Showing papers on "Tumor antigen published in 1987"

Anti-idiotype immunization of cancer patients: modulation of the immune response.

Abstract: Thirty patients with advanced colorectal carcinoma (CRC) were treated with alum-precipitated polyclonal goat anti-idiotypic antibodies (Ab2) to monoclonal anti-CRC antibody CO17-1A (Ab1) in doses between 0.5 and 4 mg per injection. All patients developed anti-anti-idiotypic antibodies (Ab3) with binding specificities on the surfaces of cultured tumor cells similar to the specificity of Ab1. Furthermore, the Ab3 competed with Ab1 for binding to CRC cells. Fractions of Ab3-containing sera obtained after elution of the serum immunoglobulins from CRC cells bound to purified tumor antigen and inhibited binding of Ab2 to Ab1. The Ab3, therefore, may share idiotopes with Ab1. Six patients showed partial clinical remission and seven patients showed arrest of metastases following immunotherapy. Four of the thirteen patients with measurable clinical responses had received Ab2 alone, whereas 9 patients had also received chemotherapy.

Recombinant interferon enhances monoclonal antibody-targeting of carcinoma lesions in vivo

Abstract: Heterogeneity in the expression of tumor-associated antigens, as defined by the binding of monoclonal antibodies, is a characteristic common to most, if not all, human carcinoma cell populations. Antigen-negative cells within the population can escape detection and therapy by their failure to bind the appropriate antibody. Therefore, the extent of antigenic heterogeneity is an important consideration when designing protocols for the management of cancer by administration of monoclonal antibodies. One approach to counteracting the effect of antigenic heterogeneity is the use of clone A of recombinant human leukocyte interferon (Hu-IFN-alpha A). Administration of Hu-IFN-alpha A in vivo effectively increased the amount of tumor antigen expressed by a human colon xenograft in situ and augmented the localization of a radiolabeled monoclonal antibody to the tumor site. Concomitant administration of Hu-IFN-alpha A and monoclonal antibody may thus be effective in overcoming the antigenic heterogeneity of carcinoma cell populations and in enhancing the efficacy of monoclonal antibodies in the detection and treatment of carcinoma lesions.

Variations in polyoma virus genotype in relation to tumor induction in mice. Characterization of wild type strains with widely differing tumor profiles.

Abstract: The authors have explored the effects of variations in mouse polyoma virus genotype on patterns of tumor formation in the mouse. Four "wild type" virus strains were surveyed. Two were highly oncogenic, inducing multiple tumors of epithelial and mesenchymal origin, at high frequency and with short latency. The other two strains were weakly oncogenic, inducing fewer tumors, solely of mesenchymal origin, and after a long latency. These sharply contrasting tumor profiles were reproduced with virus stocks derived from molecularly cloned viral genomes. Though vastly different in their oncogenic properties, these cloned viruses proved equally effective in transforming established rat fibroblasts in culture and showed the same patterns of tumor antigen expression in cultured mouse cells. Complexes of polyoma middle T antigen and pp60c-src were demonstrated in extracts of epithelial tumors induced by a highly oncogenic virus strain. It is concluded that polyoma viral genetic determinants for tumor induction in the mouse are more complex than those previously defined by the use of cell transformation systems.

Characterization of a mouse/human chimeric monoclonal antibody (17-1a) to a colon cancer tumor-associated antigen'

