Showing papers in "Cancer Immunology, Immunotherapy in 1981"
TL;DR: Experimental evidence is provided in support of an alternative indication for marrow transplantation adoptive immunotherapy of murine leukemia with a combi- approach.
Abstract: In the absence of specific anticancer agents, bone marrow (BM) transplantation in combination with conventional radiochemotherapy may turn out to be one of the most promising future approaches to the treatment of malignant hematological disorders, and possibly of disseminated solid tumors as well. The rationale for the treatment of leukemia by BM transplantation, in which donor cells serve to reconstitute host hematopoiesis and immunocompetency, is based on a few accepted facts as well as some attractive but as yet unproven hypotheses. Although most leukemias show a dose-related response to antitumor therapy, effective treatment with antileukemic agents at dose ranges indicated for tumor eradication is restricted, due to irreversible marrow toxicity. Hematopoietic rescue by application of marrow transplantation permits the administration of chemoradiotherapy at potentially curative doses above the level of irreversible marrow damage. In the present report we would like to provide experimental evidence in support of an alternative indication for marrow transplantation adoptive immunotherapy. Adoptive transfer of marrow cells obtained from normal tumor-free (or tumor-resistant) donors to tumor-bearing recipients is based on the assumption that immunologically competent cells may interact and possibly eliminate resident tumor cells. Similarly, allogeneic immunohematopoietic reconstitution in tumor-bearing recipients may help create allogeneic resistance to malignant relapses. The resulting effect, so-called graft versus tumor (GVT) or graft versus leukemia (GVL), may thus represent cell-mediated interactions between the donor immune system and the host tumor-associated or alloantigenic cell surface determinants [2, 11]. We describe here a new approach for adoptive immunotherapy of murine leukemia with a combi-
92 citations
TL;DR: It is emphasized that tumor cells seem not to share the membrane properties of the in vitro model lines, which exhibit high sensitivity to the natural or activated killer cells without the involvement of antigen recognition.
Abstract: A considerable proportion of human blood lymphocytes that express natural cytotoxic potential belong to the T subset. They are heterogenous with regard to their surface receptor characteristics. Results obtained with the exceptionally sensitive cell lines (such as K562, Molt-4) and freshly harvested cells as targets reveal different types of cytotoxicity. While certain cell lines may be killed without the involvement of antigen recognition, the freshly harvested cells are recognized and killed by lymphocytes that carry receptors for surface antigens on these targets. In accordance, such tests can reveal the cytotoxicity of T cells that carry receptors for histocompatibility antigens. In view of the high frequency of these cells in the lymphocyte population, enlargement of the clone is not always necessary and activation suffices.
46 citations
TL;DR: The results suggest that carcinomatous pleural effusions contain at least two classes of suppressor cells for NK activity, monocyte/macrophages, and nylon wool-nonadherent lymphocytes, which could be one of the causes of impaired NK activity in carcinom atous pleurally effusions.
Abstract: Carcinomatous pleural effusions of 25 of 32 patients with lung cancer, which had markedly low or no natural killer (NK) activity against K562 cells in a 4 h chromium release assay, contained cells capable of suppressing the lytic function of blood NK cells from normal donors and cancer patients. Suppressor cells were found to be Sephadex G-10- and serum coated plastic dish-adherent monocyte/macrophages in 21 of 25 patients and nylon wool-nonadherent lymphocytes in the other four cases. Nonmalignant pleural effusions did not contain any type of suppressor cells. Twenty-four-hour preincubation of suppressor cells with effector cells was required for mediation of the suppressor function. Neither culture supernatants of effusion cells and NK cells nor effusion supernatants suppressed NK activity. The presence of indomethacin during the preincubation and cytotoxicity assay did not abrogate suppressor function. Suppressor cells did not reduce the number of lymphocyte/K562 conjugates. Contaminating tumor cells were not responsible for the suppression of cytotoxic activity. NK cells precultured with suppressor cells were not able to show cytotoxic function even after removal of the suppressor cells. When effusion mononuclear cells were passed through a Sephadex G-10 column and then preincubated for 24 h, these cells showed a significant increase in NK activity. The results suggest that carcinomatous pleural effusions contain at least two classes of suppressor cells for NK activity, monocyte/macrophages, and nylon wool-nonadherent lymphocytes, which could be one of the causes of impaired NK activity in carcinomatous pleural effusions.
