Abstract A84: Clinical correlates and rationale for PEGylated adenosine deaminase 2 as a novel cancer immunotherapy

Abstract

Abstract Extracellular adenosine accumulates in solid tumors due to direct release or due to dephosphorylation of ATP, ADP, and AMP by extracellular enzymes such as CD39 and CD73. Adenosine signaling promotes metastasis and suppress antitumor immune responses. CD73 expression is associated with poor survival and chemotherapy resistance in triple-negative breast tumors. Adenosine deaminase 2 is a serum protein that catalyzes the deamination of adenosine to inosine. Expression of Adenosine deaminase 2 increases in pathologic conditions such as inflammation and cancer. Here we show that expression of the gene coding for ADA2 (CECR1) in lung and breast tumors is associated with increased expression of gene signatures associated with immune checkpoint blockade responsiveness. Our analyses have also indicated that increased ADA2 expression is associated with favorable outcomes among Her2+ and triple-negative breast cancer patients. Further stratification based on the expression of adenosine-generating enzymes, CD39/CD73, revealed that increased ADA2 expression is particularly associated with increased survival among patients with elevated CD39 and CD73 expression. ADA2 expression is found to be higher in stroma areas of the tumor as compared with tumor cells. Stromal expression but not tumor expression of ADA2 is associated with increased T-cell costimulation and infiltration scores. To support clinical evidence in preclinical models and to show the potential of PEGylated Adenosine Deaminase 2 (PEGADA2) as a novel therapy, we have shown that an engineered high-catalytic activity PEGADA2 variant (PEGADA2HCA) can slow growth of EMT6 syngeneic breast tumors. PEGADA2HCA also completely reversed adenosine inhibition of human T-cell activation. PEGADA2HCA treatment in humanized mice caused a linear dose-exposure relationship after repeat dosing. These results provide a strong rationale for testing PEGylated Adenosine Deaminase 2 alone or in combination in a clinical setting. Citation Format: Ozge Saatci, Luz Marina Londoño, Renee Clift, Curt Thompson, Mike LaBarre, Ozgur Sahin, Caglar Cekic. Clinical correlates and rationale for PEGylated adenosine deaminase 2 as a novel cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A84.