Abstract: Mouse monoclonal antibody 17-1A is specific for an antigen expressed on cells of human gastrointestinal malignancies and has been used in radioimmune imaging and therapy trials for patients with colon and pancreatic cancer. The cell line SG3/5 was generated by transfection of a nonproducing mouse myeloma line (SP2/0) with a chimeric gene construct composed of variable regions from the mouse 17-1A immunoglobulin (gamma 2a, kappa) and constant regions of human k and gamma 3 immunoglobulin genes. The secreted immunoglobulin was bound by mouse monoclonal antibodies to human IgG(Fc) and IgG3 but not by staphylococcal protein A. Gel filtration HPLC profiles of purified chimeric antibody were similar to normal human IgG3 but quite different from native 17-1A and normal human IgG1, 2, and 4. Native and chimeric 17-1A had similar patterns of reactivity with colon cancer, other adenocarcinoma, and leukemic cell lines. Competitive inhibition documented that native and chimeric 17-1A had identical capacities to inhibit radiolabeled native 17-1A binding to colon cancer cell lines. Thus, the chimeric 17-1A exhibits molecular characteristics of normal human IgG3 but retains the specificity and binding affinity of the native 17-1A murine monoclonal antibody. The native and chimeric 17-1A mediated similar modest degrees of human lymphocyte and monocyte ADCC in a 4-hr 51Cr release assay, and both failed to mediate complement lysis of colon carcinoma cell lines in the presence of human complement. This human/mouse chimeric monoclonal antibody may be a good candidate for use in clinical trials because it retains the tumor antigen specificity and human effector cell recognition of the native 17-1A, would presumably have a fivefold to 10-fold longer circulating half-life in man, and should be considerably less immunogenic as compared with native murine immunoglobulins.

Relationship between simian virus 40 large tumor antigen expression and tumor formation in transgenic mice.

Abstract: A line of transgenic mice containing the simian virus 40 (SV40) large tumor antigen gene under the control of the viral enhancer-promoter expressed this viral protein in the brains of these mice within the first 2 weeks after birth. Multiple foci of anaplastic cells formed in the choroid plexuses of these mice at 36 to 41 days after birth, and normal tissue coexisted with these transformed foci. Immunoperoxidase staining to detect the SV40 T antigen showed tumor-specific expression of nuclear T antigen at late times in tumor development, approximately 90 to 100 days and thereafter. The level of SV40 T antigen, on a per cell basis, appeared to be lower in the great majority of choroid plexus cells at earlier times in tumor development. These results suggest that low levels of tumor antigen (14 to 36 days) are present before detectable pathology (36 to 41 days) and the level of T antigen per cell is higher in rapidly growing late-stage tumors (older than 90 days).

Approaches to augmenting the immunogenicity of the ganglioside GM2 in mice: purified GM2 is superior to whole cells.

Abstract: The gangliosides GM2, GD2, and GD3 are differentiation antigens largely restricted to cells of neuroectodermal origin. They are expressed on most melanomas, astrocytomas, and neuroblastomas and have been shown to function as effective targets for monoclonal antibodies. In previous studies, we have immunized melanoma patients and mice with a series of melanoma cell vaccines containing these antigens, but have observed only occasional antibody responses. We report here the results of experiments in which an irradiated whole cell vaccine shown previously to be optimal was compared with a series of vaccines containing purified GM2. Mice were pretreated with low dose cyclophosphamide (Cy), or not, and were immunized twice with syngeneic melanoma cells (JB-RH) known to contain 60 micrograms of GM2 or with vaccines containing 50 micrograms of purified GM2. Serum was obtained at regular intervals and was tested by immune adherence, complement dependent cytotoxicity, and protein A assays on the JB-RH cell line. The whole cell vaccine, GM2 alone, GM2 incorporated into complete Freund's adjuvant, and GM2 attached to E. coli were all minimally immunogenic. GM2 attached to Salmonella minnesota or BCG, and GM2 attached to certain liposome preparations containing monophosphoryl lipid A, were found to be moderately immunogenic. GM2 attached to the R595 mutant of Salmonella minnesota was found to be significantly more immunogenic. Pretreatment with Cy significantly increased the immunogenicity of this vaccine. The specificities of selected sera were tested in inhibition assays and were limited to GM2. Antibodies produced after immunization were generally exclusively IgM and mediated potent complement-dependent cytotoxicity on JB-RH cells. These results identify R595 as the most effective adjuvant tested for augmenting the immunogenicity of GM2 and show that with regard to antibody production, purified tumor antigen presented optimally can be more immunogenic than optimally presented whole tumor cells containing the same amount of antigen.

Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity.

