Recruitment of helper T cells for induction of tumour rejection by cytolytic T lymphocytes

Abstract

Immunotherapy of cancer could be possible in cases in which competent effector T cells can be induced. Such an approach depends on expression of tumour-specific antigens by the tumour cells and on the availability of sufficient costimulatory support for activation of cytotoxic T lymphocytes. Here, a strategy for helper T cell recruitment for induction of tumour-specific cytotoxic immune responses is presented. Allogenic MHC class II molecules were introduced into tumour cells by cell fusion. These hybrid cells, when injected into mice, induced rejection of an established tumour. The contribution of CD4-expressing helper T cells in the induction phase and of CD8-expressing T cells in the effector phase of the immune response was demonstrated. The approach described could be applicable to cases in which a suitable tumour antigen is present but not identified; it employs regulatory interactions that govern physiological immune responses and is designed to be minimally invasive.

Comparison of four strategies for tumour vaccination in the B16-F10 melanoma model

“…Another method of cell fusion, electrofusion, is claimed to be more efficient for hybrid production. Stuhler and colleagues 28 reported good antitumour activity in the EL-4 murine model using therapeutic vaccination with hybrids produced by electrofusion from allogeneic B cells and autologous tumour cells. Clinical trials have already commenced in patients with melanoma and renal cell carcinoma using this technology.…”

Vaccination with hybrids of tumor and dendritic cells induces tumor‐specific T‐cell and clinical responses in melanoma stage III and IV patients

“…It was already established before with animal model experiments that only the hybrid cells created by electrofusion but not mixtures of tumor and antigen-presenting cells can induce antitumor immune responses. 9 In the present study, the vaccines were always injected at sites away from the tumor that do not drain into the same lymph nodes. It is therefore unlikely that injected free dendritic cells travel to the tumor sites to pick up and present antigens from indigenous tumor cells.…”

“…7 Fusion of tumor cells with antigen-presenting cells such as dendritic cells (DCs) 8 is meant to enhance the immunogenicity of antigenic tumors for induction of tumor-specific cytotoxic T cells (CTLs). 9,10 This hybrid cell vaccination concept was tested in animal models for prevention as well as therapy, 7,9 -14 and first clinical studies were reported for renal cell carcinoma, 15 melanoma 16 and glioblastoma. 17 Here we present the results of a clinical trial for patients with metastatic melanoma.…”

“…23 Consequently, it was found in animal experiments that only fused tumor and antigen-presenting cells but not mixtures of these cells induce tumor-specific immune responses and rejection of the tumor. 9 The clinical outcome of such a therapy depends on the capacity of the vaccine to induce tumor-specific CTLs effectively as much as on the susceptibility of the tumor cells to the effector mechanisms of these CTL. In order to evaluate these denominators of therapeutic efficacy, we monitored, in addition to the clinical outcome, tumor-specific T cells in the peripheral blood and antigen expression in the metastases of the patients.…”

Antigen organization regulates cluster formation and induction of cytotoxic T lymphocytes by helper T cell subsets

“…Accordingly, various trials have been initiated to improve the efficacy of CTL induction directed against defined epitopes such as virus-derived peptides or tumor antigens. Given the importance of multistep induction and varying signal requirements for efficient effector CTL generation, recruitment of Th cells could be more rewarding than replacing Th cell functions by a single stimulatory molecule (28,29).…”