Presentation Of Tumor-specific Antigens Research Articles

Antigen-specific cancer immunotherapy using a GM-CSF secreting allogeneic tumor cell-based vaccine.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cell-based vaccines are currently one of the major forms of cancer vaccines. However, the preparation of GM-CSF-transduced autologous tumor vaccines is time-consuming and technically challenging. In addition, the host antigen presenting cells, rather than the tumor vaccine cells themselves, present tumor-specific antigens and prime the host T cells. Therefore, we tested the efficacy of antigen-specific allogeneic tumor vaccines. We used human papillomavirus 16 (HPV-16) E7 protein as a model tumor antigen, which is associated with the development of most cervical carcinoma. B16, a C57BL/6 (H-2(b)) derived melanoma cell line, was genetically engineered to produce GM-CSF alone (B16GM), HPV-16 E7 alone (B16E7), or both (B16GME7). These vaccine cells were injected into BALB/c (H-2(d)) mice (10(6) cells/mouse). Two weeks later, mice were challenged with 10(5) live HPV-16 E7(+) BL-1 (H-2(d)) tumor cells and monitored for tumor progression twice weekly. To determine the effective cell population in the antitumor immunity elicited by B16GME7, we carried out in vivo antibody depletion experiments using CD4 and CD8 specific antibodies. In addition, as a measure of the immune responses produced by B16GME7, we performed an in vitro cytotoxic T lymphocyte assay using a standard chromium release method. We found that all of the mice vaccinated with B16GME7 remained tumor free 49 days post-BL-1 challenge. In contrast, mice vaccinated with B16GM and B16E7 did not show any tumor protection against a similar dose of BL-1 cells. Furthermore, the antitumor immunity produced by B16GME7 was dependent on both CD4 and CD8 T cells. In addition, E7-specific cytotoxic T lymphocyte activity could be readily demonstrated in mice immunized with B16GME7. These results suggest that allogeneic tumor cells transduced with GM-CSF and the tumor antigen, HPV-16 E7, cannot only generate an E7-specific cytotoxic T lymphocytes response in vitro, but can also elicit a potent antitumor immune response against an E7 expressing tumor in vivo.

Immuntherapie des Pankreaskarzinoms

Pancreatic carcinoma cells present tumor-specific antigens on their surfaces, thus an immunological reaction similar to transplant rejections is possible and may be used in tumor therapy. But tumors are rarely rejected due to their immune-escape mechanisms. In active-specific immunotherapy (ASI) tumor cells are infected by viruses to induce presentation of highly immunogenic antigens. This paper retrospectively summarizes long-term results of a series of ASI in the Surgical Clinic of the Knappschaftskrankenhaus Bochum-Langendreer and presents the clinical progress made on this field during the last 5 years. Because of the limited success of conventional tumor therapy, immunotherapy will continue to be an attractive alternative.

Cancer vaccines.

A better understanding of immune recognition of cells has led to identification of potential new targets on tumor cells. Noticeable successes in melanoma have been immunization with the GM2 ganglioside vaccine, and the identification of novel antigens such as MAGE, BAGE and GAGE recognized by T cells cloned from cancer patients with regressing disease. However, the unexpected finding that other antigens recognized by these T cells were overexpressed normal differentiation antigens such as tyrosinase. Pmel 17 and Melan A have led to vaccines developed against differentiation antigens expressed in other solid tumors. Monoclonal antibody, anti-idiotype and antigen based vaccines for colorectal target antigens 17-1A, CEA and 791Tgp72 are all in clinical development. Similarly HER2/neu and mucin overexpression in breast cancer represent promising targets. Mutations in tumor oncogenes or suppressor genes which lead to malignant transformation can also present tumor-specific antigens. The most effective vaccines against infectious disease are live viruses. The development of DNA vaccines which act like viruses in entering cells and show continuous production of antigens offers great potential for the future.

HLA expression and tumor-infiltrating immune cells in uveal melanoma.

In uveal melanoma, both the amount of tumor-infiltrating cells and the level of expression of HLA antigens are quite variable. We hypothesized that low levels of HLA expression lead to a lack of antigen presentation, which might prevent proper immunologic recognition of the tumor. This lack of recognition might subsequently lead to low levels of tumor-infiltrating cells. To test this hypothesis, we determined the type and number of tumor-infiltrating cells in tumor sections from 24 uveal melanomas. We applied monoclonal antibodies directed against different types of immune cells and compared the results with the expression of HLA class I and class II antigens on the tumor cells. Infiltrating immune cells were observed in all uveal melanomas (although in small amounts), with a predominance of T lymphocytes. Significant positive correlations were observed between the number of CD3+ cells (T lymphocytes) and monomorphic HLA class I expression, allele-specific HLA-A2 and Bw4 expression, and HLA class II expression. Furthermore, the number of CD4+ cells (T helper cells, monocytes/ macrophages) and of CD11b+ cells (monocytes/macrophages) was significantly correlated with the level of monomorphic HLA class I expression. These data support our hypothesis that low levels of HLA expression (and therefore a lack of presentation of tumor-specific antigens) may lead to a low level of tumor infiltrate.