Abstract: The successful application of a non-oncogenic virus, Newcastle disease virus (NDV), which can be used to modify a highly metastatic tumor to become more immunogenic is reported. Such NDV modified tumor cells were found to be effective as tumor vaccine for anti-metastatic therapy in combination with surgical removal of the primary tumor. The protection in the animals seen after this treatment is paralleled by an establishment of specific systemic anti-tumor immunity. This protective immunity depended on recognition of a distinct tumor antigen. The therapy protocol also worked in animals bearing the plastic adhesive variant ESb-MP. It did not work, however, when using an immune escape variant not expressing a specific tumor antigen]

Induction of specific immunity to human colon carcinoma by anti‐idiotypic antibodies to monoclonal antibody CO17‐1A

Abstract: Anti-idiotypic antibodies (Ab2) to murine monoclonal antibody (mAb) CO17-1A (Ab1), which defines an antigen associated with human colon carcinoma, were produced in goats. The Ab2 inhibited binding of Ab1 to colon carcinoma cells, and purified tumor antigen inhibited binding of Ab1 to Ab2. The Ab2 elicited in rabbits anti-anti-idiotypic antibodies (Ab3) that bound to cultured human cells of various tissue origins with a binding pattern identical to that of Ab1. Moreover, both Ab1 and Ab3 bound to the isolated tumor antigen, and the Ab3 lysed human colon carcinoma cells in culture in the presence of rabbit complement. Thus, Ab2 raised to mAb CO17-1A are candidates for use in immunotherapy trials in cancer patients.

Immunotherapy of murine sarcomas with auto-anti-idiotypic monoclonal antibodies which bind to tumor-specific T cells.

Abstract: Hybridomas producing monoclonal antibodies (mAb) were obtained from BALB/c mice immunized against either of two transplanted, chemically induced syngeneic sarcomas, MCA-1490 or MCA-1511. Two mAb, 4.72 and 5.96, were obtained, one from each immunization. They were found to have apparent anti-idiotypic specificity in that they, when injected s.c., primed naive BALB/c mice for delayed-type hypersensitivity that was specific for the immunizing tumor and required homology at genes linked to the Igh-1 allotype locus. Neither mAb bound tumor antigen. When mice with established transplants of MCA-1490 or MCA-1511 were treated by repeated i.p. injections of the appropriate anti-idiotypic mAb (4.72 and 5.96, respectively), a significant reduction in tumor growth was observed in those mice that had received the appropriate mAb. The idiotope defined by mAb 4.72 was expressed by T cells in mice responding to MCA-1490. mAb 4.72 bound to T cell suppressor factors that were specific for MCA-1490 and were derived from T cell hybridomas or sera of mice bearing MCA-1490. mAb 4.72 also bound to cells from lymph nodes draining the area of a growing MCA-1490 tumor. It was used, in combination with cell sorting, to establish a T cell line, which mediated delayed-type hypersensitivity to MCA-1490 and inhibited the outgrowth of MCA-1490 in BALB/c mice. Thus, mAb specific for idiotopes on T cells responding to syngeneic tumor antigen had both direct immunotherapeutic activity and could be used to establish cultures of tumor-reactive T cells.

Current status of cancer imaging with radiolabeled antibodies.

Abstract: This editorial reviews the development, current status, and future prospects of cancer imaging with radioactive antibodies, termed radioimmunodetection (RAID). There has been a slow and steady development of this field for more than 35 years, with more recent activity and progress resulting from the identification of human tumor-associated antibodies and suitable human tumor xenograft models, the demonstration that circulating antigens do not prevent radioantibody localization in tumor, the development of computer-assisted and biological methods for reducing non-target background radioactivity, and the advent of hybridoma-produced monoclonal antibodies. At the present time, tumor sites in the range of 1.5 to 2.0 cm can be imaged, with the best resolution of 0.4–0.5 cm being reported with new chelates of 99mTc. A number of factors, including character of the radioantibody and its bioavailability, the tumor antigen site and bioavailability, the character of the radiolabel, and the target tumor's size, location and vascularization, contribute to the sensitivity, specificity, accuracy, and resolution of the method. Already at this early stage of development, RAID has been shown to have, in certain tumor types and with particular antibody and imaging systems, an accuracy of tumor site detection of over 90%, with the disclosure of occult lesions. Carefully designed prospective trials are needed to fully assess the role of this new modality in the management of cancer patients, particularly in early detection of primary and recurrent tumors.

Target-selective cytotoxicity of methotrexate conjugated with monoclonal anti-MM46 antibody.

