Showing papers on "Tumor antigen published in 1992"

A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E.

Abstract: We have reported the identification of human gene MAGE-1, which directs the expression of an antigen recognized on a melanoma by autologous cytolytic T lymphocytes (CTL). We show here that CTL directed against this antigen, which was named MZ2-E, recognize a nonapeptide encoded by the third exon of gene MAGE-1. The CTL also recognize this peptide when it is presented by mouse cells transfected with an HLA-A1 gene, confirming the association of antigen MZ2-E with the HLA-A1 molecule. Other members of the MAGE gene family do not code for the same peptide, suggesting that only MAGE-1 produces the antigen recognized by the anti-MZ2-E CTL. Our results open the possibility of immunizing HLA-A1 patients whose tumor expresses MAGE-1 either with the antigenic peptide or with autologous antigen-presenting cells pulsed with the peptide.

Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product.

Abstract: The adenovirus E1A gene product, the simian virus 40 large tumor antigen, and the human papillomavirus E7 protein share a short amino acid sequence that constitutes a domain required for the transforming activity of these proteins. These sequences are also required for these proteins to bind to the retinoblastoma gene product (pRb). Recent experiments have shown that E1A can dissociate complexes containing the transcription factor E2F bound to pRb, dependent on this conserved sequence element. We now show that the E7 protein and the simian virus 40 large tumor antigen can dissociate the E2F-pRb complex, dependent on this conserved sequence element. We also find that the E2F-pRb complex is absent in various human cervical carcinoma cell lines that either express the E7 protein or harbor an RB1 mutation, suggesting that the loss of the E2F-pRb interaction may be an important aspect in human cervical carcinogenesis. We suggest that the ability of E1A, the simian virus 40 large tumor antigen, and E7 to dissociate the E2F-pRb complex may be a common activity of these viral proteins that has evolved to stimulate quiescent cells into a proliferating state so that viral replication can proceed efficiently. In circumstances in which a lytic infection does not proceed, the consequence of this action may be to initiate the oncogenic process in a manner analogous to the mutation of the RB1 gene.

Tumor antigen presentation by epidermal antigen-presenting cells in the mouse: modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and ultraviolet radiation.

Abstract: I-A+ epidermal antigen-presenting cells (APCs, Langerhans cells) have been shown to present tumor-associated antigens (TAAs) and to induce tumor immunity in vivo. This study examined the effects of ultraviolet radiation (UVR) and the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha) on the ability of epidermal cells (ECs) to induce or to elicit immunity against the murine spindle cell tumor S1509a. Naive syngeneic mice were immunized three times at weekly intervals with ECs that had been cultured in GM-CSF for 18 h and then pulsed with TAA derived from S1509a. This resulted in protective immunity against subsequent tumor challenge, providing a model to study the conditions required for sensitization against TAAs by epidermal APCs. Culture of ECs in GM-CSF was required for induction of significant protective tumor immunity, and UV irradiation or incubation in TNF-alpha for 2 h after GM-CSF incubation abrogated the immunostimulatory effect of GM-CSF. However, unlike UVR, TNF-alpha did not significantly inhibit the induction of immunity when ECs were exposed to TNF-alpha before overnight incubation in GM-CSF, together with GM-CSF, or after pulsing with TAA, and anti-TNF-alpha antibody treatment did not abrogate the effects of UVR on this system. Furthermore, TNF-alpha incubation of ECs augmented their ability to elicit delayed-type hypersensitivity (DTH) and also enhanced elicitation of DTH by GM-CSF-cultured ECs, whereas UV-irradiation reduced it in a dose-dependent fashion. Taken together, these results demonstrate that GM-CSF, TNF-alpha, and UVR are significant regulators of tumor antigen presentation by epidermal APCs and that the effects of the cytokines examined differ with regard to induction or elicitation of immunity.

A quantitative analysis of tumor specific monoclonal antibody uptake by human melanoma xenografts: effects of antibody immunological properties and tumor antigen expression levels.

