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

Journal for Immunotherapy of Cancer · 18 authors, 6 centres

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TL;DR

A small clinical trial tested a systemic chemokine-modulating regimen in six patients with metastatic triple-negative breast cancer.

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The primary endpoint was the change in intratumoral CD8α expression post- versus pre-treatment. The regimen increased CTL-attracting chemokines CCL5 and CXCL10 but not Treg attractants. One patient experienced a clinical response (breast tumor autoamputation) and three had stable disease. Limitations include the very small sample size and the sequential, not concurrent, administration with checkpoint blockade, which limits conclusions on clinical efficacy.

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RCT

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oncology

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ORIGINAL PAPER

PMC10649898

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

Journal for Immunotherapy of Cancer

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ABSTRACT

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

CITATION EXPORT

Shipra Gandhi, Mateusz Opyrchal, Melissa J Grimm et al.. Systemic infusion of TLR3-ligand and IFN-α in patients with breast cancer reprograms local tumor microenvironments for selective CTL influx. Journal for Immunotherapy of Cancer. (2023). https://doi.org/10.1136/jitc-2023-007381

AUTHORS

18 · 6 CENTRES

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

1 Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
2 Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
3 Advanced Tissue Imaging Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
4 Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
5 Clinical Research Services, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
6 Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA