Immune effects of combinatorial repurposing drugs in refractory ovarian and colorectal cancer patients.

Abstract

Abstract Background Some refractory cancer patients have a good Karnofsky despite refractory disease. We studied the potential immunomodulatory properties of approved drugs. We used fresh PBMC from refractory patients to study the immune effects of several drugs such as metformin, pidotimod, erdostein, esomeprazole, colchicine, bortezomib, gemcitabine, zoledronic acid and naproxen. Methods 25 high-grade serous ovarian cancer (HGSOC) and 25 colorectal cancer (CRC) subjects were included after approved protocol. The inclusion criteria include Karnofsky 80–100%, complete CT scan, acute phase proteins, granzyme B ELISPOT and antigen-specific ELISA. Results We found after 24 months of treatment in HGSOC 80% of complete response (CR), 15% of stable disease (SD) and 5 % of pseudo-progressive disease (PPD). In CRC we had 50% of CR, 30% of SD and 20% of PPD. In the patients with CR there was an immunological correlation of CD8 persistent immune response by granzyme B ELISPOT in HGSOC and CRC (p=0.0001) and PR (p=0.001), respectively. The combination was well tolerated and after 10 months of stopping the treatment some patients have persistent CD8 specific immune response by ELISPOT and ELISA. Discussion The combination of daily oral metformin, colchicine, pidotimod, erdostein, and naproxen plus weekly low dose of intravenous (IV) esomeprazole (80 mg), bortezomib (0.5 mg/m2), gemcitabine (0.5 mg/m2) and zoledronic acid (100 mg) is clinically feasible, with limited clinical toxicity. We now understand the importance of preserving the CD8 immune response and the use of immune biomarkers such as antigen specific ELISA to improve the rational and generate new combinations to improve clinical outcomes in patients with refractory HGSOC and CRC.