46 citations
TL;DR: The Immunoadjuvant effect of CA and of other ‘classic’ immunoadjuvants, such as BCG and Corynebacterium parvum, was completely abolished by total-body irradiation (400 R) given 5 h before the first administration of the agent on day −7 prior to tumor challenge.
Abstract: Chemical, ultrastructural, and immunoadjuvant properties of Candida albicans (CA) and of a number of its fractions have been characterized through the analysis of the antitumor activity of soluble and insoluble cell wall components.
45 citations
TL;DR: The data indicate that liposome-encapsulated lymphokines do not cause significant toxicity in vivo and are able to activate macrophages in specific anatomic compartments.
Abstract: Multilamellar liposomes containing lymphokines from mitogen-stimulated rat lymphocytes were injected IV into BALB/c or (C57BL/6×C3H)F1 mice and Beagle dogs to evaluate their potential toxicity. Animals received either single or multiple (×3, ×4, or ×6) injections. All animals receiving liposomes remained clinically healthy. No hematologic changes were detected in liposome-treated mice, but lymphocytosis was detected in the treated dogs. Slight elevation of serum alkaline phosphatase and glutamine oxalo-acetic transaminase levels was also found in treated dogs, and occasional animals showed elevated serum bilirubin levels. No histologic evidence of liver damage was found in these animals. No gross or histologic changes were detected in any major organ systems in treated animals. Mononuclear cells isolated from the peripheral blood of dogs that received liposome-encapsulated lymphokines IV were tested for in vitro cytotoxicity against allogeneic tumor cell lines. Lymphocyte-, monocyte-, and natural killer cell-mediated cytotoxicity in vitro was unaltered. Murine alveolar and peritoneal macrophages harvested 24 h after injection of liposome-encapsulated lymphokines exhibited significant tumoricidal activity in vitro, but activation depended on the route of liposome administration. These data indicate that liposome-encapsulated lymphokines do not cause significant toxicity in vivo and are able to activate macrophages in specific anatomic compartments.
43 citations
TL;DR: Effector cells in carcinomatous pleural effusions of patients with primary or secondary lung cancer were examined for natural killer activity against K562 cells in a 4-h chromium release assay, and for mitogenic responses and lymphocyte subpopulation constitutions.
Abstract: Effector cells in carcinomatous pleural effusions of patients with primary or secondary lung cancer were examined for natural killer (NK) activity against K562 cells in a 4-h chromium release assay, and for mitogenic responses and lymphocyte subpopulation constitutions. NK activity of lymphocyte-rich mononuclear cells isolated from carcinomatous pleural effusions by centrifugation on a discontinuous gradient of Ficoll-Hypaque was markedly low in seven of 40 patients studied, and absent in the other 33 cases. NK activity of peripheral blood mononuclear cells from the patients was lower than that of cells from normal donors, but always higher than that of effusion cells from the same patients. NK cells in the peripheral blood and in pleural effusions had some characteristics in common, in that they lacked a capacity to bind sheep erythrocytes, were nonadherent to Sephadex G-10 beads and nylon wool, and belonged to large granular lymphocytes. On the other hand, nonmalignant effusions of patients with congestive heart failure had significant NK activity. The effector cells in the effusions included a higher frequency of T cells than those in the peripheral blood of the same patients. Proliferative responses to phytohemagglutinin and concanavalin A of effusion cells were comparable to those of normal blood cells and were higher than those of blood cells from the same patients. The reason for low NK activity and high mitogenic response in carcinomatous pleural effusions is as yet undefined.
42 citations
TL;DR: It was shown that patterns of surface antigens were distinct from that of the parental line in human malignant melanoma cell lines assayed for secretion of plasminogen activator (PA) and for growth in the nude mouse.
