Abstract A172: TP-317, a first-in-class resolvin E1 small molecule, drives adjuvant efficacy in solid tumors by engaging innate and adaptive anti-tumor immunity in the tumor microenvironment (TME) and has neoadjuvant potential
Authors: Parkinson John F , Rothenberger Eva , Kelly Abigail , Bielenberg Diane , Attaya Ahmed , Huang Sui , Pflieger Lance , Klohs Wayne , Mathias Gary , Panigrahy Dipak 
Published: December 2023

Background: TP-317 is a novel salt of resolvin E1 (RvE1), an endogenous lipid agonist of ChemR23 that stimulates tumor debris phagocytosis/clearance by myeloid cells (Sulciner et al., 2018, J.Exp.Med). We recently reported TP-317 anti-tumor efficacy in murine solid tumors as monotherapy and in combination with immune checkpoint inhibitors (ICI) and chemotherapy (Kipper,  2023, Can. Res, 83 (7_Supp: 1135). Here we elaborate on the mechanism of action (MOA) of TP-317 in the adjuvant setting and report TP-317 efficacy in a neoadjuvant regimen

Methods: 125-240 mm3 established subcutaneous murine melanoma (B16F10) and pancreatic (Panc02-H7; KPC) tumors were treated with placebo, TP-317 or ICI and tumors excised at 12-14 days for bulk RNAseq or flow cytometry. Placebo, TP-317 (300 ug/kg s.c. 2 hr prior to and Q6D after resection), cisplatin (5 mg/kg i.p. 24 hrs prior to resection) or anti-PD1 (8 mg/kg i.p. 24 hr prior to resection only)  or TP-317 + anti-PD1 were evaluated in the LLC lung tumor model with tumors resected when reaching ~ 1500 mm3. Endpoints were lung/lymph node metastases or survival.

Results: RNAseq analysis showed that adjuvant TP-317 broadly engages innate (macrophage, dendritic, NK cells) and adaptive (CD8, CD4, B cells) immune pathways in the TME of PANC2-H7, KPC and B16F10 models. Depletion studies suggest TP-317 efficacy is CD8- and NK cell-dependent, consistent with the RNAseq data and flow cytometry, which confirmed expression of ChemR23 (RvE1 receptor) on M1/M2 macrophages, conventional cDC1/cDC2, NK and lymphoid subsets. In the TME of PANC2-H7, KPC and B16-F10 models, TP-317 induced a gene signature with upregulated IFNg responses, effector CD8/NK receptors, antigen-presenting pathways, cDC1/NK cell cross-talk, and chemokines/cytokines involved in anti-tumor immunity. In the B16F10 model TP-317 + dual ICI combined therapy synergistically upregulated an IFNg response signature relative to dual ICI therapy. In the LLC resection model, TP-317 monotherapy reduced lung (p&lt;0.05) and lymph node metastases (p&lt;0.01) 19 days post-resection, but cisplatin was not effective. Neoadjuvant cisplatin or anti-PD1 monotherapy did not improve survival relative to placebo, but TP-317 combined with neoadjuvant anti-PD1 induced long term survival (&gt;100 days) in 3 of 7 treated mice (p &lt;0.05 vs placebo or anti-PD1).

Conclusions: In adjuvant therapy of murine tumors, TP-317 broadly modulates innate/adaptive immune cell compartments in the TME, consistent with resetting the immunogenic tone and favoring anti-tumor immunity. Mechanistic synergy was observed for TP-317 combined with dual ICI therapy. TP-317 monotherapy shows metastasis control when initated prior to surgical resection and long term survival when combined with neoadjuvant anti-PD1 in the LLC model of NSCLC.

Citation Format: John F Parkinson, Eva Rothenberger, Abigail Kelly, Diane Bielenberg, Ahmed Attaya, Sui Huang, Lance Pflieger, Wayne Klohs, Gary Mathias, Dipak Panigrahy. TP-317, a first-in-class resolvin E1 small molecule, drives adjuvant efficacy in solid tumors by engaging innate and adaptive anti-tumor immunity in the tumor microenvironment (TME) and has neoadjuvant potential [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A172.