Abstract: In studies on antitumor antibody-cytotoxic drug conjugates as potential tumor-selective cytotoxic agents, methotrexate (MTX) was conjugated via its active ester derivative with a murine monoclonal antibody (aMM46) to a mouse mammary tumor antigen (MM antigen) on syngeneic, ascitic C3H/He mouse mammary tumor MM46 cells. The conjugate retained full antibody activity, as assayed by complement-dependent cytolysis. The target-selective cytotoxicity of aMM46-MTX was verified by the observations that this conjugate showed greater cytotoxicity than the corresponding normal mouse immunoglobulin (nIg) conjugate to MM46 cells, neither aMM46 nor nIg being cytotoxic, and that it showed less cytotoxicity to MM antigen negative mouse mammary tumor MM48 cells than to MM46 cells, its cytotoxicity to MM48 cells being similar to that of the nIg conjugate. From the results of assays of cell binding and uptake of 131I-labeled aMM46 and aMM46-3H-MTX, aMM46 and aMM46-MTX were internalized after their binding to MM46 cell surface antigen. Leupeptin, an inhibitor of the lysosomal endopeptidase cathepsin, decreased the cytotoxicity of aMM46-MTX, supporting the involvement of lysosomal degradation of the conjugate in its action.

Inhibition of growth of human tumor xenografts in athymic mice treated with ricin toxin A chain-monoclonal antibody 791T/36 conjugates.

Abstract: Immunotoxin constructed by conjugating ricin A chain to monoclonal antibody 791T/36 specifically inhibits growth of human tumor xenografts which express the gp72 antigen recognized by the antibody component. Dose schedule tests showed that the major response was obtained during the first 5 days of treatment and further prolonged treatment did not improve therapy. Expression of gp72 antigen on tumor cells derived from xenografts in immunotoxin-treated mice was not markedly altered indicating that treatment did not lead to the expansion of tumor antigen deficient tumor cells. The experiments indicate that treatment for short duration with immunotoxin may be the most effective protocol.

Characterization of an epithelial and a tumor-associated human small cell lung carcinoma glycoprotein antigen.

Abstract: The small cell carcinoma (SCC) antigens recognized by LAM2 and LAM8 antibody were characterized by comparison of their tissue expression and analysis of their biochemical composition. LAM2, but not LAM8 antigen could be demonstrated in lipid extracts of SCC cells. By immunohistochemical staining the SCC antigen LAM2 was shown to be an epithelial type membrane antigen. Immunoblotting experiments and competition solid phase radioimmunoassays showed LAM2 antigen to be a native conformation of a glycoprotein with major bands at Mr 100,000-120,000 and a minor band at Mr 210,000. L-Fucose was a dominant part of the epitope which appeared to be closely related to the carbohydrate epitope of the blood group antigen H(O). The tumor-associated membrane antigen LAM8 was shown to be a glycoprotein with major bands at Mr 90,000-135,000 and a minor band at Mr 200,000. Neuraminic acid was the predominant part of the carbohydrate epitope. LAM8 antibody recognized a structure in the saliva of Lea positive probands, but untreated and neuraminidase-treated SCC extracts were unreactive with anti-Lea antibody. Anti CA 19-9 (sialo-Lea antigen) and LAM2 antibodies did not compete for LAM8 binding in direct radioimmunoassays. The sialo-GP90-135 antigen recognized by LAM8 antibody therefore is likely to represent a novel tumor antigen.

Interactions between polyomavirus medium T antigen and three cellular proteins of 88, 61, and 37 kilodaltons.