Abstract: Human malignant melanoma cell lines were assayed for secretion of plasminogen activator (PA) and for growth in the nude mouse. It was observed that cell lines that were high producers of PA also grew in the nude mouse. In order to detect differences in membrane constituents of cells related to these parameters of malignancy, antisera were raised in non-human primates against the high producer (Mel A-375) and the non-producer cell of PA (SK-Mel 25). After extensive absorption the two antisera showed little or no cross-reactivity with the other cell line. Several subclones were isolated from SK-Mel 25 and assayed for PA production and growth in the nude mouse. Two sublines (S 5 and S 13) were found that produced moderate amounts of PA and grew in the nude mouse, whereas five other sublines were negative in both respects. By means of antisera against sublines it could be shown that patterns of surface antigens were distinct from that of the parental line.
37 citations
TL;DR: These molecular hybrids maintain both their antibody-binding activity and the toxic activity of the A-chain of the plant toxin ricin and specifically bind to and kill the breast carcinoma cells in vitro.
Abstract: We coupled monoclonal IgMk antibodies directed against human breast carcinoma cells to the A-chain of the plant toxin ricin. These molecular hybrids maintain both their antibody-binding activity and the toxic activity of the A-chain. Thus, they specifically bind to and kill the breast carcinoma cells in vitro.
35 citations
TL;DR: Levels of natural cell-mediated cytotoxicity appear to fluctuate with tumor burden, being highest in patients with large tumor masses and lowest in Patients with no clinical evidence of tumor following a successful response to therapy.
Abstract: Natural cell-mediated cytotoxicity has been shown to be age-dependent in both rats and mice. The present study was undertaken to study age-related levels of natural cytotoxicity in humans. Mononuclear peripheral blood cells from over 200 normal volunteers were co-incubated with 51Cr-labeled K-562 for 4 h and the supernatants assayed for released isotope. No striking age-related variations in natural cytotoxicity were observed. Cord blood was shown to exhibit both high and low levels of natural cell-mediated cytotoxicity. There was no significant difference in the levels of natural cytotoxicity between males and females. Thoracic duct lymphocytes (TDL) from prospective kidney graft recipients were tested for natural cytotoxicity at intervals during drainage. Natural cytotoxic activity was undetectable in samples from initial drainage but increased as the drainage progressed. This increased activity was correlated with decreased in vitro responsiveness to PHA and decreased levels of E-rosettes in these TDL.
35 citations
TL;DR: Findings indicate that in vivo administration of HFIF results in an augmentation of NK activity in man, as long-term treatment with HFIF seems to ‘exhaust’ the NK cell system.
Abstract: Short- and long-term effects of IV administration of human fibroblast interferon (HFIF) on natural cytotoxicity was studied in patients with HBsAg-positive chronic active hepatitis. Short-term kinetics demonstrated a transient decrease of natural cytotoxicity, when measured 2 or 4 h after IV administration of HFIF (1−10×106 U/injection). Twenty-four hours after the initial injection of HFIF natural cytotoxicity was increased to 196%–282% of pretreatment values. The kinetics of NK activity during chronic stimulation with HFIF revealed the following features: (a) The highest relative increase was seen during the initial phase of HFIF application; (b) enhanced NK activity could be maintained for 2–4 weeks of therapy; (c) at a plateau of high activity short-term increases were much less pronounced; (d) in all patients monitored so far over a period of several weeks a gradual decrease of augmented NK activity has been observed despite continued administration of high doses of HFIF.
34 citations
TL;DR: This preliminary trial, in which the same dose of vaccinia oncolysate was used in 29 patients, showed the vaccine to be safe, non-toxic, and potentially effective.
Abstract: A live vaccinia virus-augmented tumor cell vaccine (vaccinia oncolysate) has been used as a specific active immune mechanism stimulator against certain advanced human cancers. This preliminary trial, in which the same dose of vaccinia oncolysate was used in 29 patients, showed the vaccine to be safe, non-toxic, and potentially effective. This study was designed as a toxicity/feasibility trial at a single vaccine dose. There was no effort to look at other dose levels. The heterogeneity of this early tumor group only reflects the type of patient available to the study during the early phase of vaccine testing. Randomized prospective trials have begun to make future analysis easier.
TL;DR: These two natural antitumor surveillance systems are compared and a better knowledge of manipulating the tumoricidal function of these cells in vivo may provide a valuable addition to the more conventional approaches to cancer therapy.
