Radiation and TGFβ Inhibition Combo Elicits Activity in Metastatic Breast Cancer

Dörthe Schaue, PhD

A strategy to stimulate an immune response in radiation-damaged tumor cells resulted in preliminary evidence of activity—including longer survival—in a small clinical trial of patients with metastatic breast cancer.

Following metastasis-specific irradiation, patients who received the higher of 2 doses of the anti-TGFβ1 antibody fresolimumab had an early immune response characterized by an increase in CD4 T-regulatory cells (Tregs), a decrease in peripheral blood mononuclear cells (PBMCs), and an increase in central memory CD8-positive T cells. The observations were consistent with reduced myeloid suppression, Dörthe Schaue, PhD, reported at the 2016 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston, Massachusetts.

Patients who received the 10-mg dose of fresolimumab lived about 10 months longer than did patients who received 1-mg doses of the anti-TGFβ1 agent, along with the targeted irradiation, said Schaue, an adjunct assistant professor of Radiation Oncology at the University of California, Los Angeles.

“Patients in the higher-dose fresolimumab arm tended to do better and showed some interesting immunological changes in the periphery,” said Schaue. “The effects included prevention of radiation-induced white-cell nadirs, reduced regulatory network in the myeloid compartment, and stronger immunological memory.”

TGFβ1 has wide-ranging immunoregulatory activity involving multiple cell types. The activity generally is immunosuppressive in nature, including inhibition of T-cell proliferation and driving proliferation. In breast cancer, the TGFβ pathway is part of an immune-disabled phenotype.

A multifaceted rational-supported TGFβ1 blockade in the treatment of metastatic breast cancer. Inhibition of the protein could limit tumor growth, tumor spread, and immune suppression. Additionally, disruption of TGFβ might enhance the response of irradiated tumors and improve the function of dendritic cells and T cells.

Considerable preclinical evidence has supported TGFβ blockade as a therapeutic, said Schaue. TGFβ inhibition has been shown to aid radiation-induced production of tumor-specific CD8-positive T cells and tumor regression in mice (Cancer Res. 2015;75:2232-2242). Disruption of TGFβ signaling has been associated with T-cell killing of brain tumors in a preclinical model (Proc Natl Acad Sci USA. 2014;111:e3458-e3466). Also in a preclinical model of metastatic melanoma, the combination of radiation and TGFβ inhibition led to increased levels of tumor-specific CD8 T cells in the circulation (Clin Cancer Res. 2016;22:1161-1172). Additionally, phase I clinical experience with fresolimumab yielded evidence of activity melanoma and renal cell carcinoma (PLoS One. 2014;9:e90353).

Schaue reported findings from a 22-patient pilot trial of fresolimumab in combination with selective irradiation of metastatic lesions. Patients with at least 3 metastatic lesions were randomized to receive 1 mg or 10 mg of fresolimumab administered over 5 3-week cycles.

Radiation therapy consisted of conformal external-beam RT delivered in 3 7.5-Gy fractions on consecutive days to selected metastatic lesions. The rationale was to use the targeted radiation to create personalized antigenic reservoirs for the monoclonal antibody.

Patients in the high-dose fresolimumab group responded with a rise in circulating Tregs, often accompanied by tumor-specific T-cell responses, Schaue reported. Most patients in the high-dose group also responded with decreased levels of circulating monocytic myeloid-derived suppressor cells (MSDCs) in the myeloid compartment. The combination of decreased levels of MSDCs and increased levels of Tregs was associated with improved surivival in the patients who received the 10-mg dose of fresolimumab (MSDC/Tregs at week 2, P = .026; at week 5, P =.036).

Patients in the high-dose arm lived significantly longer. The 10-mg group had a median overall survival of 64 weeks compared with 20 weeks in the 1-mg fresolimumab arm (P = .0154). In general, patients in the 10-mg group lived longer, but the overall difference appeared to be driven by several patients who had especially prolonged survival, leading Schaue to question whether some patients in the 10-mg group did worse than expected, and if so, why.

Patients in the 10-mg group had “striking increases” in central memory CD8-positive T cells and decreases in effector T cells. Memory T-cell infiltration has previously been reported to correlate with better prognosis in colorectal cancer. Additionally, infiltrating CD8 memory T cells have proved to be a biomarker for response to anti—PD-1 treatment in melanoma.

Planned and ongoing trials are continuing the investigation of fresolimumab and other TGFβ inhibitors in breast cancer, non—small cell lung cancer, and hepatocellular carcinoma, said Schaue.

Schaue D. Shaping the immune landscape in irradiated breast cancer patients with systemic TGF-β blockade. Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 25-28, 2016.