Abstract: The time-dependent (5 min-72 h) localization of 3 radiolabeled anti-melanoma monoclonal antibodies (MAbs 436, IND1, and 9.2.27) was studied in paired label experiments in small (4-12 mg) s.c. human melanoma xenografts (SK-MEL-2 and M21) in athymic nude mice. MAb 436 recognizes a Mr 125,000 cell surface melanoma-associated glycoprotein antigen (125 kDa-MAA); MAbs IND1 and 9.2.27 recognize a high molecular weight melanoma-associated antigen, but with equilibrium association constants differing by 2 orders of magnitude (10(8)-10(10) M-1). The two tumors were found to differ in their antigen expression levels and in both interstitial and vascular volumes. Accumulation of MAbs in both tumors was determined primarily by antigen expression levels and also by physiological factors such as vascular permeability and vascular volume; at the dose administered (20 micrograms/mouse), differences in MAb affinity among specific MAbs had minimal effect on accumulation. Quantitative flow cytometry measurements showed that antigen expression in vivo differed from that of cultured tumor cells. In vivo, expression of the Mr 125,000 MAA decreased by a factor of about 2.5 in both tumors. In contrast, the in vivo expression of the high molecular weight MAA decreased in M21 tumors but increased by 2.0-3.5-fold in SK-MEL-2 tumors. Data were analyzed using a three-compartment pharmacokinetic model (C. Sung et al., Cancer Res., 52:377-384, 1992) to provide plasma-to-tissue transport constants (k), the interstitial fluid flow rate (L), and estimates of the in vivo interstitial MAb binding site concentration (B0). For all MAbs, the plasma-to-tissue transport constants were consistently greater for M21 tumors (0.44-0.85 microliter/min/g) than for SK-MEL-2 tumors (0.28-0.66 microliter/min/g), and values of k for both tumors were approximately 1 order of magnitude greater than those for skeletal muscle (0.06-0.08 microliter/min/g). The model-estimated binding site concentration of melanoma-specific antibodies was 15-70 times lower than that predicted by experimental measurements of tumor antigen concentrations. Factors that may contribute to this discrepancy include inaccessibility of tumor cell binding sites to MAb and MAb catabolism. In summary, these results indicate that, for the MAb dose used in this study, variables pertaining to the tumor target (i.e., antigen expression levels, vascular volume, and vascular permeability) are the most important for determining MAb accumulation in tumors.

Tumor-bearing mice exhibit a progressive increase in tumor antigen-presenting cell function and a reciprocal decrease in tumor antigen-responsive CD4^+ T cell activity.

Abstract: Splenic CD4+ T cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 2 to 3 wk after the inoculation with CSA1M cells produced IL-2 and macrophage-activating factor upon in vitro cultures. This lymphokine production was achieved without stimulation of these T cells with exogenous stimulating tumor Ag. However, elimination of APC from spleen cells resulted in almost complete abrogation of the capacity of CD4+ T cells to produce IL-2/macrophage-activating factor. The lymphokine production was regained when APC from CSA1M-bearing mice were added back to cultures. APC from normal or another syngeneic tumor (Meth A)-bearing mice failed to regain the lymphokine production. These observations demonstrated that the lymphokines were produced by CD4+ T cells from CSA1M-bearing hosts through their collaboration with APC binding CSA1M tumor Ag in the tumor-bearing state. The lymphokine-producing capacity of whole spleen cells from tumor-bearing mice reached the maximal level around 2 to 3 wk after tumor implantation but gradually decreased with the progress of tumor-bearing stages. Importantly, tumor-bearing stage-related changes were observed in a different fashion in the capacities of anti-CSA1M CD4+ T cells vs CSA1M tumor Ag-binding APC. The capacity of APC increased with the progress of tumor-bearing stages as demonstrated by the stimulation of CSA1M-immunized T cells with APC from different CSA1M-bearing stages. In contrast, the reactivity of anti-CSA1M T cells to APC from a given CSA1M-bearing stage decreased with the tumor-bearing stage. These results demonstrate a stage-related increase tumor Ag-binding APC function, as well as a reciprocal reduction in tumor Ag-responsive CD4+ T cell activity.

Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas.

