Abstract OT3-01-02: CNIO-BR-008 trial: Reversion of T-cell exhaustion caused by chronic treatment with hypoxia-inducing antiangiogenic treatment by durvalumab in HER2-negative breast cancer: A pilot proof-of-concept trial
Authors: M Quintela-Fandino, L Manso, S Mouron, JF Lopez-Acosta, JA García-Saenz, E Holgado, T Pascual-Martinez, L Medicna, J Guerra, L Gonzalez-Cortijo, S Mañes
Journal: Cancer Research (2017)

Abstract Background: The role of immune checkpoints in tumor progression is less relevant in breast cancer than in other malignancies. However, in preclinical experimentation we found a niche for immune checkpoint inhibitors. In an immunocompetent model of HER2-negative breast cancer (MMTV-PyMT) we observed that antiangiogenic agents may induce either a tumor normoxic or hypoxic adaptation. Normoxic adaptation leads to a therapeutically exploitable dependence on mitochondrial metabolism (Cell Rep 2016; 15: 1-14). Hypoxic adaptation (usually caused by monoclonal antibody type antiangiogenics) induces an increase in PGE2 and PGA synthesis, followed by a switch of the tryptophan metabolism from 5HIAA to kinurenine that culminates in differentiation of naive T-cells to Tregs and expression of PD-L1 in the hypoxic areas. The exhausted T-cell response observed in this model can be restored with PD-L1 inhibitors. We sought to prove the relevance of T-cell exhaustion an its reversibility by the anti-PD-L1 antibody durvalumab in patients receiving chronic bevacizumab (Bev). Trial design Single-arm, prospective, multicentric, phase II open-label trial. Patients receiving Bev maintenance after a chemotherapy+Bev regimen administered in the first line of metastatic disease that experience disease progression (PD) during maintenance will be candidates. The treatment will start by adding durvalumab (10 mg/kg q2w) to the ongoing Bev (15 mg/kg q3 w). Patients will undergo serial tumor biopsies, tumor-cfDNA sequencing (baseline and progression), and immunophenotyping (baseline and q4w). RECIST/I-RECIST and NCI CTC AE V4.03 criteria will be used for assessing disease response and toxicity. Elegibility criteria Women &amp;gt;18 year old diagnosed of HER2-negative advanced breast cancer; 2) have received chemotherapy plus Bev for the first line treatment and experienced PR, CR or SD, 3) followed by maintenance with three-weekly Bev in monotherapy for at least 6 weeks before diagnosis of PD. 4) Concurrent hormonal therapy is allowed for ER+ patients, but reception of previous immunotherapy is precluded. 5) Adequate organ function defined according to standard parameters. Specific aims Primary: 1) To determine the relative percentages of innate and adaptive immune cell subpopulations and ascertain the status of T-cell function and polarization by multiparametric flow cytometry in patients with acquired resistance against Bev 2) To assess the reversibility of the abnormalities evidenced in (1) by durvalumab 3) To determine the disease control rate of the combination, and its relationship with (1) and (2) Secondary: 4) To determine potential tumor neoantigens generated by chronic tumor hypoxia secondary to the antiangiogenic treatment. Statistical methods The sample size is calculated on the basis of the expected change in the Treg percentage in peripheral blood (10%), with an alpha and beta errors of 5% and 20% respectively. The minimum number of patients necessary to observe a 10% decrease is 25. Changes in lymphocytes will be compared with intra-subject measurements and Z-scores. Accrual: 2 of 25 (target accrual) patients have been recruited. Contact info: mquintela@cnio.es. Citation Format: Quintela-Fandino M, Manso L, Mouron S, Lopez-Acosta JF, García-Saenz JA, Holgado E, Pascual-Martinez T, Medicna L, Guerra J, Gonzalez-Cortijo L, Mañes S. CNIO-BR-008 trial: Reversion of T-cell exhaustion caused by chronic treatment with hypoxia-inducing antiangiogenic treatment by durvalumab in HER2-negative breast cancer: A pilot proof-of-concept trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-02.