TL;DR: No changes in liver, kidney, or other organ function could be observed after BCG-CWP therapy, and significant immunological changes have not been detected so far.
Abstract: Based on animal experiments a clinical study with BCG cell wall preparation (CWP) was developed. Patients with head and neck carcinomas stage T1/2N0–2M0 were randomized. One group received surgical treatment only and a second group received preoperative intralesional BCG-CWP. So far 12 patients have been included in each group. After 3 years the CCR (complete cancer remission) in the surgery only group was 39% and that in the preoperative BCG-CWP group, 69% (P=11%). The cumulative proportion of surviving patients was 50% in the surgery only and 73% in the BCG-CWP group (P=21%). BCG-CWP injection was followed by an increase in body temperature and a decrease in peripheral blood lymphocytes. No changes in liver, kidney, or other organ function could be observed after BCG-CWP therapy. Complications and severe secondary effects such as have been described for living BCG were not observed, and significant immunological changes have not been detected so far.
TL;DR: In this paper, it is suggested that rigidification of the cell membrane lipid layer exposes latent tumor-associated antigens, which enhances the cell-specific tumor immunogenicity.
Abstract: Skin tests were carried out with irradiated autologous tumor cells in patients with solid tumors (large-bowel carcinoma, gastric carcinoma, malignant melanoma, and breast cancer). With untreated cells, the skin reaction was negative or very weakly positive. A strong skin reaction, however, was elicited with cells of elevated membrane lipid microviscosity. This was induced by incorporation of cholesterol or, more effectively, by cholesterly hemisuccinate (CHS). A fair correlation was observed between the level of skin reaction with CHS-treated cells and the clinical stage of the tumor. It is suggested that rigidification of the cell membrane lipid layer exposes latent tumor-associated antigens, which enhances the cell-specific tumor immunogenicity. CHS-treated cells could therefore be of clinical value in active immunotherapy of human cancer.
TL;DR: A 44-hour incubation microcytotoxicity assay (MA) was used to titrate the lymphocyte-mediated cytotoxicity in 47 transitional cell carcinoma (TCC) bladder cancer patients and 65 clinical control patients, revealing a significantly lower survival rate for patients with LSC compared with patients with HSC.
Abstract: A 44-hour incubation microcytotoxicity assay (MA) was used to titrate the lymphocyte-mediated cytotoxicity in 47 transitional cell carcinoma (TCC) bladder cancer patients and 65 clinical control patients. All titrations included three target cell lines: HU 456 (TCC), HU 609 (normal urothelium), and SAOS 2 (osteosarcoma). Tumor-specific cytotoxicity (TSC) was calculated as the difference between cytotoxicity to HU 456 and HU 609, and tumor type-specific cytotoxicity (TTSC) as the difference between cytotoxicity to HU 456 and SAOS 2. On the basis of TSC and TTSC values obtained before treatment TCC patients were divided into one group with high-grade specific cytotoxicity (HSC) and another with low-grade specific cytotoxicity (LSC). A prospective follow-up study of these patients revealed a significantly lower survival rate for patients with LSC compared with patients with HSC, even when the groups were corrected for differences in distributions according to clinical and histological tumor gradation. This indicates a growth-controlling function of the cellular immune reaction.
TL;DR: 3 M KCl extracts contain at least two biologically active components, one immunoprotective and one tumor-facilitating, and TSTA purified by the rapid method of isoelectric focusing may be a more suitable reagent for immunotherapy by virtue of the absence of facilitating antigens.
Abstract: Crude 3 M KCl extracts of the methylcholanthrene-induced fibrosarcoma of C3H/HeJ mice, MCA-F, were demonstrated to contain two fractions, one inducing tumor resistance and the other facilitating the outgrowth of neoplastic cell challenge. In immunoprotection tests in syngeneic C3H/HeJ mice, optimal doses of crude solubilized tumor antigen afforded only a 28% reduction in growth compared with saline-treated controls. When crude extracts were fractionated by preparative isoelectric focusing (pIEF) in a slab of superfine Sephadex G-75, significant biologic activity was demonstrated in two fractions. Fraction (Fr) 1, pI 2.5–3.6, induced potent tumor facilitation, increasing the tumor size by more than 100%, while Fr 15, pI 5.8–6.0, engendered resistance that reduced their respective biological effects to MCA-F, but not the antigenically unrelated MCA-D tumor. Thus 3 M KCl extracts contain at least two biologically active components, one immunoprotective and one tumor-facilitating. Since the weak immunoprotective activity of crude materials may represent the vectorial effect of these antagonistic components, subsequent molecular characterization of both moieties may afford insight into the complex response of hosts toward tumors. Furthermore, TSTA purified by the rapid method of isoelectric focusing may be a more suitable reagent for immunotherapy than the parent crude 3 M KCl extracts by virtue of the absence of facilitating antigens.