Abstract: K1 is a murine monoclonal antibody (MAb) derived from a hybridoma generated by the fusion of splenocytes of BALB/c mice immunized with a human ovarian tumor cell line, OVCAR-3. This antibody reacts strongly with epithelial ovarian tumors and mesotheliomas. The antigen recognized by MAb K1, designated CAK1, has recently been characterized as a 40-kDa protein probably anchored to the cell surface by glycosyl-phosphatidylinositol. Using immunoperoxidase histochemical methods, we examined 37 squamous-cell carcinoma (SqCC) samples from cervix, lung, esophagus and other origins, and 12 normal squamous epithelia of the cervix and esophagus for their reactivity with MAb K1. Of the SqCC specimens, 81% showed K1 reactivity with variable intensity, but none of 12 normal tissue samples of squamous epithelia did so. Two patterns of CAK1 expression in tumor samples were found, i.e., a heterogeneous pattern with strong intensity, and a homogeneous pattern with weak intensity. Three carcinomas in situ of the larynx, vulva and esophagus were moderately positive with K1, suggesting that CAK1 antigen may occur in the early stage of carcinogenesis of SqCC. The expression of CAK1 was also compared with expression of CA125, HER-2/neu, p53 and P-glycoprotein, and MAb K1 was found to react most consistently with SqCC. Since K1 reacts with a majority of cervical and esophageal carcinomas but has no detectable reactivity in normal epithelia of the cervix uteri and esophagus, MAb K1 could be of value as a reagent to help distinguish between normal and neoplastic cells on sections as well as in cytological samples.

Intraperitoneal administration of interferon-gamma to carcinoma patients enhances expression of tumor-associated glycoprotein-72 and carcinoembryonic antigen on malignant ascites cells.

Abstract: PURPOSEThe study was designed to determine whether in vivo interferon gamma (IFN-gamma) administration could enhance tumor antigen expression on the surface of human tumor cells.MATERIALS AND METHODSEight patients (six with ovarian and two with gastrointestinal tumors) with a diagnosis of adenocarcinoma with secondary malignant ascites were given weekly escalating doses of IFN-gamma (ie, 0.1 to 100 MU) intraperitoneally (IP) each week for 8 weeks. Tumor cells were isolated from the patients' ascites samples, which were collected three times per week: before and 24 and 48 hours post-IFN-gamma administration. The level of expression of tumor-associated glycoprotein-72 (TAG-72) and carcinoembryonic antigen (CEA) was measured using flow cytometry and immunocytochemistry.RESULTSIFN-gamma administered IP dramatically increased TAG-72 (as measured by binding of anti-TAG-72 monoclonal antibodies [MoAbs] B72.3 and CC 49) and CEA (measured by MoAb COL-1) expression on the surface of the carcinoma cells. The ascites...

Simian virus 40 mutants with amino-acid substitutions near the amino terminus of large T antigen.

Abstract: A series of amino-acid substitution mutants has been made with changes in the region of simian virus 40 large tumor antigen (T antigen) that is shared with the small tumor antigen (t antigen). Both single and multiple amino-acid replacements were obtained using the heteroduplex deletion loop method and sodium bisulfite as the mutagen. The mutants could be divided into five phenotypic classes on the basis of their biological properties: a) mutants whose changes did not affect their ability to propagate on permissive monkey cells, nor to transform nonpermissive rodent cells; b) mutants that were not viable, replicated their DNA to 5% or less of wild type, but were positive for transformation; c) mutants that were not viable, replicated their DNA to 5% or less of wild type, and were defective for transformation; and d) mutants that completely lost all three activities coordinately. In addition, one mutant with changes in this region, 5002, replicated its DNA to about 50% of wild type, had an impaired transformation activity, and produced virions at a level of about 4% that of wild type.

Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1.

Abstract: We examined the ability of bryostatin 1 (Bryo), a novel protein kinase C activator, plus ionomycin (Io), a calcium ionophore, to activate T-cells with specific antitumor activity. Lymphocytes from the draining lymph nodes (DLN) of MCA-105 tumor-bearing host mice were stimulated with Bryo/Io, either fresh or after in vitro stimulation with autologous tumor, and then were incubated in interleukin-2 at 20 units/ml. Lymphocytes sensitized with tumor cells in vitro and then stimulated with Bryo/Io exhibited significant expansion (12-fold) after a total of 3 weeks in culture and moderate cytolytic activity (40% at an effector:tumor cell ratio of (80:1) and were exclusively CD8+ T-cells. DLN cells activated immediately with Bryo/Io, without tumor antigen sensitization in vitro, displayed marked growth (130-fold expansion) over 3 weeks in culture, had weak cytolytic activity (8% at an effector:tumor ratio of 80:1), and were a mixed population of CD8+ and CD4+ cells. Despite the differences in phenotypes and in cytotoxicity, both groups of DLN cells were highly effective in vivo against MCA-105 pulmonary metastases. Bryo/Io-activated DLN cells from MCA-105 tumor-bearing hosts had no therapeutic efficacy against B16 melanoma or MCA-203 sarcoma metastases. Lymph node cells from normal mice and non-draining lymph node cells from tumor-bearing hosts could be expanded with Bryo/Io to a degree similar to that of DLN cells but had no antitumor activity. Phenotypic analyses and in vitro and in vivo depletion studies demonstrate that CD8+ cells mediated tumor regression.

