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Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). α4β7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n=15), skin GVHD (n=20) and no GVHD (n=10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of α4β7 integrin-expressing memory CD8+ T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P=0.03. No differences were found in α4β7 expression in any CD4+ T-cell subsets or naive CD8+ T cells. This study adds to the evidence that α4β7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD. [ABSTRACT FROM AUTHOR]

Background: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938)., Patients and Methods: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt., Results: Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease., Conclusions: The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors., Competing Interests: Disclosure HP reports research funding from Ambrx, Aprea Therapeutics, Array BioPharma, BJ Bioscience, Bristol Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD-Serono, Genentech, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Merck, Mirati, Novartis, Oncologie, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, and Xencor Inc. GIS reports research funding from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology, and has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen and Xinthera, and holds a patent entitled, ‘Dosage regimen for sapacitabine and seliciclib’, also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, ‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition’, together with Liam Cornell. XG reports consulting or advisory roles for Exelix, Bayer, Guardant Health, and Flare Therapeutics, and research funding (to institution) from Arvinas, Exelixis, Pfizer, Harpoon therapeutics, Aprea Therapeutics, Takeda, Aravive, Merck, Poseida therapeutics, TopAlliance BioSciences Inc., Janssen, Novartis, and Silverback Therapeutics. AM reports participation on an advisory board for QED Therapeutics and Taiho Oncology. JS reports research funding from Aprea Therapeutics, Macrogenics, Rafael Therapeutics, Xencor, Cardiff Oncology, Merus Therapeutics, Daiichi-Sanyko, and Amgen, and consulting for Advanced Accelerated Applications, Ipsen, Pfizer, Taiho, Tersera, Natera, and Cancer Expert Now. MF reports participation on an advisory board for Mirati, AstraZeneca, Pfizer, and Beigene. PS reports participation on an advisory board for Janssen, EMD Soreno, Aveo, and Seattle Genetics. LG reports participation in scientific advisory boards for Xilio, Surface Oncology, Mersana, Beigene, Bristol Myers Squibb, Eisai, and Tentarix; consultancy for Tempus, TwentyEight-Seven Therapeutics, and Pliant Therapeutics; and is a member of the Board of Directors for Bright Peak Therapeutics. AG reports research support (drugs) from Aprea Therapeutics and consultancy for Adivo Associates. DH, PDG, AW, ECA, and MMA report current employment and equity holder (publicly traded company) with Aprea Therapeutics. SD reports receiving honoraria for consultancy for AAA/Novartis, Ipsen, and TerSera Therapeutics. EED reports grants from Bayer Pharmaceuticals, Immunocore, Amgen, NCI, Aileron Therapeutics, Compugen, TRACON Pharmaceuticals, Unum Therapeutics, Immunomedics, Bolt Biotherapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen, Mereo BioPharma, and Sanofi, Astex Therapeutics during the conduct of the study, and personal fees and other from Bolt Biotherapeutics and Catamaran Bio outside the submitted work. AA has declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Isocitrate dehydrogenase 1 ( IDH1 ) and 2 ( IDH2 ) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2 -mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1 / 2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.

The Axl receptor tyrosine kinase is a transforming oncogene in NIH3T3 cells. In order to define structural requirements of the Axl receptor necessary for transformation we passaged recombinant retroviruses carrying the axl cDNA in NIH3T3 cells, generating randomly mutated axl variants. Using this strategy, we have isolated three axl viral strains (1B1, SV8, and FFa4) that show augmented 3T3 cell transforming capacity associated with elevated p140Axl. Upon sequencing, the 1B1 and SV8 proviruses possessed only silent mutations, making p140Axl overexpression the most likely explanation for their increased transformation activity. However, the characterization of FFa4 revealed a deletion of sequences encoding the carboxy-terminal 45 amino acids leading to the generation of a chimeric transcript comprised of a truncated Axl receptor with a segment of the 3' UTR region. Mutational analysis revealed that the transforming activity of FFa4 was specific to the formation of the chimeric receptor rather than to the carboxyl-terminal truncation. Intriguingly, none of the viral strains were able to transform the murine cell lines NR-6 and 32D despite equivalent expression of surface p140Axl protein. Further analysis showed that Axl's transforming potential is dependent on the host cell type, the presence of a putative pp190 as a facilitator for transformation, and the level of p140Axl expression. Taken together, these results underscore the complexity of Axl biology which is dependent on receptor stoichiometry and the cellular background.