Abstract: Affinity-purified medium T antigen of wild-type polyomavirus and dl8, a transforming mutant with a deletion in the medium T gene, is associated with three cellular proteins with apparent molecular weights of 88,000 (88K protein), 61,000 (61K protein), and 37,000 (37K protein). Medium T antigen encoded by the nontransforming hrt mutants fails to associate with these proteins, whereas medium T antigen of the nontransforming mutant dl1015 is able to do so. Medium T antigen of the nontransforming mutant dl23 binds to the 61K and 37K proteins; however, binding to the 88K protein is uncertain. The pattern of complex formation between these proteins and medium T antigen resembles that of pp60c-src and medium T antigen. The binding of medium T antigen to the 88K, 61K, and 37K proteins, as well as to pp60c-src, might represent a necessary but insufficient step in transformation. By mixing extracts from infected and uninfected cells, complex formation between medium T antigen and the 88K, 61K, and 37K proteins can be demonstrated in vitro. Pulse-chase experiments indicated that in vivo the association between medium T antigen and the 61K and 37K proteins is a slow process. The latter two proteins are probably bound to each other in uninfected cells. On two-dimensional gels of whole-cell extract, the 61K protein comigrated with a minor protein with an isoelectric point of 5.2. The 61K protein was neither phosphorylated nor glycosylated. Polyomavirus tumor serum precipitated the 61K and 37K proteins independently of medium T antigen. Therefore, the 61K protein or the 37K protein or both have the properties of a cellular tumor antigen.

Development and Recognition of the Transformed Cell

Abstract: 1 Cytogenetics of Neoplasia.- 2 The Structure and Function of the Normal c-myc Gene and Its Alteration in Malignant Cells.- 3 Protooncogene Expression in Lymphoid Cells: Implications for the Regulation of Normal Cellular Growth.- 4 Oncogene Products as Receptors.- 5 Monoclonal Antibodies Reactive with the neu Oncogene Product Inhibit the Neoplastic Properties of neu-Transformed Cells.- 6 Relationship of the c-fms Protooncogene Product to the CSF-1 Receptor.- 7 Two erbB-Related Protooncogenes Encoding Growth Factor Receptors.- 8 The Receptor for Epidermal Growth Factor.- 9 The Role of the abl Gene in Transformation.- 10 Comparison of the Structural and Functional Properties of the Viral and Cellular src Gene Products.- 11 Protein Kinase C as the Site of Action of the Phorbol Ester Tumor Promoters.- 12 Involvement of Human Retrovirus in Specific T-Cell Leukemia.- 13 Mechanisms of Virus-Induced Alterations of Expression of Class I Genes and Their Role on Tumorigenesis.- 14 Antigenic Requirements for the Recognition of Moloney Murine Leukemia Virus-Induced Tumors by Cytotoxic T Lymphocytes.- 15 SV40 Tumor Antigen: Importance of Cell Surface Localization in Transformation and Immunological Control of Neoplasia.- 16 Correlation of Natural Killer Cell Recognition with ras Oncogene Expression.- 17 A Regulatory Role of Natural Killer Cells (LGL) in T-Cell-Mediated Immune Response.- 18 Immune Regulation in Neoplasia: Dominance of Suppressor Systems.- 19 The Generation and Down-Regulation of the Immune Response to Progressive Tumors.- 20 Origin and Significance of Transplantation Antigens Induced on Cells Transformed by UV Radiation.- 21 Cellular and Molecular Mechanisms Involved in Tumor Eradication in Vivo.- 22 Application of T Cell-T Cell Interaction to Enhanced Tumor-Specific Immunity Capable of Eradicating Tumor Cells in Vivo.- 23 Antigens Expressed by Melanoma and Melanocytes: Studies of the Immunology, Biology, and Genetics of Melanoma.- 24 Malignant Transformational Changes of the Sugar Chains of Glycoproteins and Their Clinical Application.- 25 Ganglioside Involvement in Tumor Cell-Substratum Interactions.- 26 Specific Adoptive Therapy of Disseminated Tumors: Requirements for Therapeutic Efficacy and Mechanisms by Which T Cells Mediate Tumor Eradication.

Tumor antigen TA-4: an aid in detecting post-operative recurrences of esophageal carcinoma.

Abstract: Radioimmunoassay for serum TA-4 was performed in 35 patients with squamous cell carcinoma of the esophagus. The results were positive in 13 of 35 patients (37.1 per cent) in whom squamous cell carcinoma of the esophagus was present at the time of assay. Preoperatively, undetectable TA-4 levels in patients with esophageal carcinoma suggested localized tumor and a good prognosis, whereas, strongly positive TA-4 levels correlated with extensive tumors and a poor prognosis. Postoperatively, a positive result for TA-4 levels indicated the presence of a residual tumor. Negative TA-4 levels, however, did not exclude a residual tumor. Therefore, assessment of periodic TA-4 levels in patients who have undergone resection of esophageal carcinoma may lead to detection of a tumor recurrence.

