Chemoattractant properties of Corynebacterium parvum and pyran copolymer for human monocytes and neutrophils.

Both pyran copolymer and the Burroughs-Wellcome vaccine of Corynebacterium parvum were able to elicit a migratory response by human neutrophils or monocytes when incubated with serum. However, in the absence of serum, neither agent elicited such a response. The generation of the chemotactic factor by pyran was dependent on heat-labile components in the serum, while suggested involvement of the complement sequence. Conversely, the migratory response of C. parvum in heated serum was equivalent to that in normal serum. No specificity for either monocytes or neutrophils was observed.

Immunomodulatory effect of various molecular-weight maleic anhydride-divinyl ethers and other agents in vivo.

Various molecular-weight maleic anhydride-divinyl ether copolymer polyanions were evaluated in six in vivo systems. Low- and high-molecular-weight MVE's were effective adjuvants with irradiated L1210 tumor cell vaccine. A high percentage of L1210-challenged survivors were refractory to a second challenge of tumor cells. Azimexon and Bacillus Calmette-Guérin were also effective adjuvants, but Bestatin was without adjuvant effect. All the MVE's demonstrated a marginal antitumor effect against the L1210 and LSTRA tumors. The MVW's, regardless of molecular weight differences, were effective in enhancing macrophage tumoricidal activity and retarding the development of M109 tumor growth in the lungs. Enhancement of delayed-type hypersensitivity by all six MVE's indicates their ability to stimulate T-cells.

Enhancement of a tumor allograft in BALB/c x DBA/2 F1 mice by pyran copolymer.

Pyran copolymer (NSC 46015) was evaluated with respect to its effect on the rejection of a murine leukemic allograft by BALB/c x DBA/2 F1 (CD2F1) mice. Significant prolongation of allograft survival with production of progressively growing lethal tumors was found following pyran administration. This phenomenon occurred at nontoxic doses of the drug and appeared to be closely related to the timing of pyran injection. Nonspecifically stimulated lymphocyte blast transformation by concanavalin A was not impaired by pyran when lymphocytes were exposed in vitro to the drug. The mechanism of tumor allograft enhancement remains obscure but may be related to allograft size at the time of pyran administration.

Evaluation of the immunological and toxicological properties of MVE-2 in phase I trials.

Pyran copolymer enhances resistance to infections and transplantable tumors in mice. It induces interferon, activates macrophages, increases antibody-dependent cellular cytotoxicity (ADCC), functions as an adjuvant, and has direct antitumor effects. MVE-2, a low-molecular-weight (15,000) component of pyran copolymer, exhibited less toxicity and essentially the same positive biological effects as pyran copolymer. MVE-2 was, therefore, chosen for clinical trials. This study was designed to determine the toxicity and immunological effects of MVE-2 in humans. Fourteen patients who received biweekly MVE-2 had lymphocyte and monocyte ADCC, natural killer activity, and monocyte to macrophage maturation measured 2, 3, 7, 10, and 13 days after each of the first three doses of MVE-2. Lymphocyte antibody-dependent cellular cytotoxicity and monocyte maturation increased significantly following MVE-2 administration and the effect persisted at least 4 weeks. Although numbers were small, the enhanced ADCC seemed related to both single dose and cumulative dose of MVE-2. Five of six patients receiving more than 2 g of MVE-2 had improvement in lymphocyte ADCC. Increases in lymphocyte and monocyte natural killer activity approached, but did not attain statistical significance. Proteinuria was the dose-limiting toxicity, but was reversible. MVE-2 induced a modest, but real enhancement of lymphocyte and monocyte function at doses that were well tolerated.

Immunomodulation and antitumor effects of MVE-2 in mice.

The biological response modifier maleic anhydride-divinyl ether (MVE-2) can activate natural killer (NK) cells and macrophages and can act as an immunoadjuvant for T and B cells. MVE-2 activates macrophages following intravenous or intraperitoneal injection in a compartmentalized manner, i.e., peritoneal macrophages (i.p. injection) or alveolar macrophages (i.v. injection). It activates NK cells in vivo but not in vitro, a dichotomy that may be secondary to interferon production. Splenic NK cell activity is not prolonged by the multiple injection of MVE-2; instead, it induces a state of NK cell hyporesponsiveness, which may limit its therapeutic efficiency. Therapeutic properties of MVE-2 are largely limited to nonspecific immunoprophylaxis, which may be associated with NK cell activation but which does not necessarily correlate with the level of splenic NK cell activation. Minimal therapeutic efficiency consisting of a slight prolongation in survival is observed in mice with preexistent disease treated with MVE-2. Prolonged survival is observed only in those animals placed on therapy soon after tumor cell challenge (experimental metastasis) and not in mice with established spontaneous metastasis. The need to manipulate the animal model (MVE-2 injection prior to or rapidly following tumor challenge) seems to predict that this agent is unlikely to be clinically useful against preexistent metastatic tumor burden, although some efficiency may be associated with local treatment into the pleural or peritoneal cavity.

Non-cytotoxic activity of pyran copolymer-induced macrophages associated with potentiation of tumour vaccine in recipient mice.

Mice inoculated with both L1210 murine tumour vaccine and pyran copolymer were more resistant to L1210 than those inoculated with either of these agents alone. Rabbit anti-mouse thymocyte globulin and silica reduced the augmented resistance of these mice, suggesting the involvement of activated anti-tumour T cells and macrophages in the augmented resistance. We studied the activation of these two cells separately and examined the possible contribution of pyran copolymer-induced peritoneal cells to the augmented resistance to an inoculation of live tumour. Pyran copolymer-induced peritoneal cells endowed the tumour vaccine-primed mice, but not unprimed mice, with resistance to implanted L1210 and, among those peritoneal cell populations, macrophages but not T cells were responsible for this effect since the activity was associated with a cell population which was adherent to nylon wool columns, sensitive to silica and insensitive to anti-Thy 1.2 antibody plus complement. The pyran copolymer-induced peritoneal cells had very little antiproliferative activity when tested against L1210 in vitro and mice inoculated with these peritoneal cells did not survive a challenge of live L1210 cells much longer (less than 1 day) than L1210 inoculated control mice. Furthermore, the survival of L1210 vaccine-primed mice inoculated with one-tenth the amount of live L1210 (10(2)) was still much shorter than that of mice primed with L1210 vaccine plus pyran copolymer and challenged with ten times as many (10(3)) live L1210 cells. Therefore, direct tumoricidal activity was probably not a major factor in the in vivo immunological augmenting activity of the pyran copolymer-induced macrophages.