The Needle. Issue #6
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Welcome to the latest issue of the Needle, a newsletter from Haystack Science on preclinical biotech. This week, we look forward to the American Society for Clinical Oncology (ASCO) Annual Meeting in Chicago and describe a new mechanism to improve on the efficacy of cancer immunotherapy by inhibiting adenosine transport in lymphocytes. We also highlight new substantial risk investment funding designated to early-stage dementia therapies, as well as state-led funding efforts in cancer and regenerative medicine.
Haystack chat Unlike previous years, ASCO’s annual shindig later this week is notable for the paucity of companies presenting adenosine blockade as an anticancer strategy. Like many other second-generation checkpoint inhibitor targets, potent preclinical activity for adenosine-targeting drugs has so far failed to translate into compelling clinical outcomes. Last year, iTeos Therapeutics discontinued its small-molecule adenosine 2 alpha receptor (A2aR) antagonist, following low efficacy in a phase 2 trial in metastatic non-small cell lung cancer; several months earlier, Novartis also quietly shelved a mAb targeting CD73—the ecto-5ꞌ nucleotidase that generates adenosine from extracellular AMP—after a combination trial with an anti-PD1 mAb yielded zero responses among 104 patients. These setbacks notwithstanding, there has been intense investment in IO drugs targeting extracellular adenosine. Apart from CD73, companies are going after other targets trying to restore cytotoxic T cell/NK cell activity and reverse the immunosuppressive effects of regulatory T cells/myeloid-derived suppressor cells in the tumor microenvironment. These targets include ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and NAD+ nucleosidase (CD38) on tumor cells. Now a group from iTeos Therapeutics, led by Erica Houthuys, has gone after another component of the adenosine axis: the equilibrative nucleoside transporter 1 (ENT1; SLC29A1). In a paper in Nature Immunology, the authors show that intracellular uptake of adenosine by ENT1 on T cells is an important mechanism that suppresses anti-cancer responses in a humanized mouse model of breast cancer. By transporting the nucleotide into the cytosol of activated T cells, ENT1 raises intracellular adenosine levels and reprograms metabolism by inhibiting uridine monophosphate synthase and suppressing pyrimidine nucleotide synthesis. This hampers T cell proliferation and function, thereby weakening the immune response against tumors. By blocking human ENT1 with the selective small-molecule antagonist EOS301984, Houthuys and her colleagues show the drug prevents intracellular accumulation of adenosine. This enhanced both the cytotoxic activity of memory T cells and the expansion of tumor-infiltrating lymphocytes expressing the markers Ki-67, PD-1 and TIM-3. Furthermore, combining EOS301984 with an anti-PD-1 therapy in a humanized mouse model of triple-negative breast cancer resulted in synergistic anti-tumor activity. Although ENT1 inhibition provides a new ‘intracellular’ mechanism to dampen adenosine’s dampening effects on CD8+ T cells, considerable work lies ahead. It will be important to assess how redundancy in adenosine transport pathways affects this approach and to define the therapeutic window of EOS301984, given its ubiquitous expression (see Figure). According to Human Protein Atlas data, patients with melanoma or thyroid, colorectal, stomach, or renal cancers appear to express more ENT1 than those with other malignancies. Lung cancer does not look like a great target for ENT1 modulation, but this is the malignancy where definitive clinical data is closest for the first generation of adenosine modulators. In 2026, AstraZeneca is expecting to read out its phase 3 trial of oleclumab, an anti-CD73 IgG1 lambda with reduced Fc effector function, in combination with a PD1 inhibitor. Similarly, I-Mab’s uliledlimab, a IgG1 kappa mAb with an aglycosylated Fc (targeting a C-terminal CD73 epitope to avoid the ‘Hook effect’ seen with oleclumab) is now in phase 2. Other mAb programs in safety testing include Jacbio Pharmaceuticals, Innate Pharma, Corvus Pharmaceuticals and Innovent Biologics. Small molecule programs lie someway behind. By the end of the year, Arcus Biosciences (together with Tahio)—which is developing a small-molecule, selective dual antagonist of A2aR and A2bR—aims to finish recruiting patients for a phase 3 trial in pancreatic cancer based on a post-hoc analysis of phase 1 data showing a 37% reduction in risk of death and a 5.9 month improvement in overall survival. Oric Pharmaceutcials and Abbisko Therapeutics also have small-molecule programs in early-stage testing. Given that patients available for trials of these investigational agents are already receiving multiple lines of chemo, multiple targeted therapies, and first-generation checkpoint inhibitors, the use of biomarkers and signatures to stratify patients into those more likely to respond to adenosine suppressants will be increasingly important to increase the chances of success. Papers: Best of the rest Target biology Acyl-CoA–binding protein as a driver of bone metastasis | Science Translational Medicine Therapeutics An engineered viral protein activates STAT5 to prevent T cell suppression | Science Immunology Platforms and new modalities Framework to identify innovative sources of value creation from platform technologies | PNAS Startup news One of the most successful investors for early-stage therapeutics in neurodegenerative disease raises second venture fund: Several ventures received accolades last week: Texas and Maryland announced funding pushes: CPRIT award $93 million in grants for cancer research and prevention Maryland Stem Cell Research Fund awards over $18 million to regenerative medicine Meanwhile MassBIo gets on the tech bio bandwagon: Preclinical funding Preclinical deals
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