Abstract 7300: Resolvin E1 in solid tumor cancer: towards clinical translation of a novel oral agonist targeting the LTB4-BLT1 pathway to sensitize tumors to immune checkpoint inhibition
Authors: Joyce Steinberg, Richard Newman, Beverly Paperiello, Tracy Jennings, Wayne D. Klohs, Sui Huang, Dipak Panigrahy, Gary Mathias, John Parkinson
Journal: Cancer Research (2025)

Abstract Background: Resolvin E1 (RvE1) and leukotriene B4 (LTB4) are both agonists of the BLT1 receptor (aka LTB4R1) but elicit distinct biological outcomes due to biased agonism. Activation of BLT1 promotes CD8+ T cell recruitment to the tumor, which enables effective immune checkpoint inhibitor (ICI) immunotherapy. However, LTB4, a pro-inflammatory lipid mediator, also promotes tumor progression through neutrophilic inflammation and is found at elevated levels in human cancers. In contrast, RvE1 selectively activates BLT1 to promote phagocytosis of tumor debris without causing inflammation. TP-317, a stabilized RvE1 molecule, effectively suppresses solid tumors in various murine models (CT26 colon carcinoma, Lewis lung carcinoma, B16F10 melanoma, KPCy pancreatic adenocarcinoma) when administered once daily, both alone and with ICI +/- chemotherapy. The effect of TP-317 as monotherapy required the presence of CD8 T cells and was largely abrogated in animals co-treated with a BLT1 antagonist. Whole-tumor transcriptomes of resected tumors of TP-317-treated versus control animals displayed broad upregulation of IFN-γ response genes and antigen presentation machinery, consistent with the synergism observed when given in combination with ICI. TP-317 is being developed as oral therapy for colorectal cancer and non-small cell lung cancer. The present study describes the pharmacokinetics, pharmacodynamics and safety profile of oral TP-317 given as an enteric-coated tablet to healthy volunteers. Methods: Twenty-four subjects were randomized 3:1 to single oral doses of TP-317 at 10, 40 and 80 mg (n=8/group). Safety, tolerability and PK/PD were assessed using standard methods. Subjects receiving the 80 mg dose underwent frequent CBC testing to assess short-term fluctuations in circulating neutrophils. Results: Oral TP-317 was well tolerated, achieving peak plasma concentrations of RvE1 that exceeded the EC50 for BLT1 activation (∼10 nM) by 1.2, 2.8, and 6.7 times at 10, 40, and 80 mg doses, respectively. All subjects receiving the 80 mg dose exhibited transient neutropenia, with neutrophil counts dropping below 1500/mL near plasma tmax and recovering to normal range within about 2 hours. A similar pattern, also without safety concerns, was previously observed in healthy subjects receiving an oral RvE1 drug (150 mg bid) for 10 days. Conclusions: Oral TP-317 demonstrates good tolerability and achieves adequate systemic RvE1 levels to engage the BLT1 receptor, suggesting a dose range of 40 to 80 mg once per day for patient studies. Transient neutropenia, a known effect of BLT1 activation by RvE1, indicates target engagement in humans. TP-317's unique ability to promote antigen presentation in myeloid and tumor cells offers a novel approach to sensitize tumors to ICI, warranting clinical investigation in cancer patients. Citation Format: Joyce Steinberg, Richard Newman, Beverly Paperiello, Tracy Jennings, Wayne D. Klohs, Sui Huang, Dipak Panigrahy, Gary Mathias, John Parkinson. Resolvin E1 in solid tumor cancer: towards clinical translation of a novel oral agonist targeting the LTB4-BLT1 pathway to sensitize tumors to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7300.