Studies of murine CD8 T cells have demonstrated that class I/peptide antigen complexes must be displayed on a cell-size surface for effective recognition and activation to occur . CD8 T cells are optimally stimulated by antigen on 5-μm diameter microspheres, and do not respond when the same antigen is displayed on 1-μm diameter beads. This finding prompted experiments to examine whether in vivo delivery of antigen on cell size beads, termed 'large multivalent immunogen', might activate or enhance CTL responses . Administration of class I alloantigen on beads did not initiate responses, but dramatically augmented CTL responses generated upon challenge with allogeneic tumor cells. A similar augmentation of CTL response, and concomitant reduction of tumor growth, was observed when LMI were prepared by coating beads with plasma membranes isolated from tumor cells and administered to mice at the same time that they were challenged with live syngeneic tumor. When mice bearing established, progressing subcutaneous P815 mastocytoma (7 to 12 days) were treated with LMI, there was little effect on tumor growth or survival. However, combined treatment with Cytoxan and LMI had highly synergistic effects, resulting in prolonged reduction of tumor growth and significant extension of survival . In some experiments tumor became undetectable in the majority of treated mice; these mice survived indefinitely and rapidly rejected rechallenge with tumor. Similar results were obtained in experiments examining survival of mice bearing established fibrosarcoma in a lung metastasis model. Antigen delivery on LMI was uniquely effective in these experiments. Antigen in the form of irradiated tumor cells or plasma membrane in adjuvant was ineffective, and free plasma membrane antigen (not on microspheres) had only a marginal effect. Based on the results obtained in murine models, a small phase I trial for melanoma was done. Two in vitro grown melanoma cell lines were used as the source of plasma membrane antigen to prepare the LMI. Three dose levels were tested and no significant toxicity was found. Of 16 patients, 10 had an increased frequency of pCTL reactive to the melanoma cell line following therapy. One partial response was obtained, and disease was stable for more than 12 months in three patients. A second trial has recently been initiated for melanoma and renal carcinoma plasma membrane isolated from autologous tumor is used for preparation of the LMI. Patients are being randomized to one of three groups: LMI only, Cytoxan and LMI, or Cytoxan, LMI and a short course of low-dose IL-2. Ongoing murine studies are employing adoptive transfer of TCR transgenic CD8 T cells to allow visualization of CTL responses to tumors. Experiments using this approach have demonstrated that IL-2 can be effectively used to sustain tumor-specific responses following their initiation, but that the dose and duration of administration must be limited. Additional results are suggesting that class I/peptide tetramers can be used to prepare LMI that are effective in augmenting tumor growth reduction, suggesting that LMI immunotherapy using well-defined tumor antigens may be feasible.
|Original language||English (US)|
|Journal||Cancer Immunology, Immunotherapy|
|Issue number||SUPPL. 1|
|State||Published - Dec 1 2003|