Studies on the special tumor marker of cervical cancer of the uterus.

Abstract: Although cervical cancer is the most common malignancy of the gynecologic system, very few tumor markers have been specially prepared for this disease. This article reviews some of the current investigations of those markers, particularly describing TA-4, a tumor antigen of cervical squamous cell carcinoma, which has currently been widely used in clinical practice.

Immunohistochemical studies on tumor antigen-4 in squamous cell carcinoma of uterine cervix

Abstract: Immunohistochemical localization of Tumor Antigen 4 (TA-4) in squamous cell carcinoma (SCC) tissues of the uterine cervix was studied by means of the immunoperoxidase methods. Light microscopic detection of TA-4 was carried out by means of the avidin-biotin-peroxidase complex method on formalin-fixed paraffin-embedded sections from 92 cases of invasive cervical cancer of the uterus. These tumors were histologically SCC, consisting of 68 of the large cell non-keratinizing (LNK) type and 24 of the keratinizing (K) type. TA-4 positive cells were detected in 65% of LNK cases and 100% of K cases. Positively stained neoplastic cells were seen frequently around the hyperparakeratotic lesions, and they showed a tendency to keratinization.TA-4 localization was also confirmed in the cells of stratum spinosum of the non-cancerous squamous epithelium.Subcellular localization of TA-4 was studied by the preembedding indirect immunoperoxidase method. TA-4 was localized in the cytosols of the neo-plastic cells, but not in tonofilaments. It was suggested that TA-4 was a structural protein of SCC. Therefore, unlike keratin, TA-4 can be considered as an index of differentiation of SCC cells, and TA-4 should be useful as a tumor marker which expresses the characteristics of the neoplastic tissue during squamous maturation.

Origin and Significance of Transplantation Antigens Induced on Cells Transformed by UV Radiation

Abstract: Many experimentally induced cancers express cell surface antigens not normally found on the tissue of origin. Some of these antigens induce complete or partial protection against a lethal challenge with the tumor cells. Because of their ability to induce resistance to tumor transplantation, they have been termed tumor-specific transplantation antigens (TSTA), and they are defined primarily on the basis of their ability to induce a protective immune response in vivo.

A prospective study of squamous head and neck carcinoma immunologic aberrations in patients who develop recurrent disease

Abstract: In a prospective study of squamous head and neck cancer, the pretreatment peripheral blood of 125 patients was examined for lymphocyte subclass and in vitro immunologic function. After 4 years of followup, 49 recurrences of disease were observed. Lymphocytes from patients with recurrent disease showed elevated interleukin-2 (IL-2) production and a tendency towards increased response to mitogens in comparison to those without recurrence. When disease-free survival is analyzed on the basis of IL-2 levels, patients with high relative IL-2 synthesis (21) had a 40% poorer prognosis than patients with low relative IL-2 levels (4). The difference is significant at a P value of 0.02. Since IL-2 synthesis occurs with antigenic stimulation, it is postulated that patients who have a high IL-2 synthesis in their pretreatment lymphocytes may have had prior stimulation by circulating tumor antigen. Such immune response by the host may be successful in destroying the antigenic tumor cells but may leave the undifferentiated, less antigenic tumor cells to grow and metastasize. Thus, elevated IL-2 synthesis in pretreatment lymphocytes predicts a poorer prognosis. S solid tumors, usually has a predictable biologic and clinical behavior. This carcinoma presumably begins with a precancerous condition and progresses to an invasive state manifested by local and regional involvement, followed subsequently by dissemination to distant organs.' In the initial stages of disease, surgery and/or radiation are curative methods of treatment. For advanced stages, these two modalities of treatment are insufficient to control the disease. The role of adjunctive chemotherapy is presently under close investigation. Many important factors have been observed to affect the outcome of treatment, namely, anatomic origin of the cancer, extent of the disease as determined by staging, biologic behaviors expressed either by the tempo of disease progression clinically, or invasiveness and metastatic potential as determined by resectability and early recurrence, age of the