Lymphokine gene therapy of cancer.

Abstract: A novel method of tumor immunotherapy is described comprising the genetic modification of cells resulting in the secretion of cytokine gene products to stimulate a patient's immune response to tumor antigens. In one embodiment, autologous fibroblasts genetically modified to secrete at least one cytokine gene product are utilized to immunize the patient in a formulation with tumor antigens at a site other than an active tumor site. In another embodiment, cells genetically modified to express at least one tumor antigen product and to secrete at least one cytokine gene product are utilized in a formulation to immunize the patient at a site other than an active tumor site.

Physiological factors influencing radioantibody uptake: a study of four human colonic carcinomas.

Abstract: We evaluated the accretion of 131I-labeled NP-4 anticarcinoembryonic antigen (CEA) into 4 size-matched human colonic carcinomas grown s.c. in nude mice. Antibody uptake for LS174T and GW-39 tumors was relatively high (19 to 23% ID/g on day 3), whereas moderate uptake was seen in the Moser tumor (7.5% on day 3) and low uptake was detected in the GS-2 tumor (1.8% on day 3). Blood clearance of radioantibody was twice as fast in mice with GS-2 tumors than in mice with GW-39, LS174T or Moser tumors. Seven physiological parameters that might influence radioantibody accretion were evaluated in order to better understand the differences in observed tumor targeting: vascular volume, blood flow rate, vascular permeability, tumor antigen content, serum antigen content and complexation of radioantibody, intratumoral antigen distribution, and intracellular antigen distribution. Although marked variability in vascular physiology, antigen content and antibody complexation of the 4 tumors grown in the same host and site existed, it was insufficient to explain the differences in antibody uptake. However, intra-tumoral distribution of antigen, and sub-cellular accessibility of antigen for radioantibody were important considerations. GS-2 tumors are well differentiated and have polarized cells. CEA in GS-2 is largely inaccessible to radioantibody; most of the antigen is located in the lumen of the glands or on the apical surface of gland cells and most of the antibody distributes to the stromal region on the basolateral surface. The low antibody targeting in GS-2 could therefore be explained by restricted intra-tumor accessibility of antibody. Scatchard analysis of NP-4 binding to Moser cells under non-internalizing and internalizing conditions revealed that 90% of the antigen is found within the cell, unavailable to bind with the NP-4 antibody, which is slow to internalize. In contrast, CEA in LS174T cells was almost entirely accessible. The reduced antibody targeting to Moser xenografts might therefore, be explained by restricted antibody accessibility at the cellular level.

Tumor-antigen-specific humoral immune response of animals to anti-idiotypic antibodies and comparative serological analysis of patients with small-cell lung carcinoma.

Abstract: We have previously developed 3 monoclonal anti-idiotypic antibodies (Ab2) of LOU rat origin directed against the binding site of the murine monoclonal IgM LAM8, which recognizes the small-cell lung carcinoma (SCLC)-associated sialoglycoprotein antigen sGP 90-135. The aim of this study was to compare the efficiencies of these 3 Ab2, designated LY8-229, LX8-531 and LX8-632, to induce antigen-specific immunity in different animal species without prior exposure of the recipients to the nominal antigen, and thereby possibly select an Ab2 candidate for active immunotherapy against SCLC in patients. The feasibility of this approach was further evaluated by a serological analysis of patients with SCLC compared with healthy individuals, in whom the spontaneous antibody reactivities against SCLC cell lines and Ab2 were tested. LY8-229 was shown to be the most effective Ab2 in inducing antigen-specific antibodies in BALB/c mice, CBA/J/Zur mice and one NZW rabbit. Furthermore, LY8-229 was the only Ab2 against which significantly elevated idiotype-specific antibody reactivities existed in sera of patients with SCLC. These reactivities correlated positively with binding to antigen-positive tumor cells. Our findings suggest that LY8-229 represents in its reactivity pattern the nominal SCLC antigen in humans also, and therefore may be of diagnostic and possibly therapeutic relevance for patients with SCLC.

Membrane association and shedding of the GPI-anchored Ca-MOv18 antigen in human ovary carcinoma cells.