Role of IL‐2, IL‐4 and IL‐6 in the growth and differentiation of tumor‐specific CD4+ T helper and CD8+ T cytotoxic cells

We have earlier observed that 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), a chemotherapeutic drug, cured 90-100% of mice bearing a syngeneic Ia- T-cell lymphoma (LSA) and furthermore, 100% of the BCNU-cured mice could reject homologous tumor rechallenge. In the present study, purified CD4+ and CD8+ T cells isolated from BCNU-cured mice were used to investigate the mechanism by which such T cells recognized and responded to the tumor-specific antigens. The responsiveness of CD4+ T cells to LSA was dependent on processing and presentation of tumor-specific antigens by syngenic Ia+ splenic antigen-presenting cells (APC). Such activated CD4+ T cells endogenously produced IL-2 but not IL-4 and only IL-2 acted as an autocrine growth factor inasmuch as anti-IL-2 receptor antibodies but not anti-IL-4 antibodies inhibited the CD4+ T cell proliferation. In contrast, the CD8+ T cells failed to produce endogenous growth factors when stimulated with LSA alone or with LSA plus APC, and therefore failed to proliferate. However, in the presence of exogenous recombinant IL-2 (rIL-2), CD8+ T cells could proliferate directly in response to LSA-stimulation, even in the absence of APC. Addition of exogenous rIL-4 alone to cultures induced CD4+ but not CD8+ T cells to proliferate. However, rIL-4 in the presence of rIL-2, could synergize and induce tumor-specific proliferation of CD8+ cells. These data suggested that for IL-4 to act as a T-cell growth factor, the presence of IL-2 was essential, either in the form of endogenously secreted IL-2 (CD4+ T cells) or exogenous IL-2 (for CD8+ T cells). In contrast to rIL-2 and rIL-4, rIL-6 failed to induce growth when used alone or in combination with rIL-2 or rIL-4. Furthermore, when tested individually, only rIL-2 but not rIL-4 or rIL-6 could support the cytotoxic differentiation of CD8+ T cells. The present study suggests that the early events in responsiveness to LSA tumor may involve activation of the IL-2-producing Th1 subpopulation of CD4+ helper cells which in turn activate IL-2 dependent CD8+ cytotoxic T cells. IL-4 if produced subsequently, may act synergistically with IL-2 to promote the growth of CD4+ and CD8+ T cells.

Ovarian tumor-specific antigens

The presence of tumor-specific antigens in a limited number of specimens of serous cystadenocarcinoma, mucinous cystadenocarcinoma, and solid epidermoid carcinoma of the human ovary has been demonstrated. Immunoelectrophoresis and immunodiffusion were employed to reveal the presence of the antigens and to relate the antigens of one tumor type to those of another. A maximum of four antigens per tumor sample was found. None of these antigens was found in normal ovary or normal human serum.

Immnological diagnosis of the cancer of the corpus uteni

An attempt was made to demonstrate the presence of tumor specific antigens in cancer cell of the human endometrial adenocarcinoma and to apply it to the diagnosis of malignant cells in endometrial smear using immunofluorescent antibody technique.Rabbits were divided into 3 groups. The different groups were immunized with nuclear, mitochondrial and microsomal fractions prepared from cancer cells of endometrial adenocarcinoma by the method of W.C. Schneider.The sera obtained from each groups were absorbed by the each fractions prepared from normal epithelial cells of the endometrium. Their specifities were determined by the Ouchterlony plates.On agar gel diffusion tests, tumor specifities were shown in antimitochondrial and antimicrosomal sera.In the immunofluorescent staining for tissue sections of endometrial adenocarcinoma and aspiration smears, the indirect technique of Coons was carried out using the sheep anti-rabbit globulin antiserum conjugated to fluorescein.On the histologic sections and aspiration smears prepared with antimitochondrial and antimicrosomal sera, the specific fluorescence was seen in the cytoplasm and a few granules in the nucleus of cancer cells. On the contrary, no fluorescence was seen in normal endometrial cells.From above mentioned facts, it is evident that the cancer specifity existed in mitochondrial and microsomal fractions, and this specific fluorescence can contribute largely to detection of cancer cell in aspiration smears and endometrial tissue.

SEARCH FOR VIRUS-INDUCED ANTIGENS IN HUMAN TUMORS USING THE SV40-HAMSTER SYSTEM AS A MODEL.

SummaryCell cultures derived from various types of human cancers were examined for the presence of tumor specific antigens by both immunofluorescence and complement fixation methods, in which the serum of the patient was tested against cells grown from his cancer. The methods, previously used successfully to detect a new intranuclear antigen induced by the papovavirus SV40 in transformed human and hamster cells, and in hamster tumors, failed to reveal the presence of immunologically reactive components.

Characterization of Antibodies Produced in a Horse Following Injections of Mycosis Fungoides Lymphoma Tissue

The presence of tumor specific antigens in human malignancy has not been established although some work has suggested this possibility (1,2,3,4,5,6,7).