Abstract P4-06-07: Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer
Authors: Gandhi Shipra , Opyrchal Mateusz , Ford Cayla , Slomba Ronald , Attwood Kristopher , O’Connor Tracey , Levine Ellis , Kalinski Pawel 
Published: March 2023

Abstract
BACKGROUND: Pathologic complete response (pCR) or microinvasive residual breast cancer (ypTmic) following neoadjuvant chemotherapy (NAC) is critical for good long-term outcomes in triple negative breast cancer (TNBC) patients (pts) but is achieved only in 40-50% of pts. Its combination with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant immune-related and permanent toxicities. Higher intratumoral levels of CD8+ cytotoxic T-lymphocytes (CTLs) and low levels of regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) predict improved relapse-free survival (RFS), overall survival (OS) and higher probability of pCR, a surrogate marker for RFS. Locally produced chemokines CCL5, CXCL9, CXCL10 and CXCL11 are critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction, with high CXCL9 expression being associated with a 3-fold higher rate of achieving pCR in response to NAC. Our preclinical data show that Chemokine-modulatory (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b and celecoxib (COX-2 inhibitor), selectively induces CTL-attractants but decreases MDSC- and Treg-attractants in the tumor microenvironment (TME). We hypothesized that the combination of CKM with paclitaxel 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 the phase I study NCT04081389, 9 pts with stage I-III TNBC were enrolled with median age of 47 (37-55) years. All patients were treated with paclitaxel 80 mg/m2 IV weekly for 12 weeks, and for first 3 weeks days 1-3 also received CKM regimen consisting of rintatolimod 200 mg IV and celecoxib 200 mg oral twice daily. IFN-α2b was administered in an accelerated titration design at doses 0 or 5 million units (MU)/m2 [Dose Level (DL) 1,2 respectively] in first 2 pts (no intra-patient dose escalation), then 10 MU/m2 [DL 3] in 4 patients and then 20 MU/m2 [DL 4] in 3 patients. Pre- and 3 week-on treatment biopsies were performed at DL 3 and DL 4 (5 patients). This was followed by standard dose-dense AC and surgery. Dose-limiting toxicity (DLT) was defined as grade 3 or higher toxicity within the first 3 weeks of treatment. The primary endpoint was safety and tolerability, to determine the recommended phase II dose (RP2D) of CKM for extended efficacy study. The secondary endpoints included the efficacy (pCR), along with RFS and OS. Tumor and blood 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. Two additional severe adverse events (pneumonia and squamous cell carcinoma of skin in situ) were observed, unrelated to study treatment. Paclitaxel- or AC-related toxicities were not higher than expected. There was no evidence of delayed or immune-related toxicities 90 days post-treatment. 5/9 (56%) pts attained pCR, and 1 additional pt had ypTmic at the time of surgery. There were no patients with progressive disease. All patients were able to get planned surgery with no additional delays observed. There was consistent (p=0.07) selective increase in CD8α (CTL marker) in on-treatment tumor biopsies with concomitant decrease in CD8α in the blood (p=0.04). CONCLUSIONS: The treatment was well-tolerated and no DLTs were observed and we determined RP2D for future studies. We observed promising clinical activity with pCR + ypTmic rate of 66%, comparable to pembrolizumab combination with NAC. A larger phase II study is being designed to confirm the observed efficacy and to determine if CKM regimen would be a safer short-term alternative to pembrolizumab or if CKM can overcome the resistance to the standard pembrolizumab/NAC therapy.
Citation Format: Shipra Gandhi, Mateusz Opyrchal, Cayla Ford, Ronald Slomba, Kristopher Attwood, Tracey O’Connor, Ellis Levine, Pawel Kalinski. Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-07.