31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Abstract

Background While sustained cytotoxic chemotherapy may be associated with lymphopenia and immunosuppression, chemotherapy may also facilitate antigen release/presentation, adaptive expression of PD-L1, and relative depletion of suppressive immune cell populations. Metastatic triple-negative breast cancer (MTNBC) is an aggressive and incurable disease associated with high mutational load and tumor-infiltrating lymphocytes, and is treated conventionally with sequential, sustained cytotoxic chemotherapy. In heavily pre-treated patients, anti-PD-1/L1 monotherapy yielded modest response rates of 9-19% [1]. However, we hypothesize that up-front treatment with 1st/2nd line chemotherapy plus anti-PD-1/L1 might minimize immunosuppression (by treating patients before they are exposed to prolonged chemotherapy) and maximize immunostimulation (by treating less chemo-resistant disease and maximizing antigen release). In a preliminary cohort, anti-PD-L1 plus chemotherapy (nab-paclitaxel) was safe, with favorable response rates compared to historical controls [2]. Methods In a pilot/phase II investigator-initiated trial, we will evaluate the safety and tolerability of anti-PD-1 (pembrolizumab 200mg IV every three weeks) plus investigator-selected 1st/2nd line standard-of-care chemotherapy with either weekly paclitaxel (80mg/m2 IV) or oral capecitabine (2,000mg twice daily, weekly 1 on/1 off). Secondarily, we will evaluate efficacy of each combination employing a Simon 2-stage design, as measured by week 12 radiographic response. Because chemotherapy-associated immunosuppression could potentially influence immunotherapy efficacy, we will serially characterize general immune status and T cell activation using a validated realtime multi-parametric flow cytometry platform and peripheral blood T cell receptor sequencing (to measure clonal repertoire diversity). Via a companion biospecimen protocol, these data will be compared with data from MTBNC subjects receiving paclitaxel or capecitabine alone. Furthermore, baseline and post-treatment tumor-infiltrating lymphocytes will be characterized using multi-spectral immunofluorescence (using a validated panel including CD3, CD8, CD163, FOXP3, PD-L1, DAPI, and CK) and T cell receptor sequencing. Results As of 8/7/2016, five subjects have been registered for enrollment. Conclusions This investigator-initiated trial will provide important data, evaluating the efficacy of commonly used chemotherapies (paclitaxel or capecitabine) plus anti-PD-1, as well as evaluating the effect of these regimens on general immune status, peripheral T cell activation, and tumor infiltrating lymphocytes. A registrational MTNBC trial of nabpaclitaxel +/- anti-PD-L1 is ongoing.