Clonal analysis of cytotoxic T lymphocytes (CTL) against autologous melanoma

Hersey, Peter; MacDonald, Malcolm; Schibeci, Stephen D.; Burns, Christine

doi:10.1007/bf00205711

Cited by 35 publications

(19 citation statements)

References 30 publications

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“…In contrast anti-melanoma CTL clones described recently needed a weekly restimulation to keep their lytic potential [4,8,14]. In previous studies CTL clones derived from PBL from cancer patients usually exhibited various levels of killing on autologous and allogeneic tumor cells [5,6,9,11,12,151.The very homogeneous cytotoxic activity of the 13 CD8+ clones studied here is probably the result of their clonal origin and support a role of the TcR in their specificity.…”

Section: Discussionmentioning

confidence: 73%

Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

et al. 1990

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In vitro culture of metastatic melanoma fragments with 150 units of recombinant interleukin 2 resulted in the successive expansion of CD4+ and then CD8+ tumor-infiltrating lymphocytes (TIL) throughout a 2-month period. TIL cultured for 43 days and consisting of 95% CD8+ and 10% CD4+ T lymphocytes were cloned by limiting dilution (LD). Thirteen CD8+ and thirty-one CD4+ clones were obtained, indicating that the frequency of clonogenic CD8+ proliferative T lymphocytes was much lower than that of their CD4+ homologues. When LD was performed in the presence of autologous melanoma cells the frequency of CD8+ clones was increased by factor 4. The DNA from TIL of day 43 bulk culture and of six CD8+ clones was hybridized with T cell receptor (TcR) beta and gamma probes. Identical configuration of the nonfunctional gamma and functional beta TcR genes was found in "bulk culture" and cloned TIL. The CD8+ clones therefore derived from a clonal population of CD8+ cells which had expanded in vitro before the LD. All the CD8+ clones tested were strongly cytotoxic for autologous melanoma cells but did not kill autologous fibroblasts or concanavalin A blasts, or any of the 10 allogeneic tumor targets tested, including 5 melanomas, 2 breast cell lines, 1 neuroblastoma, K-562 and the Epstein-Barr virus-transformed cell line used as a feeder. Furthermore, specific killing was inhibited by monoclonal antibodies against CD3, CD8, TcR alpha/beta and against class I major histocompatibility complex antigens indicating that these cytotoxic T lymphocyte clones recognized autologous tumor cells through the TcR, in an HLA class I-restricted manner. These data show that it is feasible to obtain tumor-specific cytotoxic T lymphocytes from melanoma TIL with a simple culture technique and that a single clone could be expanded to more than 10(10) cells which should allow testing of immunotherapeutic potential of these cells by adoptive transfer into melanoma patients.

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Section: Discussionmentioning

confidence: 73%

Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

et al. 1990

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“…Identification of such a molecule on specific subsets of APC or other cellular elements which mimics the effects produced by R24 mAb would improve our understanding about the physiologic regulation and control of antigenspecificTcel1 responses. It will also be important to understand what signals up-regulate expression of GD3 on the surface of Tcells, since GD3 is detected by immune fluorescence on only 15-20 % of unstimulated T cells, but its expression appears to increase with mitogenic activation [21]. Moreover, further elucidation of the different functional properties of GD3' and GD3-Tcells may help to clarify the physiologic role of this molecule in normal T cell immune response.…”

Section: Discussionmentioning

confidence: 97%

“…Within the hematopoietic system, R24 detects GD3 on fetal thymocytes and 15-20 % of peripheral blood Tcells [2,21]. Therefore, several studies have examined the functional outcome of GD3 binding by R24 mAb on T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

R24 anti‐GD3 ganglioside antibody can induce co‐stimulation and prevent the induction of alloantigen‐specific T cell clonal anergy

et al. 1996

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R24 is a monoclonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell clonal anergy. Binding of GD3 by R24 also prevented anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoclonal antibodies for the alpha and beta chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell clonal response.

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“…This suggested the possibility that allogeneic pancreatic tumor cell lines could be used, in place of autologous tumor, as stimulating antigen in the in vitro expansion of pancreatic-tumor-reactive T cells. Tumor-reactive CTLs that kill both autologous and allogeneic melanomas had been reported (5,6). This approach proved justified and we reported (7,8) the establishment of tumor-antigen-specific CTLs using allogeneic pancreatic tumor cell lines as stimulating antigen for lymph-node cells from pancreatic cancer patients.…”

mentioning

confidence: 85%

Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells.

Barnd

Lan

Metzgar

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

383

208

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We have previously reported the establishment of cytotoxic T-cell lines, from pancreatic cancer patients, by continuously stimulating tumor-draining lymph node cells with allogeneic pancreatic tumor cell lines. After the preliminary characterization of their phenotype and tumor specificity, detailed studies performed with one of the cell lines, W.D., show that it recognizes a specific antigen, a large and heavily glycosylated mucin molecule, expressed on pancreatic and breast tumors and tumor cell lines. Although this recognition appears major histocompatibility complex (MHC)-unrestricted, the antigen receptor used by the cytotoxic T cell is the a/fl heterodimer, typically found on MHC-restricted T cells.The target antigen is atypical, however, in its ability to directly bind and activate the T cells in the absence of self MHC, presumably by abundant and regularly repeated antigenic epitopes. These rmfings are important because they demonstrate a specific T-cell response against a human tumorassociated antigen. In addition to pancreatic and breast tumors, various mucin molecules are known to be produced by other tumors of epithelial cell origin and could be expected to stimulate similar T-cell-mediated immune responses.

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Clonal analysis of cytotoxic T lymphocytes (CTL) against autologous melanoma

Cited by 35 publications

References 30 publications

Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

R24 anti‐GD3 ganglioside antibody can induce co‐stimulation and prevent the induction of alloantigen‐specific T cell clonal anergy

Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells.

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Clonal analysis of cytotoxic T lymphocytes (CTL) against autologous melanoma

Cited by 35 publications

References 30 publications

Selective expansion of a specific anti‐tumor CD8+ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

Selective expansion of a specific anti‐tumor CD8+ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

R24 anti‐GD3 ganglioside antibody can induce co‐stimulation and prevent the induction of alloantigen‐specific T cell clonal anergy

Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells.

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Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements

Selective expansion of a specific anti‐tumor CD8⁺ cytotoxic T lymphocyte clone in the bulk culture of tumor‐infiltrating lymphocytes from a melanoma patient: Cytotoxic activity and T cell receptor gene rearrangements