Adoptive transfer of antigen-specific CD4 ؉ and CD8 ؉ T cells is one of the most efficient forms of cancer immunotherapy. However, the isolation of antigen-specific CD4 ؉ T cells is limited because only few tumor-associated helper epitopes are identified. Here, we used T cell antigen receptor gene transfer to target CD4 ؉ T cells against an MHC class I-presented epitope of a model tumor antigen. IFN-␥-producing CD4 ؉ T cells were unable to expand in vivo and to provide help for tumor rejection. In contrast, CD4 ؉ T cells producing high levels of IL-2 expanded in vivo, provided help for cytotoxic T lymphocyte-mediated tumor rejection, and developed T cell memory. The data demonstrate in vivo synergy between T cell antigen receptor-transduced CD4 ؉ and CD8 ؉ T cells specific for the same epitope resulting in long-term tumor protection.T cell antigen receptor gene transfer ͉ tumor immunotherapy T he infusion of allogeneic T cells into patients with leukemia can provide long-term leukemia-free survival. Similarly, the adoptive transfer of Epstein-Barr virus-specific donor-derived T cells has been successfully used to treat Epstein-Barr virus-induced malignancies after allogeneic stem cell transplantation (1, 2) and solid organ transplants (3-5). More recently, it was demonstrated that adoptive T cell transfer into patients conditioned by lymphoablative chemotherapy resulted in strong antitumor effects in melanoma patients (6, 7).Indirect evidence suggests that the success of the adoptive immunotherapy treatments described above may be related to the use of antigen-specific CD4 ϩ and CD8 ϩ T lymphocytes. For example, in melanoma the clinical response to infusion of CD8 ϩ T cell clones was much less impressive than the effect of adoptive transfer of mixed CD4 ϩ and CD8 ϩ T cells, although a direct comparison in patients after lymphoablative conditioning has not yet been performed (6,8). Administration of IL-2 can improve the antimelanoma efficacy of transferred CD8 ϩ T cells (9), suggesting an important role of this cytokine that is typically produced by CD4 ϩ T helper cells. Superiority of mixed CD4 ϩ and CD8 ϩ T cells was also suggested by adoptive cell transfer experiments in immunocompromised patients at risk of CMV disease. The cell dose of cloned CD8 ϩ T cells used to control CMV was Ϸ1,000-fold higher than the dose of CMV-specific CD8 ϩ T cells given together with CMV-specific CD4 ϩ T cells (10, 11).The generation of tumor antigen-specific CD4 ϩ helper T cells is limited by the paucity of known MHC class II-binding tumor epitopes and the lack of expression of MHC class II molecules on most tumor cells. In contrast, a large number of CD8 ϩ T cellrecognized tumor epitopes presented by MHC class I molecules has been identified, and in many cases cytotoxic T lymphocyte (CTL) clones against such epitopes were isolated. In this study, we explored in a murine model system whether the T cell antigen receptor (TCR) genes of tumor-specific CTL can be transferred to CD4 ϩ T cells to generate MHC class I-restricted, tumor-...

SummaryAdoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (

No abstract

No abstract