TL;DR: There is no systemic imbalance in T cell subsets in malignant melanoma and that quantitation of these subsets cannot predict the clinical course of this disease.
Abstract: T lymphocyte subset profiles were determined by monoclonal antibodies on cryopreserved peripheral blood lymphocytes from 57 patients with malignant melanoma and 19 healthy controls. Quantitation of percentages of total T cells (OKT3.PAN), helper (OKT4.IND) or suppressor (OKT8.SUP) cells, and the ratio of helper/suppressor subsets revealed no correlation of these markers with stage of disease or clinical outcome. A sequential study of these markers on peripheral blood lymphocytes from three stage I melanoma patients with subsequent recurrent disease showed no fluctuations that could be correlated to tumor progression. This study indicates that there is no systemic imbalance in T cell subsets in malignant melanoma and that quantitation of these subsets cannot predict the clinical course of this disease.
TL;DR: It is suggested that microtubules and microfilaments play a role in the destruction of tumor cells by activated macrophages.
Abstract: The effects of vinblastine, colchicine, lidocaine, and cytochalasin B on tumor cell killing by BCG-activated macrophages were examined. These four drugs were selected for their action on membrane-associated cytoskeletal components, microtubules, and microfilaments. Colchicine and vinblastine, which block microtubular synthesis, inhibit macrophage-mediated tumor-cell cytotoxicity at a concentration of 10−6 M. Cytochalasin B, which disrupts microfilaments, enhances tumor cell lysis and stasis due to activated macrophages at a concentration of 10−7 M. Lidocaine, which may induce the disappearance of both microtubules and microfilaments, has the same inhibiting effect as vinblastine at a concentration of 5×10−7 M. Whereas vinblastine and lidocaine seem to act on the macrophage itself, cytochalasin B exerts its effect predominantly on the tumor cell. These results suggest that microtubules and microfilaments play a role in the destruction of tumor cells by activated macrophages.
TL;DR: A correlation is made relating the presence of BCGcw-induced suppressor cells with the observed in vivo enhancement of tumor growth by BCG cw immunization with a profound decrease in Con-A and MLR reactivity.
TL;DR: Serum from those vaccinated patients was found to elevate chemiluminescence levels of resting PBMC from normal subjects, and serum activity did net correlate with levels of immune complexes measurable in the Clq or Raji cell assay.
Abstract: Levels of chemiluminescence were measured in peripheral blood mononuclear cells (PBMC) from normal subjects and from solid tumor cancer patients. Patients with advanced malignant disease were found to have significantly elevated baseline chemiluminescence activity in their ‘resting PBMC’ as compared to normal subjects or to cancer patients with, at most, minimum residual disease. Patients with either advanced disease or minimum residual disease, however, were found to exhibit significantly elevated activation of chemiluminescence by treatment of cells with phorbol myristic acetate (PMA). Treatment of surgically resected stage I lung cancer patients with Freund's complete adjuvant alone or emulsified with extracted lung cancer antigens was found to elevate chemiluminescence levels in patient PBMC. Serum from those vaccinated patients was found to elevate chemiluminescence levels of resting PBMC from normal subjects. That serum activity did net correlate with levels of immune complexes measurable in the Clq or Raji cell assay.
TL;DR: The results show that a drug-mediated increase of tumor immunogenicity (DMITI) can be induced by triazene derivatives not containing the imidazole moiety.
Abstract: Five aryltriazenes were studied for efficacy in mediating immunogenic changes of tumor cells by in vivo treatment of lymphoma-bearing mice. It was found that four analog compounds produced increase in cell immunogenicity similar to that described for 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC), one of the five being by contrast completely inactive. Moreover, the use of a drug-resistant lymphoma illustrates that cytotoxic activity is not mandatory for the appearance of the immunogenic changes.