SV40 Tumor Antigen

Abstract: The concept of immunosurveillance is nowhere as readily demonstrated as in the SV40 tumor system. The age-related resistance to tumor induction by SV40, abrogation of that resistance by thymectomy and x irradiation, immunological intervention during the latent period resulting in the abrogation of virus carcinogenesis, high rate of spontaneous regression of primary SV40 tumors in the host, prevention of SV40 tumor transplantation in the preimmunized host, and involvement of thymus derived lymphocytes in the immunologically mediated rejection of SV40 tumor cells are all indicative of the fact that SV40-tranformed cells derived either SV40-induced tumors or, transformed in vitro, possess strong antigens at the cell surface. In this article, we will review the nature and viral origin of the transplantation rejection antigen and will discuss evidence that the protein involved in the initiation and maintenance of transformation by SV40 tumor or T antigen also provides a target for the cellular immune response by virtue of its location at the surface of SV40-transformed cells.

Studies on the recovery from tolerance to tumor antigens. II. Accelerated recovery of tumor-specific effector T cells in tolerant mice by applying T-T cell interaction mechanism.

Abstract: C3H/He mice were injected i.v. with heavily X-irradiated syngeneic X5563 tumor cells three times at 4-day intervals. This regimen resulted in the abrogation of the potential to generate X5563 tumor-specific T cell-mediated immunity as inducd by i.d. inoculation of viable X5563 tumor cells followed by surgical resection of the tumor, representing the tolerance induction. Although such a tumor-specific tolerant state was long-lasting, the recovery of anti-X5563 effector T cell responses was observed when the above ordinary immunization procedure was performed 6 months after the tolerance induction. The present study investigated whether the recovery from the tolerance can be accelerated by applying a helper-effector T-T cell interaction model in which enhanced anti-X5563 immunity is obtained by priming mice with BCG and by immunizing X5563 tumor cells modified with BCG cross-reactive MDP hapten (designated as L4-MDP) in the presence of anti-L4-MDP helper T cells preinduced with BCG. The results demonstrated that BCG-primed mice which received the tolerance regimen failed to generate anti-X5563 immunity when the ordinary immunization was performed 2 or 3 months after the tolerance induction. In contrast, the immunization of BCG-primed and X5563-tolerant mice with L4-MDP-coupled X5563 tumor cells at comparable timing to that of the ordinary immunization were capable of generating potent X5563-specific in vivo protective T cell-mediated immunity. As control groups, BCG-primed or unprimed tolerant mice did not develop anti-X5563 immunity when immunized with L4-MDP-uncoupled or L4-MDP-coupled tumor cells, respectively. These results indicate that immunization of BCG-primed, tumor-tolerant mice with L4-MDP-modified tumor cells results in accelerated recovery from the tumor tolerance.

Antigen-specific cultured T cells can mediate tumor therapy and provide long-term immunologic memory in vivo.

Abstract: One goal of our research has been to define the principles necessary to utilize cultured T cells as reagents in vivo in order to augment specific T cell immunity and to utilize the augmented immunity as a form of cancer therapy. A potential barrier for the use of cultured T cells in vivo has been the previously demonstrated inability of cultured T cells to survive in vivo. As an example, studies to be reviewed below showed that a small precursor population of tumor-specific T cells could be grown to large numbers in vitro by repeated supplementation of media with exogenous Interleukin 2 (IL 2) and that the resultant long-term cultured T cells could mediate specific tumor therapy in vivo. However, T cells grown with IL 2 lost the ability to proliferate in response to immune stimulation by tumor antigen, became dependent upon exogenous IL 2 for survival, and thus died rapidly in vivo without repeated administration of exogenous IL 2. By contrast, T cells grown long-term in vitro in response to antigen-stimulation, as opposed to exogenous IL 2, were able to proliferate in vivo in response to stimulation by tumor antigen, mediate tumor therapy and persist long-term in vivo as functional memory T cells. Thus, the previously demonstrated inability of cultured T cells to survive and persist in vivo apparently resulted from the culture conditions utilized and did not reflect an intrinsic defect of all cultured T cells.

