Abstract 1135: TP317, a first-in-class resolvin E1 small molecule, potentiates the efficacy of immune checkpoint (ICI) inhibitors in ICI-resistant and ICI-sensitive tumors
Authors: Kipper Franciele C. , Rothenberger Eva , Kelly Abigail , Gillespie Michael , Attaya Ahmed , Bielenberg Diane R. , Huang Sui , Pflieger Lance , Sciavolino Frank , Mathias Aaron , Klohs Wayne , Parkinson John , Mathias Gary , Panigrahy Dipak 
Published: April 2023

Background: TP317 is a novel, highly stable chelate salt of resolvin E1 (RvE1), a pro-resolution mediator that stimulates myeloid cell phagocytosis of tumor debris and attenuates pro-tumoral inflammation through activation of the GPCR, ChemR23 (Sulciner et al., 2018, J. Exp. Med). We hypothesized that RvE1 shifts the immunosuppressive tumor microenvironment (TME) to an immunogenic state, thus offering combination potential with immune checkpoint inhibitors (ICI) in ICI-resistant and ICI-sensitive tumors.

Methods: Subcutaneous murine models of lung (LLC), melanoma (B16F10), and pancreatic (Panc02; KPC) tumors were used to investigate TP-317 monotherapy and combinations with ICI. Treatment was initiated when tumors reached 125-240 mm3.

Results: In the LLC model (N=5/group), TP317 (0.75 µg QD) inhibited tumor growth (1419 ± 266 mm3) compared to placebo (2348 ± 542 mm3; p=0.068) and anti-PD1 (200 µg IP, Q3D; 3015 ± 730; p=0.078). TP317 + anti-PD1 dual therapy was superior to placebo and anti-PD1 alone (893 ± 166 mm3; p&lt;0.05). In the B16F10 model (N=8/group), TP317 (7.5 µg Q6D) was efficacious compared to placebo (787 ± 367 vs 1964 ± 208 mm3; p&lt;0.01) and comparable to the ICI dual therapy of anti-PD1 + anti-CTLA4 (100 µg 1st dose, 200 µg IP Q3D up to 4 doses). Triple therapy with TP317 + anti-PD1 + anti-CTLA4 was superior to ICI dual therapy (340 ± 91 vs 757 ± 260 mm3; p&lt;0.05). In the Panc02 model (N=8/group), TP317 (0.75 µg Q7D) was efficacious compared to placebo (1148 ± 178 vs 1992 ±165 mm3; p&lt;0.001) and comparable to anti-PD1. TP317 + anti-PD1 dual therapy demonstrated significant anti-tumor activity compared to anti-PD1 alone (329 ± 72 vs 1446 ± 305 mm3; p&lt;0.01). In KRAS-mutant KPC tumors (N=10/group), TP317 (7.5 µg Q6D) demonstrated significant anti-tumor activity compared to placebo (500 ± 110 vs 1314 ± 106 mm3; p&lt;0.001) and was comparable to anti-PD1, while TP-317 + anti-PD1 was superior to anti-PD1 alone (353 ± 82 vs 710 ± 106 mm3; p&lt;0.01). In Panc02 and KPC models, TP317’s anti-tumor efficacy was attenuated by CD8+ T cell or NK cell depletion. Consistent with the depletion study results, RNAseq analysis with cell-type deconvolution showed that TP317 enhanced CD8 and NK cell associated programs in Panc02 and B16F10 tumors, and also promoted macrophage, dendritic cell, B cell and antigen presentation functions in the TME.

Conclusions: TP317 monotherapy and ICI combinations significantly inhibited tumor growth in various murine models of cancer. The effects on various immune cell functions and the surprising efficacy of short half-life RvE1 (&lt;2 hours) dosed weekly suggests that TP317 is reprogramming the TME to an immunogenic state. In summary, TP317, an RvE1 drug with a high therapeutic index, has potent single agent efficacy and offers a novel approach in combination with ICI to treat ICI-resistant and ICI-sensitive tumors.

Citation Format: Franciele C. Kipper, Eva Rothenberger, Abigail Kelly, Michael Gillespie, Ahmed Attaya, Diane R. Bielenberg, Sui Huang, Lance Pflieger, Frank Sciavolino, Aaron Mathias, Wayne Klohs, John Parkinson, Gary Mathias, Dipak Panigrahy. TP317, a first-in-class resolvin E1 small molecule, potentiates the efficacy of immune checkpoint (ICI) inhibitors in ICI-resistant and ICI-sensitive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1135.