Abstract: The antigen recognized by the MOv18 MAb (Ca-MOv18) was recently shown to be a glycosylphosphatidylinositol (GPI)-linked protein. In this report we show that GPI-anchorage is not limited to IGROVI cells nor to other ovary carcinoma cell lines, but Ca-MOv18 was also found to be sensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment on fresh ovarian cancer cells. Furthermore, we found a heterogeneous sensitivity of Ca-MOv18 to PI-PLC cleavage, not only among the different cells studied but also in different experiments performed on the same cell line, during extended periods of time in culture. Sensitivity to PI-PLC cleavage was determined by immunofluorescence on live cells and by double-determinant radioimmunoassay of the antigen released in the supernatant. The specificity of the PI-PLC cleavage was demonstrated as follows: (a) TX114 solubilized Ca-MOv18 shifts from the detergent to the aqueous phase after treatment with PI-PLC; (b) on membrane preparations, PI-PLC specifically released a fraction of the antigen, which is distinct from the weakly associated form released by high-salt treatment; (c) Ca-MOv18 from IGROVI expressed the cross-reacting determinant (CRD), which is characteristic of GPI-linked molecules. The absence of CRD expression on the spontaneously released protein and the possibility of artificially inducing antigen shedding during the resynthesis of Ca-MOv18 which follows bacterial PI-PLC treatment are interesting points which need to be further investigated in order to understand the physiology of the Ca-MOv18 tumor antigen.

Bryostatin 1 activates T cells that have antitumor activity.

Abstract: Several strategies have been used to stimulate the growth of tumor-specific T cells in place of tumor antigen. One approach is to use pharmacologic agents to activate the second messenger pathways of T-cell activation. In the present study, we examined the ability of the protein kinase C activator bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to stimulate the growth of lymphocytes obtained from the axillary lymph nodes (DLN) draining a progressively growing intradermal plasmacytoma tumor. Draining lymph node cells were initially cultured with autologous tumor cells and 20 U/ml of interleukin-2 (IL-2) for 7 days. The lymphocytes were then incubated with various concentrations of bryostatin 1 plus 1 microM ionomycin and cultured for an additional 14 days in IL-2. DLN cells initially cultured with autologous tumor and then restimulated with 5 nM bryostatin 1 and 1 microM ionomycin exhibited marked in vitro proliferation and 15-fold expansion of cell numbers over 2 weeks. The cells expanded with B/I were predominantly CD8+ T cells and retained specific in vitro cytotoxicity against autologous tumor. When adoptively transferred to mice with established liver metastases, DLN cells restimulated with B/I-mediated specific tumor regression.

Tumor antigen phenotype, biologic staging, and prognosis in head and neck squamous carcinoma.

Abstract: Prior studies of alterations in tumor expression of normal blood group antigens and A9/alpha 6 beta 4 integrin, an extracellular matrix receptor, have suggested that these immunohistologic markers reflect the biologic aggressiveness of head and neck squamous carcinomas. To confirm these preliminary observations, prospective long-term follow-up of 82 previously untreated head and neck squamous carcinoma patients was performed. All patients were treated with conventional therapy. Median follow-up was 57 months. Tumor immunohistology for ABH blood group and A9/alpha 6 beta 4 integrin expression was performed and correlated with measures of host cellular immunity, disease-free survival, and overall survival. Loss of blood group expression and high A9/alpha 6 beta 4 integrin expression were each directly related to an increased frequency of early tumor recurrence. The combination of both variables was significantly associated with both disease-free (P = .029) and overall survival (P = .05). Increased expression of A9/alpha 6 beta 4 was associated with impaired T-lymphocyte function (P = .005), and loss of blood group expression was associated with decreased peripheral blood levels of CD8+ T-lymphocytes (P = .013). The findings suggest that these phenotypic characteristics of antigen expression in head and neck squamous carcinomas are important markers of biologically aggressive cancers and impaired host immune response. The clinical use of these biologic staging parameters in the initial assessment of patients should allow selection of more aggressive primary treatment strategies for individual patients.

Immunotherapy of advanced ovarian carcinomas by activation of the idiotypic network.