TL;DR: A systemic effect of BCGcw inoculated intraperitoneally is described by observing its influence on the development of Morris hepatomas inoculated intramuscularly by observing an enhancement of tumor growth in two strains of inbred rats.
Abstract: The present studies describe a systemic effect of BCGcw inoculated intraperitoneally by observing its influence on the development of Morris hepatomas inoculated intramuscularly. In none of our studies did we observe an inhibition of tumor growth. Instead, an enhancement of tumor growth was seen with four antigenically distinct Morris hepatomas (3924a, 9098, 7777, and 5123tc) in two strains of inbred rats (Buffalo and ACI). Extensive studies with Morris hepatoma 3924a showed consistent enhancement of intramuscular tumor growth in eight of eight experiments with a tumor cell dose of 1×105 and a BCGcw dose of 900 μg. In BCGcw-inoculated animals, palpable tumors (1–2 g) were detected approximately 1 week earlier than in controls, and significantly larger tumor masses were noted on the day of sacrifice. With the threshold dose of cells, 1×104, an increase in tumor incidence was observed. It was not necessary for the host to be immunized with BCGcw prior to tumor inoculation as enhancement of tumor growth occurred when the BCGcw were inoculated the same day or 7 days after tumor inoculation. Splenectomized animals also demonstrated BCGcw-mediated enhancement of tumor growth. BCGcw immunization blocks the induction of tumor-specific immunity. When 3924a ascites tumor cells were inoculated intradermally into normal animals, no tumor growth was observed and tumor-specific immunity resulted. When 3924a ascites tumor cells were inoculated intradermally into BCGcw-immunized animals, progressive intradermal tumors grew in all the animals, implying that tumor-specific immunity was not induced. The administration of BCGcw did not effect established tumor-specific immunity to line 3924a as assessed by tumor-specific rechallenge resistance. Studies with an allograft system showed that the ACI tumor 3924a would not grow in normal Buffalo rats, but transient tumor growth was observed when the Buffalo rats were immunized with BCGcw.
TL;DR: Supernatants from tumor cell cultures of melanoma, carcinoma (lung, colon, breast), sarcoma, and normal fibroblasts inhibited normal lymphocyte response to PHA, but the inhibition was not due to nutrient deficiencies and the supernatants were not directly toxic to the lymphocyte cultures as judged by trypan blue exclusion.
Abstract: Human tumor and normal cell lines in culture were examined for the release of factors capable of inhibiting lymphocyte blastogenesis. Supernatants from tumor cell cultures of melanoma, carcinoma (lung, colon, breast), sarcoma, and normal fibroblasts inhibited normal lymphocyte response to PHA. Only supernatants from the tumor cell lines C1 (colon carcinoma), 734B (breast carcinoma), and 231 (breast carcinoma) were found to inhibit both PHA and ConA responses significantly. The two breast carcinoma cell lines, 734B and 231, which also were capable of inhibiting lymphocyte responses to PPD and alloantigens, were investigated further. The inhibition of lymphocyte blastogenesis caused by the supernatant of these two cell lines could not be overcome by the addition of added mitogen. Further experiments showed that the inhibition was not due to nutrient deficiencies and the supernatants were not directly toxic to the lymphocyte cultures as judged by trypan blue exclusion.
TL;DR: The standardization of terminology the authors propose is intended to facilitate precision of understanding in the exchange of immunological information, and may be particularly helpful to students not privy to the wavering nuances with which these words have been variously invested.
