Expansion of melanoma-specific T cells from lymph nodes of patients in stage III: Implications for adoptive immunotherapy in treating cancer (original) (raw)
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International Journal of Cancer, 1998
Several tumor antigens have been described as candidates for immunotherapy. Our study compared HLA-A2-restricted epitopes from 5 antigens commonly expressed by melanomas, i.e., Melan-A/MART-1 peptides (26-35 and 27-35), tyrosinase (368-376), gp-100 (280-288), MAGE-3 (271-279) and NA17-A (1-10), for their relative capacity to promote the development of cytotoxic and cytokine-producing specific CD8 ؉ lymphocytes within melanoma-invaded lymph nodes.
Melanoma-Specific Cytotoxic T Cells Generated from Peripheral Blood Lymphocytes
Annals of Surgery, 1989
lymphocytes (CTL) specific for autologous human melanoma have been generated in vitro from peripheral blood lymphocytes (PBL) of five patients with resectable stage II malignant melanoma. The PBL were cultured with 5u/ml recombinant IL-2 and were repeatedly stimulated with irradiated fresh or cultured autologous tumor cells. Cytotoxicity was determined by four-hour chromium release assays. Specific cytotoxicity developed in 30 to 40 days, after three or four stimulations with tumor. The PBL-derived CTL are CD3+ and are mixed for CD4+ and CD8+ phenotypes. They lysed autologous melanoma and failed to lyse allogeneic melanoma, K562, or autologous lymphocytes. The lysis of autologous tumor was maintained for more than 4 months. The cells proliferated in response to autologous, but not allogeneic melanoma cells, in a dose-dependent manner. Lysis of the autologous tumor target was inhibited with w6/32, a monoclonal antibody to HLA Class I antigens. It is concluded that PBL may serve as a plentiful and renewable source of precursor cells for the generation of autologous tumor-specific CTL, which may be useful in specific adoptive cellular immunotherapy of melanoma. T n HE TREATMENT OF HUMAN solid tumors requires multiple treatment modalities, including surgery, chemotherapy, and/or radiation therapy. For many solid tumors, however, these treatments are not curative. As a result, additional therapeutic alternatives continue to be explored. A treatment arm under active scrutiny is immunotherapy.
Annals of Surgery, 1989
Cytotoxic T lymphocytes (CTL) specific for autologous human melanoma have been generated in vitro from peripheral blood lymphocytes (PBL) of five patients with resectable stage II malignant melanoma. The PBL were cultured with 5u/ml recombinant IL-2 and were repeatedly stimulated with irradiated fresh or cultured autologous tumor cells. Cytotoxicity was determined by four-hour chromium release assays. Specific cytotoxicity developed in 30 to 40 days, after three or four stimulations with tumor. The PBL-derived CTL are CD3+ and are mixed for CD4+ and CD8+ phenotypes. They lysed autologous melanoma and failed to lyse allogeneic melanoma, K562, or autologous lymphocytes. The lysis of autologous tumor was maintained for more than 4 months. The cells proliferated in response to autologous, but not allogeneic melanoma cells, in a dose-dependent manner. Lysis of the autologous tumor target was inhibited with w6/32, a monoclonal antibody to HLA Class I antigens. It is concluded that PBL may serve as a plentiful and renewable source of precursor cells for the generation of autologous tumor-specific CTL, which may be useful in specific adoptive cellular immunotherapy of melanoma. T n HE TREATMENT OF HUMAN solid tumors requires multiple treatment modalities, including surgery, chemotherapy, and/or radiation therapy. For many solid tumors, however, these treatments are not curative. As a result, additional therapeutic alternatives continue to be explored. A treatment arm under active scrutiny is immunotherapy. Immunotherapeutic approaches to cancer have been attempted for several decades. The recent availability of recombinant IL-2 has simplified the culture of human lymphocytes in vitro, making it feasible to generate large numbers of lymphocyte effector cells. As a result, several Supported in part by NIH Grant 2-POI-CA-32672-05A1, Veterans' Administration Project #821, and the DuPont Corporation.
Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes
Journal of immunotherapy (Hagerstown, Md. : 1997), 2016
Our laboratory has previously demonstrated that melanoma draining lymph node (MDLN) samples from stage III patients contained both CD4 and CD8 T cells that can be readily expanded to mediate tumor cell apoptosis in vitro and improve survival in mice bearing human melanoma xenografts. In this study, we investigated whether MDLN T cells contain melanoma-reactive CD4 T-cell compartment and what they are. To test this, we performed multiparametric (11-color and 6-color) fluorescence-activated cell sorting analyses to monitor phenotypic and functional property of CD4 T cells in response to melanoma cell antigen reexposure. Our results have demonstrated that the antigen reexposure could result in a generation of CD4CCR7CD62LCD27 T-cell subsets with various effector cell-like properties. Within the CD4CCR7CD62LCD27 T-cell compartment, in response to antigen reexposure, some of the cells expressed significantly upregulated CD40L and/or CXCR5, and some of them expressed significantly upregul...
Cancer, 1988
The in vitro development of tumor-specific cytotoxic T-cells from draining and tumor-involved lymph nodes obtained from melanoma patients were examined. Fresh draining or tumor-involved lymph node cells (LNC) demonstrate no significant cytotoxic activity against a variety of tumor targets including autologous melanoma. Natural killer cell (NK) activity is very low or absent in all of these specimens. Culture of the cells with irradiated autologous tumor and expansion in recombinant interleukin 2 (rIL-2) results in strong cytotoxicity for autologous tumor cells. The cultured cells are T-cells of mixed CD4 and CD8 phenotypes. Following restimulation with autologous tumor, these lines are capable of becoming specifically cytotoxic for autologous tumor as tested in direct killing and in cold target inhibition studies.
Clinical Cancer Research, 2011
Purpose: Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors. Experimental Design: We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment). Results: Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; P = 0.01) and female patients (71% vs. 57% for males; P = 0.04) having the highest rate of success. Syste...
Cancer Immunology, Immunotherapy, 2011
Tumor-inWltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an eVective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identi-Wed. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune inWltration in vivo of ocular melanoma lesions was analyzed. An eYcient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-speciWc T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally diVerentiated T EM cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune inWltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with eVector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be eYciently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients.
Advances in the Treatment of Metastatic Melanoma: Adoptive T-Cell Therapy
Seminars in Oncology, 2012
Metastatic melanoma is notoriously resistant to chemotherapy and radiotherapy regimens. The prospect for newly diagnosed metastatic melanoma patients is grim, with a median survival of less than 1 year. Currently, the only therapies resulting in long-term disease-free intervals, high-dose interleukin-2 (IL-2) and more recently anti-CTLA-4, work through activation of the immune system. However, with both therapies the response rate is low. Advances in our knowledge of how the immune system interacts with cancer have led to a number of strategies to manipulate anti-tumor immune responses through immunotherapy. This review will focus on one avenue of immunotherapy using the transfer of T cells referred to as "adoptive cell therapy" (ACT), which involves the ex vivo expansion of autologous tumor-specific T cells to large numbers that are ultimately transferred back to the patient to boost anti-tumor immunity. This approach has been shown to be effective in the treatment of virally induced cancers, as well as metastatic melanoma. Recent successes with ACT hold promise and further emphasize the tremendous potential benefit of harnessing the immune system in the fight against cancer.