Abstract: The positive effect of an immunotherapy using tumor-associated antigens or tumor cells of ovarian carcinomas has not yet been proven. Although many unique tumor-associated antigens have been described and a tumor rejection could be seen in occasional cases, the failure of the immune system to destroy tumor cells is not clearly understood. An alternative approach is to initiate the idiotypic network utilizing antibodies (Ab1 or 2) against a tumor-associated antigen, which induces the production of anti-idiotypic-antibodies (Ab2 beta), mimicking the "internal image" of the tumor-associated antigen. These antibodies are able to induce a specific antitumor immunity in two ways: (1) the Ab2 can present the critical epitope in a different way and so modulates the immune system, or (2) it can induce the production of an Ab3, which by itself binds to the tumor antigen. Our first results on 22 patients with advanced ovarian carcinomas show that the induction of an anti-idiotypic antibody (Ab2 beta) against OC 125 mimicking the TAA Class III CA 125 leads to a prolongation of the survival rate also for extended stages. We see a beneficial role of the induction of the idiotypic network against a tumor-associated antigen showing delayed clinical courses of the disease after vaccination of the patients with antibody fragments of the OC 125.

Tumor-immunotherapy with the use of tumor-antigen-pulsed antigen-presenting cells.

Abstract: Our previous study demonstrated that the administration of antigen-presenting cells (APC) pulsed with tumor cell membrane fraction to naive syngeneic mice results in effective induction of tumor-specific protective immunity in vivo. The present study examined whether tumor-antigen-pulsed APC can produce the inhibitory effect on the growth of tumor cells when administered to tumor-bearing hosts. Naive BALB/c mice were inoculated with viable tumor cells. Five days later, these mice started to receive the relevant tumor-antigen-pulsed APC at 3- to 4-day intervals. The administration of tumor-antigenpulsed APC induced the rejection or growth inhibition of a growing tumor in approximately half of the recipient mice. Moreover, it was demonstrated that tumor-specific immunity was induced in such tumor-regressed mice. These results indicate that tumor-antigen-pulsed APC are effectively applicable to the tumor-specific immunotherapy.

Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene.

Abstract: Melanotransferrin (MTf) is a tumor associated antigen found in abundance on the surface of melanoma cells. It is a transferrin-like protein found in low amount in most adult tissues and whose gene is reminiscent of house-keeping genes. With the goal of understanding the regulatory mechanisms which might explain the enhancement of expression in tumor cells, we report here the characterization of a regulatory element located 2 kbp upstream from the promoter and whose deletion specifically impairs gene expression in melanoma cells; we show that this element is part of an enhancer composed of two modules which are each the target for the AP1 transcription factor. The two modules present a synergistic mode of action specific for melanoma cells which requires both of the 130 bp away AP1 sites. Furthermore, we show that the enhancer behaves differently according to the promoter context.

Update on tumor vaccines.

Abstract: Vaccination against tumor has always been an attractive idea for the treatment of patients bearing tumor. By harnessing the host's own immune response the attack on tumor cells would act on a continuing basis, with emerging tumor cells stimulating their own destruction. However, the approach has been hampered by our poor understanding of the nature of tumor antigens and of the pathways by which immune cells might operate against tumor growth. Recent developments in molecular biology and immunology are remedying this deficiency and bringing vaccination to the forefront of new approaches to treatment of a range of tumors. Results obtained in B-cell tumors, where the idiotypic immunoglobulin at the cell surface provides a well-defined tumor antigen, are already indicating exciting possibilities as well as delineating problems. There is considerable clinical evidence that patients have some intrinsic ability to control tumor growth and that certain tumors remain dormant for long periods. Attempts to understand and perhaps stimulate the mechanisms involved are being made through the use of biological modifiers and by manipulating potential effector cells in vitro. Ideally this approach, which may include non-specific and specific elements, could be combined with specific vaccination in order to combat the apparent ability of many tumor cells to evade host defences.

Detection of allogeneic Qa/TL and Ly specificities on murine tumor cells with IgD in tumor-regressor serum.

