Phase 1 Trial Combining Neoadjuvant Chemotherapy with Chemokine Modulatory Regimen for Triple Negative Breast Cancer

BACKGROUND. Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) of triple negative breast cancer (TNBC) predicts long-term outcomes but is achieved only in 30-40% of patients. Higher CTL in the tumor microenvironment (TME) is associated with higher pCR. Combination with anti-PD1 immunotherapy increases pCR but at the cost of immune-related adverse events (irAEs). Our clinical trial using systemic chemokine-modulatory regimen (CKM; rintatolimod [selective TLR3-Ligand], interferon (IFN)-a2b and celecoxib [COX-2 inhibitor]) in patients with metastatic TNBC selectively increased CTL in the TME, providing rationale for its combination with NAC. METHODS. Phase I study NCT04081389 evaluated nine stage I-II TNBC patients who received 3 weeks of paclitaxel with CKM, followed by 9 weeks of paclitaxel alone, standard dose-dense doxorubicin and cyclophosphamide and surgery. Primary endpoint was safety and secondary endpoint included clinical efficacy. RESULTS. Combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients attained pCR, and 1 patient had micrometastatic disease (ypTmic). Circulating CTLs were decreased (0.12-fold average decrease) with upregulation of IFN-stimulatory and downregulation of CD8 gene signatures in all patients. This was accompanied by increase in CD8b (7.07- fold increase), CD8a/FoxP3 (2.18-fold increase), CCL5 (5.49-fold increase), and CXCL12 (6.06-fold increase) transcripts and multiplex analysis revealed decrease in epithelial and stromal markers with increase in CTL among patients with pCR. CONCLUSION: Combination paclitaxel/CKM regimen was safe, with preliminary indications of promising pCR+ypTmic of 66%. Overall design: This is a phase I trial comibining dose escalated IFN with paclitaxel, followed by Doxorubicin and cyclophosphamide, then followed by surgery. Blood samples were obtained pre-treatment and same day postreatment. 7 pairs of samples (3 Non-pCR and 4 pCR) pre and post treatment; 14 samples in total.