Background: Live-attenuated Listeria monocytogenes (Lm) vectors are a clinically validated cancer immunotherapy platform, but translation requires reproducible, clinically realistic workflows for dose preparation and infusion. For live bacterial products, in-use stability and device compatibility can drive dose variability through adsorption, settling, and device losses. Methods: We developed and GMP-manufactured an attenuated Lm vaccine expressing human GUCY2C (Lm-GUCY2C) and performed translational characterization, including construct verification and immunogenicity readouts, and defined the administration-focused in-use stability and device compatibility. Post-thaw stability was assessed in primary cryovials and during preparation and delivery from 250 mL saline infusion bags using standard clinical devices (syringes/needles, filter-free IV tubing) and OnGuard2 closed-system components. Samples were collected over 24 h at room temperature, and viable Lm-GUCY2C were quantified by CFU recovery. Results: Lm-GUCY2C remained stable in thawed cryovials for 24 h with no significant CFU loss. High-dose infusion bags (3 × 109 CFU/bag) maintained CFU recovery through 6 h, whereas low-dose bags (3 × 108 CFU/bag) exhibited significant losses beginning at 3 h, supporting a practical in-use window of up to 2 h for low-dose preparations. OnGuard2 intravenous (i.v.) connectors did not measurably affect CFU recovery, while OnGuard2 vial adapters reduced recovery. Conclusions: This work provides an end-to-end, translationally focused characterization of a GMP-manufactured Lm cancer vaccine, including clinically actionable in-use handling constraints and device compatibility. These data define preparation and administration guardrails (notably, time-to-infusion limits for low-dose bag preparations) that can improve dose accuracy and reproducibility in clinical testing.

Abstract Introduction: ART6043 is a first in class, potent and selective polymerase domain inhibitor of DNA Polθ, a central mediator of the microhomology-mediated end joining (MMEJ) DNA double strand break (DSB) repair pathway. Novel biomarkers are important to demonstrate target engagement of ART6043. Polθ knock out mouse studies highlighted increased levels of MN in mouse reticulocytes (RETs) and normochromatic erythrocytes since MN are a common hallmark of genome instability. Here we describe the utility of an assay designed to monitor MN induction in reticulocytes from both preclinical models and patient samples to evaluate Polθ inhibition. Methods: This analysis builds on the MN-RETs assay, which is traditionally used as a preclinical toxicology assessment (Tometsko et al., 1995). This assay involves fixing whole blood, isolating reticulocytes (specifically in the human assay), and labelling them for nucleic acids to stain any MN. High throughput flow cytometry is then used to quantify the number of reticulocytes with MN. Results: These data demonstrated the utility of MN-RET as a target engagement biomarker for ART6043 in preclinical studies and in the subsequent clinical study (NCT05898399). In preclinical xenograft models ART6043 monotherapy and ART6043 in combination with olaparib induces MN-RET at doses where tumor regressions occurred. The MN-RET data evaluated in the phase 1 trial of ART6043 mirrored the preclinical data. Patients treated with the highest dose of ART6043 evaluated as monotherapy had elevated MN-RETs, while patients treated with ART6043 in combination with olaparib had statistically higher MN-RET levels. This suggests that the combination of two DNA repair pathway inhibitors, targeting separate mechanisms, leads to a synergistic increase in DNA damage. Summary: The increase in MN-RETs observed in patients dosed with ART6043 has demonstrated target engagement of a Polθ inhibitor for the first time in humans. MN-RETs has demonstrated potential utility as a mechanism of action target engagement biomarker for a range of therapeutics targeting different DNA damage repair pathways. References: Tometsko, A. M., Dertinger, S. D., & Torous, D. K. (1995). Analysis of micronucleated cells by flow cytometry. 4. Kinetic analysis of cytogenetic damage in blood. Mutation Research/Environmental Mutagenesis and Related Subjects, 334(1). https://doi.org/10.1016/0165-1161(95)90025-X Citation Format: Colette L. Baxter, Timothy A. Yap, Susanna V. Ulahannan, Nehal Lakhani, Minal Barve, Erika P. Hamilton, Babar Bashir, Helen M. Robinson, Jayesh B. Majithiya, Paula Costales, Sarah V. Holt, Samantha C. Skelton, Marina Roy-Luzarraga, Jeff C. Bemis, Dorothea Torous, Svetlana Avlasevich, Susana Barriga, Bryony Harrop, Gillian A. Langford, Ian Smith, Graeme C. Smith. Micronuclei (MN) dynamics in preclinical models and in patient reticulocytes as a pharmacodynamic biomarker for the first in class DNA polymerase theta (PolΘ) inhibitor ART6043 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3149.