Method for establishing antibody-forming cell strain

Abstract: PURPOSE:To obtain an antibody against tumor antigen effectively, by cultivating B cell in the presence of specific T cell and tumor antigen under a condition free from specific T cell and establishing a cell strain forming an antibody against the tumor antigen. CONSTITUTION:B cell such as splenocyte, ascites lymphocyte, lymphocyte of pleural fluid, peripheral lymphocyte, etc., of cancerous patient or normal person is cultivated in the presence of helper T cell/inducer T cell and tumor antigen under a condition wherein no suppressor T-cell/cytotoxic T cell substantially exist. The B cell can be used as a mixture with T cell. In the culture, presence of the helper T cell/inducer T cell and the tumor antigen is required, but use of the B cell as the mixture of it with the T cell does not particularly need addition of them. However, when the mixture is used, removal of the suppressor T-cell and cytotoxic T cell is required. Addition of anti-suppressor T-cell/ cytotoxic T cell antibody substantially makes absent state of the suppressor T-cell/cytotoxic T cell.

The generation of tumor-specific in vivo protective immunity in the tumor mass from mice rendered tolerant to tumor antigens.

Abstract: C3H/He mice were inoculated i.v. with 106 heavily X-irradiated syngeneic X5563 plasmacytoma cells 3 times at 4 day intervals. When these mice received an appropriate immunization procedure consisting of i. d. inoculation of viable tumor cells plus the surgical resection of the tumor which enables i.v. nonpresensitized mice to produce anti-X5563 immunity, they failed to develop tumor-specific immunity. This was demonstrated by the abrogation in potential of spleen and lymph node cells to generate in vivo protective immunity. In contrast, the tumor mass from X5563 tumor-bearing mice which had received the i.v. presensitization contained comparable anti-X5563 tumor neutralizing activity to that obtained from the tumor mass from nonpresensitized, X5563 tumor-bearing mice. Such an in vivo protective immunity was revealed to be mediated by tumor-specific T cells. These results demonstrate the differential generation and antitumor capability of tumor infiltrating T cells and T cells in lymphoid organs from mice which are in the tumor-specific tolerant state. The results are discussed in the context of potential utilization of tumor infiltrating in vivo protective T cells to enhance the local tumor-specific immunity in tumor-specific tolerant mice.

Evaluation of immunomodulatory and therapeutic properties of biological

Abstract: Biological response modifiers (BRMs) are those agents or approaches that modify the relationship between the tumor and host by modifying the host's biological response to the tumor cells with resultant therapeutic effects (1). BRMs may modify the host responses in several ways: 1. increase the host's antitumor responses through augmentation and/or restoration of effector mechanisms or mediators of the host's reaction which may be deleterious; 2. increase the host's defenses by the administration of natural biologicals (or the synthetic-recombinant derivatives thereof) as effectors or mediators of an antitumor response; 3. augment the sensitivity of the host's tumor cells to endogenous mechanisms for the control of tumor growth; 4. alter the transformed phenotype by increasing the differentiation/ maturation of tumor cells; 5. increase the ability of the host to tolerate damage by cytotoxic modalities of cancer treatment. Specifically, BRMs include immunoaugmenting, immunomodulating, and immuno­ restorative agents; cytokines (soluble protein mediators produced by the host, which include interferons, lymphokines, and monokines); cytokine inducers; inhibitors of tumor growth factors; thymic factors; tumor anti­ gens; and modifiers of tumor antigen cell surface components, antitumor antibodies, antitumor effector cells [lymphokine activated killer cells (LAK) or tumor infiltrating lymphocytes (TIL)], and maturation and differ­ entiation factors. A subset of BRMs which are termed biologics encompass those products of the immune system of the host, which mayor may not be immunomodulatory agents but which have potential therapeutic activities (1). Thus, biologics include interferons, interleukins, colony stimulat­ ing factors, tumor necrosis factor, lymphotoxin, cytolysin, etc. At present, cancer immunotherapy appears to have relatively limited clinical value (2-6). This conclusion is in contradistinction to the optimistic and premature reports in the popular press and some of the research liter­ ature, which have inflated expectations and may ultimately discredit the field. Additional and more sophisticated preclinical studies are needed