Abstract: A considerable lack of uniformity and consistency is evident in current usage of the terms 'antigen' and 'immunogen', especially in the literature of tumor immunology. Semantic anomaly often engenders conceptual uncertainties, and here contributes unnecessarily to the complexity of rapidly evolving and inherently problematic areas of biology. The standardization of terminology we propose is intended to facilitate precision of understanding in the exchange of immunological information, and may be particularly helpful to students not privy to the wavering nuances with which these words have been variously invested. The terms 'antigen' and ('antigenicity' should be taken to connote no more than the potential capacity of a substance to evoke a specific immunological response, humoral or cellular. An antigen takes on 'immunogenic' properties when this potential is realized. Realization of antigenic potential to frank immunogenicity involves multiple variables, pertaining to the physiochemical characteristics of the substance, the conditions of sensitization, and both the genetic and phenotypic (at the time of testing) immunoreactive capabilities of the animal tested; these parameters require specification in each instance. Thus, the terms 'immunogen' and 'immunogenicity' are conditional and committing, and should be restricted to refer only to the active elicitation of immunological[ reactivity by a substance. Evocation of active 'negative' immunological responses, viz induction of specific suppressor functions, and of at least some types of specific immunological unresponsiveness, is included in the definition of 'immunogenicity'. According to this nomenclature, macromolecules such as cellulose and synthetic homopolymers are not antigenic. Substances such as serum proteins, in contrast, are 'antigenic', but take on the property of immunogenicity only when administered to an organism genetically and phenotypically able to respond, and when introduced in a state (e.g., aggregation) and/or under conditions (e.g., together with an immunomodulating agent or following pretreatment of the animal with such agents) making for immunological excitation. Ambiguity is marked in application of the words 'antigenic' and 'immunogenic' to the description of tumors. Often the terms are used interchangeably, to state that a neoplasm is capable of inducing an immunological response not so evoked by analogous normal cells, and with no indication of whether or not the response affords protection on autochthonous or syngeneic hosts. Some investigators, on the other hand, employ the designations differentially: 'antigenic' to denote a tumor's ability to incite an immunological response that is of no significance for host resistance, or whose significance remains unknown or unspecified, and 'immunogenic' to qualify the elicitation of responses that do contribute to host defense. The reader is thus frequently left at sea with regard to the resistance implications of a tumor's immunostimulating properties. In the strict sense of the definition, it is in fact rather meaningless to debate or assert the antigenicity of tumors: Whether truly tumor-specific or only tumor-associated, cellular proteins and protein-containing polymolecular entities are generally antigenic, and the specification 'tumor antigen' is thus truistic, conveying no pertinent information. The attempt to abolish 'tumor antigen' from the immunological lexicon nonetheless appears unrealistic in practice. Its retention demands, however, that a differentiation between antigenicity and immunogenicity other than that appropriate for general usage be formulated with regard to tumors, for the following reasons: The active evocation by a human cancer of detectable immunological responses can be
TL;DR: It is concluded that a protocol for the quality control of bacterial vaccines used for cancer immunotherapy should include both immunological assays and a range of different animal tumor models.
Abstract: Four preparations of Bacillus Calmette-Guerin (BCG), cultured either homogeneously dispersed or as a surface pellicle, were compared with reference to their immunomodulating capacities and antitumor effects. The BCG preparations included two vaccines that originated from the same seed strain, but one had subsequently been produced in each way. The immunological assays included in vivo stimulation of lymph nodes in a mouse model, in vitro stimulation of murine spleen lymphocytes, and in vivo stimulation of macrophages in a Listeria monocytogenes clearance model in the mouse. The antitumor effect was determined in a non-immunogenic, non-metastasizing murine fibrosarcoma. The results indicated that vaccines produced as a homogeneous culture in general induced a higher lymphocyte stimulation both in vivo and in vitro. In the Listeria clearance model a markedly enhanced clearance was established with three of the four preparations, the phenomenon being related to the number of culturable particles administered. This difference was not attributed to the production method, but to other factors, including the actual composition of the vaccine. The results found in the immunological assays were not connected to the observed antitumor activities, as for each preparation a combination of route, dose, and time interval for tumor regression was found. Prophylactic administration of BCG had no effect at all; enhancement was observed after intratumoral administration of the two preparations prepared as surface pellicles. It is concluded that a protocol for the quality control of bacterial vaccines used for cancer immunotherapy should include both immunological assays and a range of different animal tumor models.
TL;DR: The patients receiving intrapleural BCG in addition to radiation and chemotherapy had a median survival of 18 weeks, significantly shorter than that for the patients receiving interventional saline (54 weeks, P=0.017), and there were no significant differences in pretreatment prognostic factors or in response to radiation therapy.
