Jon R. Schmidtke

Intralesional immunotherapy of malignant melanoma with mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate (P3).

The clinical efficacy of intralesional immunotherapy utilizing Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate attached to oil droplets was investigated in 15 patients with advanced malignant melanoma. Patients received 300 μg to 1050 μg of the CWS combined with one‐half that amount of trehalose dimycolate every 1 to 2 weeks for a total of 8 treatments. Therapy was continued if regression of injected lesions only occurred. Therapy was discontinued if regression of noninjected disease also occurred. Six of the 15 patients had regressionof at least one injected lesion. Four of these 6 patients also had regression of noninjected disease lasting 4+, 6, 16 and 18+ months. Response was highly related to immune status. Six (83%) of 7 patients who reacted to one of a battery of skin tests responded. All 8 patients who did not react to skin tests failed to respond to therapy. There was no correlation of response with sex, prior therapy, disease‐free interval or presence of visceral disease. Mycobacterial CWS and trehalose dimycolate is an effective immunotherapeutic agent. Additional studies of purified immunoadjuvants are warranted. Cancer 44:495‐503, 1979.

Phase I study of intradermal immunotherapy with oil-attached Mycobacterium smegmatis cell wall skeleton and trehalose dimycolate

SummaryThe clinical toxicity of intradermal immunotherapy with a nonviable mycobacterial vaccine consisting of oil-attached Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate (P3) was evaluated. Fifteen patients with advanced hypernephroma, lung cancer, or malignant melanoma were evaluated. Patients received one to ten separate intradermal injections in the subclavicular areas weekly for up to 8 weeks. Each separate injection usually contained 75 μg CWS and 37.5 μg P3.There were few systemic side effects. Mild fever occurred in 30% of 69 treatments. Severe local toxicity with ulceration and/or abscess formation occurred in seven patients. Regression of disease was observed in one patient to occur on two separate occasions following separate courses of therapy.Although intradermal CWS/P3 can be locally toxic, treatment with up to four separate injections of 75 μg CWS combined with 37.5 μg P3 every 1–2 weeks appears appropriate, from this study, for additional clinical trials.

Inhibition of human T-cell rosette formation by the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA)

Abstract Mononuclear cell surface markers from normal human volunteers were tested in the presence of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA). Only the T-cell surface marker, formation of rosettes with sheep red blood cells, was significantly inhibited by concentrations of EHNA in a dose-dependent manner. Metabolic compartmentalization of adenosine compounds at the site of nucleoside transport across the cell membrane may play an important role in determining T-cell rosette formation and whether or not the blastogenic response of these cells to environmental mitogens will occur.

Purification and mitogenic activation of Fc receptor bearing human peripheral blood lymphocytes

Human peripheral blood mononuclear lymphocytes (PBL) were fractionated into two distinct subpopulations by adsorption to anti-sheep red blood cell-sheep red blood cell (EA) monolayers. The mononuclear cells adhering to the EA monolayers (treated with tris-NH 4 CL to remove SRBC) contained (80 ± 5%), Fc receptor positive cells, 50 ± 5% EAC rosette forming cells and 60 ± 10% Ig bearing cells. Lymphocytes not adhering to the EA monolayer were enriched for cells forming rosettes with SRBC (85 ± 5%) compared to unfractionated PBL which contained 65% rosette forming cells (RFC). The nonadherent lymphocytes also had reduced number of rosettes formed with antibody-complement coated SRBC (EAC) and immunoglobulin (Ig) bearing cells compared to unfractionated PBL. The ability of these two enriched subpopulations of cells to be mitogenically activated by phytohemagglutinin (PHA) or concanavalin A (Con A) was examined. Both adherent and nonadherent populations responded to PHA and Con A with 3 H-thymidine uptake but the kinetic pattern and magnitude of activation differed significantly for each subpopulation compared to the mitogenic response of unfractionated PBL.

In vivo elimination of equine antilymphocyte globulin by renal allograft recipients

Abstract We evaluated the elimination of Minnesota equine ALG-horse γ-globulin (HoGG) in 13 renal allograft recipients. The half-life in plasma of Minnesota ALG-HoGG was 12.1 days (±0.8 SEM). The active fraction was characterized as that fraction from plasma which binds normal peripheral blood lymphocytes. Comparison of the elimination of ALG and the active fraction indicated that total ALG is eliminated with a high degree of homogeneity while the active fraction was eliminated heterogeneously with wide individual variation.

