Abstract 3261: Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.3261-3261
• Main Authors: Parra, Karla, Valenzuela, Paloma, Gallegos, Alejandra E., Lerma, Natzidielly, Reza, Luis, Rodriguez, Georgialina, Emmenegger, Urban, Manciu, Marian, Di Desidero, Teresa, Bocci, Guido, Felder, Mitchell S., Kirken, Robert A., Francia, Giulio
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-3261

Although we previously reported that metronomic cyclophosphamide can augment the anti-tumor impact of anti-CTLA-4 immunotherapy, the effectiveness of this strategy to treat drug resistant tumors remains to be evaluated. To that end, the parental, drug sensitive, EMT-6/P murine breast cancer, or its cisplatin (DDP) or cyclophosphamide (CTX) resistant variants, were implanted into Balb/c mice (n = 5-8 mice per group), either subcutaneously or orthotopically. Established tumors where monitored for relative growth following treatment with anti-CTLA-4 antibody (mouse anti-CD152, clone 9H10, given at 100ug on day 1 and 35ug on day 6, i.p.), 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). 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 a regimen of sequential gemcitabine. The EMT-6/P tumor showed consistent results in subcutaneous tumors and in those that were orthotopically implanted into the mammary fat pad. Tumor responses were less pronounced in drug resistant EMT-6/CTX or EMT-6/DDP tumor models than in the EMT-6/P tumor, but nonetheless even in the drug resistant models CTLA-4 targeting could be effectively combined with metronomic CTX or sequential gemcitabine (p