Viruses of the respiratory tract in Filipinos I. Para influenza types 1 and 3

In 279 serums of young adults with ages ranging from 12 to 24 tested by HI against para influenza types 3 and 1 viruses, incidence rates of 76% and 25% were obtained respectively after 20% had been deducted from each of the rates due to heterotypic responses. This is very suggestive of a widespread infection due to para influenza 3 in the Philippines. (Summary)

Enhancement of complement-dependent cytotoxicity by polyvalent melanoma cell vaccine (CancerVax): correlation with survival.

BACKGROUND: Case control studies have demonstrated that administration of CancerVax, a polyvalent melanoma cell vaccine (PMCV), after complete resection of melanoma metastases produces a significant improvement in disease-free survival (DFS). Because PMCV has no direct cytotoxic effect on melanoma cells, the authors hypothesized that it prolongs survival by enhancing antibody-mediated antimelanoma cytotoxicity. METHODS: One hundred melanoma patients participating in a trial of PMCV adjuvant therapy following complete resection of regional node metastases were randomly selected for study. Serum samples obtained immediately before (T0) and 4, 8, 12, and 16 weeks after initiation of PMCV adjuvant therapy were adsorbed with L-14 lymphoblastoid cells and then tested for in vitro complement-dependent cytotoxicity (CDC) against M-14 cells, a melanoma cell line not used in PMCV. CDC was expressed as percentage of total cells (n = 10,000) killed. Survival curves were estimated by the Kaplan-Meier method. Statistical analysis was performed by the signed rank sum test, Spearman test, log-rank test, and Cox proportional hazard regression. RESULTS: Median CDC at T0 was 4.5% (range, 0% to 40%). Within 16 weeks after initiation of PMCV therapy, CDC had increased in 82 (82%) patients. The median increase of 7.5% (range, -9% to 39%) represented a highly significant change (signed rank sum test; P = .0001). At a median follow-up of 29 months (range, 6 to 92 months), the maximum increase in CDC (deltaCDC) as a continuous variable was significantly correlated with DFS (P = .0001). Median survival and 5-year DFS were more than 54 months and less than 54%, respectively, for patients with deltaCDC > or =10% (n = 44) but only 7 months and 14%, respectively, for those with deltaCDC <10% (n = 56; P = .0001). Multivariate analysis confirmed deltaCDC as the most significant independent variable associated with DFS following initiation of PMCV therapy (P = .0001). CONCLUSION: PMCV therapy greatly enhances serum CDC against melanoma cells. This enhancement is directly correlated with DFS following initiation of vaccine therapy.

Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response.

Patients with melanoma metastatic to distant sites or at high risk for recurrent melanoma have been treated with a polyvalent melanoma cell vaccine (MCV) in phase II protocols. We assessed in vivo and in vitro cell-mediated responses to MCV in 163 patients who had undergone surgical resection of American Joint Committee on Cancer stage III melanoma. During the first 4 months of vaccine immunotherapy, 135 patients (83%) responded by developing a positive delayed-type hypersensitivity reaction > or = 6 mm to MCV. In a mixed lymphocyte tumor cell reaction using peripheral blood lymphocytes, 35 of 42 patients (83%) showed a recall proliferative response to one or more of the three cell lines of MCV. There was a significant correlation between delayed-type hypersensitivity reaction and mixed lymphocyte tumor cell reaction (P = 0.013). After 4 months of MCV therapy, 8 of 11 patients had an increased mixed lymphocyte tumor cell reaction to autologous melanoma cells. During the first 4 months of vaccine therapy, 16 of 33 patients developed more than a 50% increase in cytotoxic T-cell activity against one of the cell lines of MCV. Overall survival was significantly prolonged in patients with a positive delayed-type hypersensitivity reaction (P = 0.0054) and/or increased cytotoxic T-cell activity (P = 0.02). These findings suggest that MCV induces specific T-cell responses which are correlated with clinical course; the data also suggest that some of these responses are directed against autologous melanomas and may play a major role in controlling the progression of melanoma.

Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.

A new polyvalent melanoma cell vaccine (MCV) was administered to 136 stage IIIA and IV (American Joint Committee on Cancer) melanoma patients. Induction of cell-mediated and humoral immune responses to common melanoma-associated antigens present on autologous melanoma cells was observed in patients receiving the new MCV. This was accompanied by increased activation of tumor-infiltrating lymphocytes. Survival correlated significantly with delayed cutaneous hypersensitivity (p = 0.0066) and antibody responses to MCV (p = 0.0117). Of 40 patients with evaluable disease, nine (23%) had regressions (three complete). From our historical database of 126 stage IIIA and 1275 stage IV melanoma patients, there were no significant changes in the natural history of metastatic melanoma during the past 20 years. Univariate and multivariate analyses demonstrated prognostic significance for site of metastases (p = 0.0001) and immunotherapy with the new MCV (p = 0.0001). Overall our new MCV increased the median and 5-year survival of stage IIIA melanoma patients with regional soft tissue metastases twofold (p = 0.00024), and stage IV patients threefold (p = 0.0001) compared with previous immunotherapy and other treatments.