Experimental Models of Tumor Immunotherapy1

Publisher Summary This chapter presents the experimental models of tumor immunotherapy. It is emphasized that there are no animal models of tumor immunotherapy that reflect the situation in man. Human cancer almost always presents an established mass of malignant cells that are more or less well adapted to the immunological environment. It spreads either directly into the bloodstream and/or via lymphatics to regional nodes. Human cancers most often take months or years to kill. In contrast, most tumor models in animals involve the transfer of small numbers of tumor cells to abnormal sites. Such tumors frequently kill in a few days or few months. Metastatic disease may appear within days, or it may not appear at all. The immunological adaptation of the first graft is not immediate, and successful models of immunotherapy can operate only when the tumor is small and has been in residence for only a few days to few weeks. To utilize in human immunotherapy any empirical technique that has not been demonstrated to be effective in animal models is dangerous. Even techniques shown to be effective in animal models may prove to enhance human tumors. Until the conditions for tumor enhancement or rejection can be predicted, such dangers will persist. There is considerable evidence to support the idea that tumor immunogens are so weak that the immunological response may be misdirected and that tumor immunotherapy as a primary means of treatment is unlikely.

Immunotherapy Models in Experimental Animals

Although no animal models have been found to truly reflect the immunologic responses of man, it is from animal model systems that most of the current concepts of immunotherapy and tumor immunology were derived. This article provides an overview of the type of immunotherapeutic manipulations that have been effected in animal models, the results of such maneuvers, and their possible application to the immunologic modalities used in man.

MACROPHAGE-MONOCYTE REGULATION OF THE MITOGENIC ACTIVATION OF X-RAYED, PURIFIED HUMAN T LYMPHOCYTES

Publisher Summary This chapter reviews human monocytes that potentiate the mitogenic activation of X-rayed human T cells. The optimal activation of lymphocytes to allogeneic, antigenic, and mitogenic stimuli can be regulated by macrophages or monocytes. In a study described in the chapter, mononuclear leukocytes were isolated from human peripheral blood on Ficoll-hypaque. Monocytes were prepared by adherence to tissue culture dishes. Human T cells were X-rayed and incubated in the presence or absence of autologous monocytes with or without 10 μg Concanavalin A (ConA). The data suggest that human monocytes, in an unknown way, promote mitogen-induced DNA synthesis in X-rayed human T cells. The ability of monocytes to mediate this effect is dependent on the amount of X-ray and the number of monocytes.

AUGMENTATION OF IN VITRO GENERATED CELL MEDIATED CYTOTOXICITY BY NEURAMINIDASE

Publisher Summary This chapter presents experimental results for augmentation of in vitro- generated cell-mediated cytotoxicity by neuraminidase. The enzyme Vibrio cholera neuraminidase (VCN) has been shown to alter a variety of immunologic processes. The chapter presents a study designed to determine the effects of VCN on the in vitro generation and effect or function of cytolytic T lymphocytes. MLC generation of cytotoxic lymphocytes and cytotoxicity assays were used for the study. Cells from the in vivo as cites tumor line EL4 were used as targets. Pretreatment of the stimulator cell population with VCN does not increase the generation of cytotoxic cells. In contrast, VCN pretreated responder cells appear to be capable of killing greater numbers of specific allogeneic target cells exposed to IVCN or no VCN. Alternatively, VCN could alter the responding cell-surface membrane rendering it unresponsive to recently postulated immunoregulatory factors that limit a potential cytotoxic response.

Tumor Immunology and Immunotherapy

The first clear evidence that syngeneic tumors in experimental animals could be specifically recognized by the immune system of the host were studies in which inbred strains of mice were immunized by inoculation with syngeneic tumors. Using inbred animals with identical genetic background,the complicating factors of immunity against normal transplant antigens was avoided and specific reactivity against the tumor was assumed to be against antigens present on the tumor that were not present on normal tissues of the host.