Abstract 2741: Combination of rapamycin with immune checkpoint blockade in a syngeneic breast carcinoma model
Authors: Trachet Erin , Elders Chris , Urs Sumithra , Krueger Sarah , Wong Alden , Franklin Maryland Rosenfeld 
Published: August 2018

Many advances in the treatment of breast cancer have been driven by the development of targeted therapies that inhibit signal transduction pathways, as well as the development of therapies that activate a patient's immune system to unleash antitumor immunity. The choice of an animal model that mimic aspects of human breast cancer is crucial for evaluating new immunotherapeutic combination strategies. An excellent syngeneic model of breast cancer is 4T1. 4T1-luc2 is poorly immunogenic and shares many characteristics with human breast cancer. To understand the potential benefit from combining a targeted therapy with an immune modulator we utilized the orthotopic 4T1-luc2 model. The mTOR pathway plays an important role in metabolism, cell growth and survival. Targeting mTOR has been an active area of oncology drug discovery and clinical development for breast cancer and other malignancies. In addition, clinical success through blockade of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has resulted in a paradigm shift for drug development within the oncology community. To this end, we designed a series of experiments to evaluate rapamycin, a first generation mTOR inhibitor, in combination with the immune checkpoint inhibitor antibody against CTLA-4. We find that 4T1-luc2 tumors have very few T cells but a significant MDSC (myeloid derived suppressive cells) population. Treatment with anti-CTLA-4 (10mg/kg) produced a slight increase in T cells and a slight decrease in MDSCs. However, these changes in the immune profile did not manifest into meaningful changes in tumor burden. Treatment with low dose (8, 5 or 3mg/kg) rapamycin was well tolerated and produced a modest tumor growth inhibition (~50%) and modulation on the immune profile. The overall impact on the immune profile was like what we've seen with anti-CTLA-4 treatment, with a ~5% decrease in MDCSs but a relatively untouched T cell population. This made the paring of these agents appealing as we hypothesized that the combination may result in further reduction of MDSCs which could make the tumor microenvironment more susceptible to therapeutic intervention. To test this, we looked at rapamycin (8mg/kg) given either simultaneously with, or 1 week prior to, anti-CTLA4. Single agent activity was as expected with %T/C on day 22 at 63% with rapamycin and 84% with anti-CTLA-4. Combination therapy was well tolerated but we found that neither dosing schedule resulted in improved anti-tumor activity over monotherapies with 52% T/C following simultaneous treatment and 53% following sequential treatment. A study to evaluate the impact of the drug combinations on the immune profile is ongoing and will be presented. While both rapamycin and anti-CTLA-4 were capable of modulating the immune profile, improvements in efficacy were not observed. This model provides a system with which preclinical hypotheses can be efficiently tested.

Citation Format: Erin Trachet, Chris Elders, Sumithra Urs, Sarah Krueger, Alden Wong, Maryland Rosenfeld Franklin. Combination of rapamycin with immune checkpoint blockade in a syngeneic breast carcinoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2741.