Active specific immunotherapy in malignant melanoma.

We have recently initiated clinical trials of active specific immunotherapy evaluating a new polyvalent melanoma cell vaccine in patients with high-risk and/or recurrent melanoma. The vaccine has been administered alone, or in combination with low-dose cyclophosphamide, as an immunomodulator of suppressor cells. Cyclophosphamide is effective in lowering suppressor cell activity in some patients undergoing active specific immunotherapy. This is not associated with an enhanced humoral immune response to melanoma-associated antigens, nor is the clinical course of those patients receiving cyclophosphamide favorably influenced. We are hopeful that other immunomodulators, alone or in combination with lower doses of cyclophosphamide, may be effective in some patients, particularly in those patients whose suppressor cell activity remains high. The optimization of the vaccine and the use of immunomodulators will enhance humoral and cellular immune responses to antigens in the allogenic vaccine that cross react with those present in the autologous melanoma, which should more favorably influence the prognosis of melanoma patients.

Immunological aspects of retinoids in humans. III. Effects of retinoic acid on the natural killing of tumor cells.

We investigated the effects of retinoic acid (RA) on natural killer (NK) cell activity and on the susceptibility of various tumor target cells to NK cell lysis. These studies were undertaken to assess the overall effects of RA treatment on the natural killing of tumor cells in humans. We also evaluated how RA affects the generation of NK-like activity in mixed leucocyte culture, to determine whether or not this compound can influence the regulation of natural cytotoxicity during the induction phase of NK cell development. Our results indicate that pharmacological levels of RA have little, if any, influence on the development, cytotoxic potential, or activity of NK cells in humans. In contrast, RA can significantly reduce the sensitivity of some tumor target cells to natural killing. This effect appears to be directly related to the differentiation-promoting properties of RA, since reduced NK susceptibility was observed with target cells that were "differentiated" by RA treatment, but not with cells that were either unaffected by RA or were only growth inhibited without concomitant differentiation. These findings indicate that the immunomodulating properties of RA do not extend to human NK cell activity. However, a possible decreased susceptibility of tumor cells to natural killing should be a consideration when planning therapeutic applications of RA in certain cancers.

Immunological aspects of retinoids in humans. II. Retinoic acid enhances induction of hemolytic plaque-forming cells.

The effects of retinoic acid (RA) on the induction of antibody-producing cells from human tonsillar lymphocytes sensitized to sheep erythrocytes (SRBC) have been evaluated. Our results indicated that 10(-5) to 10(-7) M RA caused up to a three-fold increase in the number of plaque-forming cells (PFC) and a qualitative increase in the size of the plaques during the induction of PFC in 5- to 7-day cultures. Enhancement also occurred when tonsil cells were preincubated with RA for 24 hr and then washed, or when RA was added any time in the first 4 days after initiation of the culture. When T- and B-cell fractions were pretreated with RA for 24 hr, washed, and recombined with SRBC, RA-induced augmentation of PFC occurred only in conjunction with RA treatment of the B-cell fraction. Pretreatment of the T-cell fraction had no effect on PFC induction or on the RA-enhanced response when the B-cell fraction was simultaneously treated with RA. Other experiments suggested that RA did not modulate PFC induction by influencing regulatory functions of adherent accessory cells. Our study demonstrates that RA can enhance human antibody responses and shows that this effect is not caused by increased activity of T cells or adherent accessory cells, but is instead the result of a direct effect of RA on B-cell populations.

Augmentation of human thymocyte proliferative responses by retinoic acid.

When 10(-5) to 10(-7) M all-trans retinoic acid (RA) was added to human thymocyte or tonsil lymphocyte cultures in the presence of mitogens or allogeneic stimulator cells, blastogenesis was increased up to 2.5-fold. No augmentation in proliferative responses of peripheral blood or spleen lymphocytes was observed. In the thymus, lymphocytes in the subclass of cells that did not bind peanut agglutinin (PNA) were responsible for the RA-induced enhancement. RA also increased the number of mitogen-stimulated thymocyte colonies developing in soft agar. These results indicate that the targets of RA activity must be lymphoid cells at a later stage of maturation than those identified by binding to PNA, and that one mechanism of RA enhancement is an increase in the number of lymphocytes that undergo blast transformation.