Evaluation of CTLA-4 Blockage Therapy with Metronomic Chemotherapy for the Treatment of Preclinical Breast Cancer
Background: Although there are reports that metronomic cyclophosphamide can be immune stimulating, the impact of its combination with anti-CTLA-4 immunotherapy for the treatment of cancer remains to be evaluated. Methods: Murine EMT-6/P breast cancer, or its cisplatin or cyclophosphamide (CTX) resistant variants, or CT-26 colon, were implanted into Balb/c mice. Established tumors were monitored for relative growth following treatment with anti-CTLA-4 antibody alone or in combination with; a) metronomic CTX (ldCTX; 20mg/kg/day), b) Bolus (150mg/kg) plus ldCTX, or c) sequential treatment with gemcitabine (160mg/kg every 3 days). Results: EMT-6/P tumors responded to anti-CTLA-4 therapy, but this response was less effective when combined with Bolus plus ldCTX. Anti-CTLA-4 could be effectively combined with either ldCTX (without a bolus), or with regimens of either sequential or concomitant gemcitabine, including in orthotopic EMT-6 tumors, and independently of the schedule of drug administration. Tumor responses were confirmed with CT-26 tumors but were less pronounced in drug resistant EMT-6/CTX or EMT-6/DDP tumor models than in the parent tumor. A number of tumor bearing mice developed spontaneous metastases under continuous therapy. The majority of cured mice rejected tumor re-challenges. Conclusion: Metronomic CTX can be combined with anti-CTLA-4 therapy, but this therapy is impaired by concomitant bolus CTX. Sequential therapy of anti-CTLA-4 followed by gemcitabine is effective in chemotherapy naïve tumors, although tumor relapses can occur, in some cases accompanied by the development of spontaneous metastases.
Parra, Karla, "Evaluation of CTLA-4 Blockage Therapy with Metronomic Chemotherapy for the Treatment of Preclinical Breast Cancer" (2019). ETD Collection for University of Texas, El Paso. AAI22615314.