Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1

Abstract

SUMMARYWe developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.CD8+ cytotoxic T cells can be harvested from a patient with cancer, expanded in vitro, selected for specificity against a tumor-associated antigen, and infused back into the patient. Such autologous T cells have been shown in clinical trials to have a beneficial effect in some patients with cancer. [1][2][3][4][5] The cytotoxic antitumor effect of CD8+ T cells depends on CD4+ T cells, which provide CD8+ T cells with growth factors such as interleukin-2 and can mediate the destruction of tumor cells either directly or indirectly. [5][6][7][8] Growth factors such as interleukin-2 can act in an autocrine manner, which in principle would allow an infusion of CD4+ T cells to proliferate in the patient and stimulate endogenous antitumor CD8+ T cells. Until recently, however, a means of isolating and expanding antitumor CD4+ T cells in numbers sufficient for cellular therapy has not been feasible. The identification of HLA class II-restricted epitopes in tumor-associated antigens such as NY-ESO-1 and tyrosinase and the development of methods for the isolation and expansion of CD4+ T cells in vitro gave us the opportunity to implement a clinical trial to evaluate the safety, in vivo persistence, and antitumor efficacy of autologous CD4+ T-cell clones for the treatment of metastatic melanoma. We describe a patient with refractory metastatic melanoma who had a long-term complete remission after receiving autologous NY-ESO-1-specific CD4+ T-cell clones. CASE REPORTThe patient was 52 years old when he presented with recurrent melanoma and pulmonary and left iliac and inguinal metastases. His tumor had not responded to high-dose interferon alfa, four cycles of high-dose interleukin-2, and local excision. Baseline staging with magnetic resonance imaging of the brain and computed tomography (CT) of the chest, abdomen, and pelvis showed metastatic disease in the posterior right pleura, right hilum, and

CD4+, IL17 and Foxp3 Expression in Different pTNM Stages of Operable Non-small Cell Lung Cancer and Effects on Disease Prognosis

“…Thus, the tumor occurs, develops and metastasizes. In recent years, researchers (Hunder, et al, 2008) have compared the killing effect on HY antigen expressing tumors between CD8+T cells and CD4 + T cells. They find that CD4 + T cells have stronger killing effect than CD8+T cells.…”

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…Increasing evidence indicates that CD4 1 T cells are able to mediate tumor destruction without direct interaction with tumor cells and that CD4 1 T cells may provide even greater anti-tumor effect than CD8 1 T cells [5][6][7][8]. Furthermore, reports from various groups, including ours, have demonstrated the ability of CD4 1 T cells to reject cytotoxic T lymphocyte-resistant, MHC class II-negative tumors [7,9,10].…”

Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity

“…Emerging data support the idea that CD4 þ CTLs could have clinical effectiveness. A patient with metastatic melanoma, treated with an autologous CD4 þ effector clone recognizing NY-ESO-1, experienced complete disease regression, which was attributed to the expansion of T cells reactive to other tumor-associated antigens, through Ag-spreading, and the initiation of a de novo CD8 þ CTL response (24). This result underscores one of the key attractions of mobilizing CD4 þ T cells: Not only can they support anticancer responses by other effector populations, but they can also perform cytotoxic functions.…”