Tumor-promoting versus tumor-antagonizing roles of γδ T cells in cancer immunotherapy: results from a prospective phase I/II trial.

Emerging evidence suggests that nitrogen-containing bisphosphonates have direct and indirect anticancer effects including immunomodulatory effects. Using in vivo targeting of bisphosphonate-reactive γδ T cells by adding low-dose interleukin-2 to zoledronic acid, we evaluated the safety, pharmacodynamics, and antitumor activity of this immunotherapy approach in 21 adults with advanced malignancies (renal cell carcinoma [RCC], malignant melanoma, and acute myeloid leukemia). A total of 58 treatment cycles were administered and the median number of treatment cycles was 2.7 (range, 1 to 6). The regimen was well tolerated, with no grade 3 to 4 drug-related adverse events, except for fever. No objective responses were observed in both cohorts of solid tumors (RCC and malignant melanoma), whereas 2 patients with acute myeloid leukemia (25%) achieved objective tumor responses (partial remission). Pharmacodynamic analyses showed significant in vivo activation (interferon-γ production) and expansion of γδ T cells in all evaluable patients. High pretreatment serum vascular endothelial growth factor (VEGF) levels and an unexpected increase in VEGF induced by zoledronic acid plus low-dose interleukin-2 were correlated with the lack of a clinical response. In conclusion, this study indicates that immunotherapy-induced VEGF can limit clinical innate tumor immune responses, especially for angiogenesis-dependent solid tumors. Our data challenge the current cellular immunotherapy paradigms in the treatment of cancer.

Reduction of HLA-DR+ lymphocytes after treatment with enzastaurin in patients with metastatic thyroid cancer.

BACKGROUND: Cytotoxic anti-tumor agents like methotrexate or cyclophosphamide have been used in the treatment of autoimmune diseases although the exact mechanism of their immunomodulatory function is unclear. By contrast, molecularly targeted anti-tumor agents, such as the serine/threonine kinase inhibitor enzastaurin, have not been evaluated for treatments other than cancer. METHODS: Blood was sampled from patients with metastatic thyroid cancer treated with enzastaurin followed by the combination treatment of enzastaurin and the anti-folate pemetrexed. During this sequential treatment, blood was drawn every 14 days to monitor changes in the lymphocyte population. RESULTS: We observed that enzastaurin monotherapy reduced the number of HLA-DR-expressing lymphocytes. No signs of infection were observed in any patient. CONCLUSION: Our findings suggest an immunomodulatory effect of enzastaurin in addition to the anti-tumor effect.

Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.

CONTEXT: The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists. OBJECTIVE: To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more. DESIGN, SETTING, AND PATIENTS: Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups. INTERVENTION: Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175). MAIN OUTCOME MEASURES: Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat). RESULTS: More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank). CONCLUSIONS: Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.