotoxic activities of peripheral blood mononuclear (PBM) cells, including NK and LAK activity, and the ability to generate LAK cells after the treatment. The capacity of adherent cells in PBM to produce IL-1-beta was increased after the treatment in both responders and nonresponders, whereas IL-1-alpha production was not increased. In addition, a significant increase in the ability to produce TNF-alpha was observed only in responders, indicating the correlation of TNF-alpha production with clinical response to this therapy. Since these correlations had been reported in the previous studies using IL-2, the present results suggested that the therapeutic effectiveness of this therapy against advanced carcinoma, is due to IL-2 probably augmented by its combination with MMC. In addition, these parameters might be predictive of therapeutic efficacy of this treatment.

On the basis of our clinical findings that the ability of cancer patients to generate lymphokine-activated killer cells became markedly augmented after mitomycin C administration, we designed a treatment regimen comprising mitomycin C 12 mg/m2, i.v. on day 1 and recombinant interleukin-2 700 U/m2 (8000 IU/kg), i.v. every 12 h from day 4 through day 8. The treatment course was repeated at almost 7-day intervals. Altogether 33 patients with advanced carcinoma, including mainly gastrointestinal carcinoma, were treated with this regimen. Of these, 10 had a partial response (PR) and 4 had a minor response (MR). Since eosinophil counts peaked 1 day after either the first or second course of the therapy, the posttreatment values were compared to each pretreatment level, with regard to the clinical antitumor response to this treatment. When patients who showed PR were defined as responders, absolute eosinophil counts and the percentage of eosinophils in responders after both the first and second courses of the therapy were significantly greater than each pretreatment value or the posttreatment level in nonresponders. Further, these findings were almost identical, when both PR and MR were considered to be a true remission and therefore patients who exhibited PR or MR were defined as responders, although the difference between posttreatment levels of eosinophils in responders and nonresponders was not significant at the second course. These results indicate that eosinophilia induced by this treatment correlates with the clinical response to this therapy.

The effect of Adriamycin on the generation of cell-mediated cytotoxicity in the mixed cell culture was studied in patients with various carcinomas. Peripheral blood mononuclear cells (PBM) from the patients were cultured with the B-lymphoblastoid cell line Raji in mixed culture, and the induced cytotoxicity was measured by 51Cr release assay. In patients with various carcinomas, the capacity of PBM to be converted to cytotoxic cells was significantly augmented 5, 7, and 10 days after a single dose of 25 mg/sq m i.v., when compared to that of PBM obtained before Adriamycin injection. The peak level of the cytotoxicity observed 7 days after injection was more than 2-fold higher than that before treatment. Although the depletion of adherent cells from PBM either before or after treatment resulted in a decreased cytotoxic response, nonadherent cell fractions as well as unfractionated cells from PBM after drug treatment equally showed an augmented response when compared to that before injection. The distribution of T-cell subsets exhibited a significant increase in the percentage of OKT8 positive cells after administration. Furthermore, PBM obtained after treatment produced significantly higher levels of interleukin 2. The results appear to indicate that the imbalance of T-cell subsets and the increase of interleukin 2 production may be related to the augmenting effect of Adriamycin administration on cytotoxic response in cancer patients.

Effect of mitomycin C (MMC) administration on the generation of cytotoxic cells induced by in vitro activation of peripheral blood mononuclear cells (PBM) with OK-432, a bacterial immunopotentiator, was studied in patients with various carcinomas. Following i.v. injection of a single dose of 12 mg/m2 MMC, the ability of PBM to generate OK-432 activated killer cells was markedly increased. Thus, the cytotoxic activity observed 7 days after MMC administration was significantly augmented as compared to that before treatment. Therefore, the ability to generate lymphokine activated killer (LAK) cells was examined, and significantly increased capacity was observed 5 and 7 days after MMC injection. Then, the OK-432 activated killer cell activity significantly correlated with the LAK activity. After treatment, the distribution of lymphocyte subsets exhibited a significant decrease in the percentage of OKT8+ cells. Leu-11+ cells were also reduced. The results appear to indicate that the imbalance in T-cell subsets and the increase in the ability to induce LAK cells may be related to the augmenting effect of MMC administration on the generation of OK-432 activated killer cells in cancer patients.

The effect of mitomycin C administration on the generation of cytotoxic cells, induced by in vitro activation of peripheral blood mononuclear cells (PBM) with interleukin-2, was studied in patients with various carcinomas. The ability of PBM to generate lymphokine-activated killer (LAK) cell activity against Raji cell targets was significantly augmented 5 and 7 days after a single intravenous dose of 12 mg/m2 mitomycin C, when compared to that of PBM obtained before mitomycin C injection. Further, LAK cell activity against autologous tumor cells was also significantly increased after the drug administration. The distribution of lymphocyte subsets exhibited a significant increase in the percentage of CD3+ cells after injection, with the elevation of the CD4/CD8 ratio. Furthermore, the proportion of the CD4+ Leu8+ subpopulation, which identifies inducers of suppression, was significantly reduced. Thus, the decrease in the proportion of suppressor-inducer subsets of PBM might be at least partially, responsible for the augmented generation of LAK cells after mitomycin C administration.