174MO - The A2AR antagonist inupadenant promotes humoral responses in patients

Background

A₂A receptor (A_2AR) plays a crucial role in mediating the immunosuppressive effects of extracellular adenosine, which is highly abundant in tumors. Inupadenant is a highly potent and selective A_2AR antagonist active in high levels of adenosine, for which we previously reported a novel B cell-centric mechanism of action (Martinoli et al., AACR 2023). Here, we investigated how inupadenant modulates humoral responses in patient blood and tumor tissue.

Methods

Tumor biopsies and whole blood were collected from end-stage, all-comer patients treated with inupadenant monotherapy (NCT03873883, NCT02740985) at baseline and during treatment (On-Tx: day 21-27 for biopsies; day 28 for whole blood). FFPE blocks were analyzed by IHC and 10x Visium spatial transcriptomics. Gene expression from macrodissected tumor tissue or fixed blood was analyzed using a customized Nanostring IO360 panel. CXCL13 was quantified using Simoa in serum samples collected weekly through baseline up to 21 days on-tx.

Results

Post-hoc exploratory spatial transcriptomic analysis revealed that ASC signatures specifically increased in tertiary lymphoid structures on-Tx, and ASCs tended to localize in closer proximity to different immune players in on-Tx as opposed to pre-Tx biopsies. Serum CXCL13, a marker for germinal center reactions, increased on-Tx. A similar increase in CXCL13 gene expression, as well as an increase in B cell signatures specifically in non-progressors, was observed on-Tx in blood samples by Nanostring.

Conclusions

Altogether, these data confirm that inupadenant plays a key role in restoration of B cell maturation toward ASCs locally in the tumor microenvironment, and at least partially through a B cell-intrinsic mechanism. These effects may play a substantial role in delaying progression in end-stage patients. Additional work is ongoing to demonstrate this new mechanism of action across clinical settings and patient populations.

Clinical trial identification

NCT03873883, NCT05117177.

Legal entity responsible for the study

iTeos Therapeutics.

Funding

iTeos Therapeutics.

Disclosure

H. Shehade, P. Tieppo, N. Rosewick, F. Strozzi, M. Rossetti: Financial Interests, Personal, Full or part-time Employment: iTeos Therapeutics; Financial Interests, Personal, Stocks/Shares: iTeos Therapeutics. C. Martinoli: Financial Interests, Personal, Advisory Role: iTeos Therapeutics. S. Ma: Financial Interests, Personal, Speaker, Consultant, Advisor: iTeos Therapeutics; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: A4P Consulting Ltd. Y. McGrath: Financial Interests, Personal, Full or part-time Employment: iTeos Therapeutics, iTeos Therapeutics.