Abstract: Serum from C3H/He mice, which show regression of MM2 tumor cells after transplantation and removal (regressor serum, RS) contains non-gammaglobulin components that cross-react with various tumor cells of mice [22, 23]. In addition to tumor cells, various allogeneic lymphocytes are also susceptible to an RS-dependent lymphocyte-mediated cytotoxic reaction. To identify tumor cell surface antigens that cause the cross-reactive host response, the serum components were analyzed by absorption of RS with allogeneic lymphocytes. RS components were found to recognize allogeneic lymphocyte antigens including Qa-2 and Ly6.2. Specificity for the Qa-2 antigen was further tested using Qa-2-congenic mice. The expression of Qa-2 antigen was detected on the surfaces of MM2 and other tumor cells derived from H-2k mice (seven among nine cell lines tested) by a membrane immunofluorescence method using a Qa-2-specific mAb. Physical characteristics of the Qa-2-specific component in RS were determined and found to differ from those of regular IgGs but to be similar to those of IgDs. Using an enzyme-linked immunosorbent assay with an IgD-specific mAb and Qa-2-lacZ fusion protein, the existence of IgD in RS with specificity for Qa-2 was confirmed. These results suggest that the RS component with Qa-2 specificity is an IgD, the specificity and physiological role of which are unknown.

Effect of immunization with anti-idiotypic antibody to melanoma antigen on lung metastasis in mice.

Abstract: To determine whether the pulmonary metastases of melanoma cells could be inhibited, C57BL/6 mice were immunized with an anti-idiotypic antibody, 7C4, corresponding to a mouse melanoma antigen Three groups of mice were compared: 1) 7C4-immunized group which received an injection of 100 micrograms of 7C4 in Freund's complete adjuvant (FCA) subcutaneously on day -21 followed by intraperitoneal injections of the same dose on days -14 and -7,2) adjuvant-treated control group administered with only FCA, and 3) untreated control group On day 0, 5 x 10(5) of BL6 cells were injected into the caudal vein of all mice Two weeks later, they were sacrificed and their lungs were removed The number pulmonary metastatic colonies present on the lung surface were counted and compared among the groups The length of survival days was also compared The 7C4-immunized group showed an average of 166 +/- 44 colonies as compared to more than that of 300 colonies in each control groups, and a significant difference was observed (P < 001) The immunized group survived significantly longer than the control group (Greenwood's formulation) on day 23 (P < 001) Thus the immunization with 7C4 effectively inhibited lung metastasis of melanoma cells These findings suggest that vaccination with anti-idiotypic antibody to tumor antigen is effective on inhibiting tumor metastasis

Tumor-specific T cell lines: capacity to proliferate and produce interleukin 2 in response to various forms of tumor antigens.

Abstract: Anti-tumor proliferative T cell lines were established from cultures of lymph node cells from BALB/c mice immunized to syngeneic CSAIM fibrosarcoma with the CSAIM tumor cell membrane. The cultures were maintained throughout in the absence of exogenous interleukin 2 (IL2) J. Cell surface phenotypes of all T cell lines established were Thy-1+, Ig-, L3T4+ and Lyt-2-. Their proliferation was induced in a tumor antigen dose-dependent fashion and a tumor antigen-specific way. Such proliferative responses were inhibited by the addition to cultures of anti-class II H-2d (anti-I-Ad) or anti-L3T4 but not of anti-class I H-2d or anti-Lyt-2 monoclonal antibody. None of the T cell lines exhibited any cytotoxic T lymphocyte activity but they all produced IL2 upon stimulation with CSAIM tumor antigens, indicating that they represent helper-type T cell (Th) lines. The activation of these tumor-specific Th lines was induced with either CSAIM tumor cells themselves, or their membrane or detergent-solubilized fraction depending on the presence of antigen-presenting cells (APC). Most importantly, activation was also inducible by membranous tumor antigen-pulsed APC, which were capable of producing potent anti-tumor protective immunity when administered in vivo into syngeneic BALB/c mice. These results indicate that the tumor-specific Th lines established here can be activated with various forms of tumor antigens for their expression of helper function. Since Th lines of this type have not been described previously, our Th lines provide an intriguing tool for investigating the cellular and molecular mechanisms by which tumor-specific Th recognize tumor antigens.

Anti-Growth Factor Receptor Antibodies as Therapy for Cancer

Abstract: The idea of attacking cancer cells at the cell surface was revived in the past decade by the availability of monospecific heteroantisera. Phase I trials using monoclonal antibodies to most tumor cell antigens have shown little anti-tumor activity (Reviewed in 1,2). The reasons for these failures are complex, but include heterogeneity of tumor antigen expression; antibodyinduced antigen modulation from the cell surface; formation of human anti-mouse antibodies; and the uncertain efficacy of the host cell anti-tumor response (1,2). Immunoconjugates employing monoclonal antibodies as carriers for toxins, drugs, or radioisotopes and chimeric human-mouse monoclonal antibodies remain under investigation (1,2).