Abstract PO1-18-03: Chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib): New strategy to drive CD8+T-cells into triple negative breast cancer
Authors: Shipra Gandhi, Cayla Jones, Mateusz Opyrchal, Ronald Slomba, Kristopher Attwood, Jianmin Wang, Eduardo Cortes Gomez, Tracey O'Connor, Ellis Levine, Pawel Kalinski
Journal: Cancer Research (2024)

Abstract BACKGROUND: Pathologic complete response (pCR) is critical for positive long-term outcomes after neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) but is achieved only in 40-50% of patients. Combination of NAC with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant and often permanent immune-related toxicities. Higher levels of CD8+ cytotoxic T-lymphocytes (CTLs) and low levels of regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) in the tumor microenvironment (TME) predict improved relapse-free survival (RFS), overall survival (OS) and pCR, a surrogate marker for RFS. Locally produced chemokines CCL5, CXCL9, CXCL10 and CXCL11 are critical for CTL infiltration, while CCL22 is responsible for Treg attraction, with high CXCL9 being associated with a 3-fold higher rate of pCR after NAC. Our preclinical data show that Chemokine-modulatory (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)α2b and celecoxib (COX-2 inhibitor), eliminates the suppressive aspects of paclitaxel-induced inflammation and induces CTL-attractants but decreases MDSC- and Treg-attractants in the TME. We hypothesized that the combination of CKM with paclitaxel-based NAC will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. METHODS: In this phase I study NCT04081389, 9 pts with stage I-III TNBC and median age of 47 (37-55) years received 3 weeks of paclitaxel with CKM, followed by 9 weeks of paclitaxel alone, followed by standard dose-dense AC and surgery. Paclitaxel was given weekly IV at 80 mg/m2 for 12 weeks, rintatolimod 200 mg IV, IFN-α2b and celecoxib 200 mg oral twice daily on days 1-3 of each of the initial 3 weeks. IFN-α2b was administered in an accelerated titration design at doses 0 or 5 million units (MU)/m2 [Dose Level (DL) 1 and 2, respectively] in the first 2 pts (no intra-patient dose escalation), then 10 MU/m2 [DL3] in 4 pts and then 20 MU/m2 [DL4] in 3 pts. Day 1 pre- and post-treatment blood samples were drawn. Pre- and post-treatment (at 3 weeks) biopsies were obtained from 5 pts at DL3 and DL4. Dose-limiting toxicity (DLT) was defined as grade 3 or higher within the first 3 weeks of treatment. Primary endpoint was safety and tolerability, to determine the recommended phase II dose (RP2D) of CKM for extended efficacy study. Secondary endpoints included efficacy (pCR), along with RFS and OS. Biomarkers were analyzed in exploratory studies. RESULTS: Treatment was well-tolerated with mostly grade 1 or 2 treatment-related adverse events (TRAEs) and no DLTs. Grade 3 TRAE were neutropenia (3/9), attributed to CKM (1/9) or paclitaxel (3/9), pneumonia (1/9) and anemia (1/9) attributed to AC. Paclitaxel- or AC-related toxicities were not higher than expected. There were no delayed or immune-related toxicities beyond treatment. 5/9 (56%) pts attained pCR, and 1 additional pt had ypTmic at the time of surgery. There was consistent (p=0.07) selective increase in CD8α (CTL marker) in post-treatment tumor biopsies with concomitant decrease in CD8α in the blood (p=0.04) measured by RT-PCR. RNA sequencing on the blood samples (7 pre- and post-treatment) showed that higher M2 macrophages and naïve B cells in the pre-treatment samples were associated with higher probability of non pCR (adjusted p=0.02 and 0.05, respectively). CKM treatment decreased CD8α and CD8β post-treatment in the blood samples. Higher CD8+ T cells and NK cells in the post-treatment blood samples, were associated with higher likelihood of pCR, although this trend did not reach statistical significance. CONCLUSIONS: We have observed preliminary indications of safety and good tolerability of the combination of CKM regimen with paclitaxel, with promising pCR + ypTmic of 66%. RNA sequencing indicates that CKM may drive CD8+ T cells from the blood into the tumor. Citation Format: Shipra Gandhi, Cayla Jones, Mateusz Opyrchal, Ronald Slomba, Kristopher Attwood, Jianmin Wang, Eduardo Cortes Gomez, Tracey O'Connor, Ellis Levine, Pawel Kalinski. Chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib): New strategy to drive CD8+T-cells into triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-03.