Abstract 169P
Background
ENPP1 is a type II transmembrane protein with nucleotide pyrophosphatase, and phosphodiesterase enzymatic activities and its expression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis and reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting anticancer immunity. RBS2418 is a potent oral ENPP1 inhibitor. Here, we report pharmacokinetic (PK) and immunomodulatory properties of RBS2418 in combination with pembrolizumab (pembro) in a checkpoint-refractory high grade adrenal cancer with an immune-desert tumor phenotype at baseline.
Methods
Pembro was given at 200mg IV every 3 weeks with escalating doses of RBS2418 weekly, at 100 mg p.o. BID, followed by 200 and 400 mg p.o BID. Blood samples were collected at each dose level to determine plasma RBS2418 concentration and serum ENPP1 inhibition. Peripheral blood immune cell subpopulations were analyzed by flow cytometry and TCR/RNA sequencing.
Results
All dose levels of RBS2418 with pembro were safe, well tolerated with no DLTs. Plasma concentrations (Ctrough) of RBS2418 corresponded to > 15-fold and > 30-fold above the 90% inhibition level of ENPP1 (EC90) for the 100 and 200 mg dose, respectively. cGAMP was fully stable in serum. Peripheral blood analyses showed a 2.1-fold increase from baseline in conventional dendritic cells (cDCs) and 2.5-fold expansion of proliferating CD4/Ki67 T cells. Furthermore, CD8/Ki67 proliferating T cells increased 19.5-fold from baseline. TCR/RNA sequencing showed a > 50-fold expansion in TCR CD3β clonotypes, an increase in hyperexpanded TCR clonotypes and upregulation of granzyme B, perforin and granulysin gene expression.
Conclusions
RBS2418 with pembro was safe, well tolerated with no DLTs. RBS2418 PK data showed excellent oral bioavailability with plasma levels leading to complete ENPP1 inhibition. RBS2418 induced increases in peripheral cDCs, proliferation of CD4 and CD8 T cells and expansion of TCR clonotypes as well as upregulation of T cell cytotoxic granule protein gene expression supporting clinical development of this novel first-in-class immunotherapy agent in an ongoing clinical trial (NCT05270213).
Legal entity responsible for the study
The authors.
Funding
Riboscience, Llc.
Disclosure
J. Glenn: Financial Interests, Personal, Member of the Board of Directors: Riboscience; Financial Interests, Personal, Stocks/Shares: Eiger Pharmaceuticals. I. Csiki: Financial Interests, Personal, Full or part-time Employment: Riboscience; Financial Interests, Personal, Stocks/Shares: Riboscience. K. Klumpp: Financial Interests, Personal, Member of the Board of Directors: Riboscience. All other authors have declared no conflicts of interest.