Abstract: Twenty-one patients with stage III M0 non-oat cell bronchogenic carcinoma confined to the thorax were randomized to receive either intrapleural BCG (107 cfu, Tice strain) or intrapleural saline 3 weeks prior to beginning combined irradiation and chemotherapy. Radiation to the primary tumor and regional nodes was given at a dose of 3,000 rad in ten sessions and was followed in 7–14 days by CAMP chemotherapy (cyclophosphamide, adriamycin, methotrexate, and procarbazine) for a planned duration of 6 months. Isoniazid, 300 mg/day, was given to all patients for 3 months starting 1 week after intrapleural therapy. There were no significant differences in pretreatment prognostic factors or in response to radiation therapy. The patients receiving intrapleural BCG in addition to radiation and chemotherapy had a median survival of 18 weeks, significantly shorter than that for the patients receiving intrapleural saline (54 weeks, P=0.017).
TL;DR: In this paper, the authors randomized 31 adults with acute myelogenous leukemia and in whom remission had been induced and consolidated with chemotherapy were randomized to receive one of three maintenance schedules: (A) splenectomy, followed 1 week later with BCG and chemotherapy; or (C) allogeneic leukemic cells, BCG, and chemotherapy.
Abstract: Thirty-one adults who had acute myelogenous leukemia and in whom remission had been induced and consolidated with chemotherapy were randomized to receive one of three maintenance schedules: (A) BCG + chemotherapy [1, 3-bis-(2-chlorethyl)-1-nitrosourea (BCNU) and cytosine arabinoside]; (B) splenectomy, followed 1 week later with BCG and chemotherapy; or (C) allogeneic leukemic cells, BCG, and chemotherapy. Serial immunologic assessments were performed at the onset of maintenance and every 3 months.
TL;DR: In this article, the adjuvant intrapleural BCG and subsequent isoniazid (INH) therapy was evaluated on 179 stage I lung cancer patients subjected to resection operations.
Abstract: Data are presented on 179 stage I lung cancer patients subjected to resection operations and then given adjuvant intrapleural BCG and subsequent isoniazid (INH) therapy and on 167 control patients given intrapleural saline and placebo pills in a two-arm randomized double-blind study. The predominant immediate response to BCG/INH therapy was hyperpyrexia, which was found to be more pronounced in patients with larger induration in pretreatment PPD skin tests. Subsequently, chemical hepatitis (6 cases after BCG/INH versus 1 case after saline/placebo), peripheral neuropathy (3 versus 1), dermatitis/hives (5 versus 2), pleural thickening (4 versus 0), and persistent fever (10 versus 0) were noted. Analysis of laboratory changes measured at 18 weeks following randomization revealed that patients with BCG/INH lost 1.1 kg in weight and 0.30 g/dl in hemoglobin concentration on average, whereas control patients gained 1.2 kg and 0.33 g/dl, respectively. Modest rises in SGOT and alkaline phosphatase were apparent at 6 weeks after instillation of BCG compared with controls, but these differences were no longer statistically signifikant after 18 weeks. These side effects notwhithstanding, the BCG/INH therapy was well tolerated.
TL;DR: Rigorous depletion of monocytes by adherent techniques resulted in an improvement in blastogenesis in seven of nine group II patients, whereas controls and group I patients had marked decreases in reactivity.
Abstract: Twenty-five patients with malignant melanoma were studied to determine the mechanisms underlying decreased cellular immunity in this disease. Sixteen patients were examined following surgical resections of tumor, and nine patients had evidence of metastases. Patients with metastatic disease (group II) had decreased lymphocyte transformation to concanavalin A (48,255±30,074) compared with controls (83,550±41,277) and patients free of disease (group I) 110,231±59,990) (P>0.01). Rigorous depletion of monocytes by adherent techniques resulted in an improvement in blastogenesis in seven of nine group II patients, whereas controls and group I patients had marked decreases in reactivity. Indomethacin also improved lymphocyte reactivity; a mean of 166.4% was recorded in five metastatic disease patients studied, as against a mean of 2% in group I and 9.65% in controls. In seven patients followed serially the presence of adherent suppressor cells tended to correlate with progressive disease, shorter survival, and decreased skin test reactivity.