Purpose: This is a pilot study combining focal irradiation and systemic TGFβ blockade in metastatic breast cancer. The rationale for using TGFβ blockade was to limit tumor growth and further spread as well as to curb systemic immune suppression. Combining this systemic approach with hypofractionated radiation of selective tumor metastasis aimed at vaccinating each patient in vivo with her own, relevant tumor antigens by local radiation damage and allow T cells to reach their full potential while escaping TGFβ's grip.

Experimental Design: Serial blood samples from 22 patients undergoing treatment with 1mg or 10mg Fresolimumab and Radiation at the New York University School of Medicine (n=15) and at the David Geffen School of Medicine, University of California, Los Angeles (n=7) were immunophenotyped based on flow cytometric analysis of 21 surface antigens.

Results: There were significant differences between the 1mg and 10mg groups with respect to several immune parameters, especially the rise in circulating central memory CD8s at the higher dose level (relative increase at 2 weeks 10mg vs 1mg, p=0.027). Regulatory networks responded to the 10mg treatment regime with a consistent expansion in CD4 Tregs while mMDSCs declined (ratio Tregs/mMDSC rising in 10mg vs 1mg, p=0.026). An overall survival benefit was seen in the 10mg Fresolimumab arm (median OS 64.1 weeks versus 20 weeks, p=0.015 log rank test) albeit not striking. CART analysis allowed accurate survival classification based on 2-week changes in CD8/mMDSC ratios and plasma Tryptophan (ROC AUC 0.979).

Conclusion: Inhibiting TGFβ in the context of focal irradiation seems to create a favorable systemic immune landscape that drives T cell memory differentiation while limiting myeloid suppression.

Citation Format: Dörthe Schaue, Michael W. Xie, Josephine A. Ratikan, Ewa D. Micewicz, Lin Hwang, Kym F. Faull, James W. Sayre, Percy P. Lee, John A. Glaspy, Sandra Demaria, Silvia C. Formenti, William H. McBride. Radiation and TGFβ blockade bring back memories in metastatic breast cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B86.