This single arm, single institution phase II study of allogeneic GM-CSF secreting cell lines as immunotherapy given in sequence with chemoradiation after pancreaticoduodenectomy supports the following 3 conclusions. First, the administration of up to 5 repetitive treatments with gene modified pancreas tumor cells is well tolerated in resected pancreatic cancer patients when sequenced with adjuvant chemoradiation. Second, the survival of patients receiving this immunotherapy in sequence with chemoradiation compares favorably with published data for resected pancreas cancer that report overall survivals ranging from 15 to 20 months.2–11
Third, the induction and maintenance of enhanced postimmunotherapy mesothelin-specific T cell responses is associated with prolonged disease-free survival in the HLA-A1+
patients who were analyzed.
These data confirm our phase I study findings that postimmunotherapy induction of mesothelin-specific CD8+
T cells correlates with improved DFS.12,16
In this phase II study, we extended our analyses to multiple HLA-A0101 and HLA-A0201 epitopes that derive from mesothelin. We observed that patients who remained disease-free demonstrated an increase in the number of epitopes against which their lymphocytes responded after the final immunotherapy treatment. One possible explanation for this finding is that each patient has a different T cell repertoire with different response capabilities. A second possibility is that each patient’s tumor, or antigen-presenting cells, processes different HLA epitopes for presentation to their T cells. These data suggest that the expansion of the T cell repertoire recognizing a more complete panel of antigen epitopes rather than the quantitation of one epitope specific T cell population, may be a better predictor of long-term DFS associated with this immunotherapy. Although we have demonstrated a correlation of the posttreatment induction of mesothelin-specific T cell responses with improved overall response, we have not directly demonstrated that mesothelin is the target antigen expressed by pancreatic tumors in this study. However, we have previously reported that mesothelin-specific T cells can lyse pancreas tumor cells that naturally expressed mesothelin.16
It is interesting that mesothelin-specific T cell frequencies were higher at baseline in the patients who demonstrated shorter DFS. Although it is possible that elevated baseline frequencies may predict poorer prognosis, the significance of this finding is currently unclear. In light of these data, baseline levels will be closely monitored in future studies to further investigate the relevance of the baseline response.
Recent studies have implicated a negative role for Tregs in the clinical outcome of patients with cancer. Specifically, these studies have demonstrated that increased numbers of tumor-infiltrating Tregs are associated with poorer prognosis.21,22
In concordance with previous studies, immunohistochemical analysis of resected pancreatic cancer tissue revealed the presence of tumor-infiltrating Tregs. However, unlike other studies, we found that these Tregs were present in substantial numbers in all patient specimens tested (data not shown). Consequently, we were unable to determine the impact of Tregs on survival or on the induction of mesothelin-specific T cell responses. However, the common presence of Tregs in pancreas cancers highlights the importance of targeting the suppressive function of these cells in future studies even in patients with earlier stage disease.
In conclusion, these findings provide the rationale for conducting a multicenter phase II adjuvant study, which will be led by The Cancer and Leukemia Group B (CALGB) in 2010. These data also provide the rationale for additional boosting beyond 18 months after pancreaticoduodenectomy. Finally, these data support the further evaluation of mesothelin-specific T cells as a surrogate marker of disease-free survival.