Systemic infusion of TLR3-ligand and IFN-α in patients with breast cancer reprograms local tumor microenvironments for selective CTL influx

• DOI: 10.1136/jitc-2023-007381
• Publication Date: 2023-11-14T12:10:18Z
• Authors: Shipra Gandhi; Mateusz Opyrchal; Melissa J Grimm; Ronald T Slomba; Kathleen M Kokolus; Agnieszka Witkiewicz; Kristopher Attwood; Adrienne Groman; Lauren Williams; Mary Lynne Tarquini; Paul K Wallace; Kah Teong Soh; Hans Minderman; Orla Maguire; Tracey L O’Connor; Amy P Early; Ellis G Levine; Pawel Kalinski
• Keywords: CTL*; Granzyme

Background Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts effectiveness cancer immunotherapies. The ability toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory cell (Treg)-attractants) TME, but healthy tissues, observed our preclinical studies, suggested that their systemic application can reprogram local TMEs. Methods Six evaluable patients (33–69 years) with metastatic triple-negative breast received six doses chemokine-modulating (CKM) regimen composed TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m 2 ; intravenous) inhibitor (celecoxib; 2×200 oral) over weeks. predetermined primary endpoint was intratumoral change expression CTL marker, CD8α, post-CKM versus pre-CKM biopsies. Patients follow-up pembrolizumab (200 mg, intravenously, every weeks), starting 3–8 days after completion CKM. Results Post-CKM biopsies showed selectively increased markers CD8α (average 10.2-fold, median 5.5-fold, p=0.034) granzyme B (GZMB; 6.1-fold, 5.8-fold, p=0.02), FOXP3 (Treg marker) relative HPRT1 expression, resulting increases average CD8α/FOXP3 ratio GZMB/FOXP3 ratio. CKM CTL-attractants CCL5 CXCL10, Treg-attractants CCL22 or CXCL12. In contrast, CD8 + cells CXCR3 subset transient decreases blood. One clinical response (breast autoamputation) three stable diseases were observed. patient remains disease free, a 46 months as data cut-off. Conclusions Short-term numbers CTL/Treg ratios while transiently decreasing Transient effects suggest its simultaneous checkpoint blockade other forms immunotherapy may be needed for optimal outcomes.