Abstract Introduction: Micronucleated reticulocytes (MN-RET) are a well-established biomarker of chromosomal damage, and their assessment is traditionally included as part of regulatory-based, product safety testing during preclinical development. Adaptation of the methodology to high-throughput flow cytometric analysis broadened the utility of the assay and enabled practical translation to human subjects. Most recently, this methodology has been used to demonstrate target engagement via the induction of MN-RET as a biomarker of efficacy during the development of therapies targeting DNA double strand break-repair pathways. Methods: To support this application, we have conducted studies in clinical models to define basic methodological parameters. In an effort to better understand baseline values over time/between subjects and reproducibility, we evaluated technical replicate variability in MN-RET frequencies based on blood specimens from 14 subjects. Intra-subject variability was based on serial blood draws from 6 subjects, and inter-subject variation was based on up to 344 subjects age 0 to 73 years. Results Human models demonstrate increased MN-RET frequencies following exposure to known DNA damaging agents. Inter-subject variation (≥77%) was much greater than intra-subject and technical replicate variability. The relatively large inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%). Neither age nor sex affected inter-subject variation of the MN-RET frequency. In a clinical setting, patients treated with PARP inhibitors at a labelled dose showed elevated MN-RETs, demonstrating the increased unrepaired DNA damage as an indicator of target engagement induced by treatment. Summary: This translational biomarker of chromosomal damage represents a unique and powerful tool for use in the development of cancer therapies that elicit DNA double strand breaks. Citation Format: Jeffrey C. Bemis, Colette Baxter, Gillian Langford, Timothy A. Yap, Susanna Varkey Ulahannan, Nehal Lakhani, Babar Bashir, Kathleen N. Moore, Payal Shah, Svetlana Avlasevich, Dorothea Torous, Stephen Dertinger. Human blood micronucleated reticulocytes: Application as a pharmacodynamic biomarker for DNA double strand breaks in oncology drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3148.

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .

3617 Background: Guanylyl cyclase C (GUCY2C) is an intestinal tumor antigen ectopically expressed in some gastroesophageal and pancreatic cancers, highly expressed in nearly all colorectal cancers (CRC), and retained in metastases. Adenovirus serotype 5 (Ad5)-based cancer vaccines, including those targeting GUCY2C, are limited by pre-existing neutralizing antibodies (NAbs) targeting Ad5. Ad5.F35-GUCY2C-PADRE is a chimeric Ad5 vector (fiber of serotype 35) developed to overcome anti-Ad5 immunity and induce durable antitumor T-cell responses. We report initial immunogenicity, safety, and recurrence outcomes from a phase 2A dose-finding study in patients with resected GI malignancies. Methods: This open-label phase 2A study enrolled patients with resected, high-risk GI adenocarcinomas (CRC, pancreatic, gastric, and small bowel) with no evidence of disease 4-24 wks after standard adjuvant therapies. Oligometastatic stage IV CRC patients were also allowed (n=8). Patients were randomized to receive three i.m. administrations of Ad5.F35-GUCY2C-PADRE at 1×10 11 , 1×10 12 , or 5×10 12 viral particles (vp) at 4-wk intervals. Primary endpoints were safety and GUCY2C-specific T-cell responses (IFNγ ELISpot). Exploratory endpoints included the impact of NAbs on T-cell responses and RFS, and the impact of dose on immunological and clinical outcomes. Results: Forty-six patients (29 CRC) completed treatment and were evaluable. Vaccination was well tolerated with no DLTs or TRSAEs; AEs were predominantly grade 1-2 flu-like symptoms. GUCY2C-specific T-cell responses increased in frequency and magnitude in a dose-dependent manner. Nearly all patients receiving higher doses produced T-cell responses regardless of NAb status (Table), supporting Ad5.F35 overcoming pre-existing NAbs. At the 2-year follow-up, there was a dose-dependent improvement in RFS among stage II-III CRC patients (Table), and RFS was significantly improved among immune responders vs non-responders ( P < 0.05). Conclusions: Ad5.F35-GUCY2C-PADRE is safe, overcomes pre-existing Ad5 immunity, and induces robust, dose-dependent GUCY2C-specific T-cell responses. Vaccine-induced immunity is associated with improved RFS in CRC, supporting further development of the off-the-shelf Ad5.F35 platform for cancer vaccines and Ad5.F35-GUCY2C-PADRE for CRC recurrence prevention. Clinical trial information: NCT04111172 . Dose (vp) Magnitude of GUCY2C-Specific T-cell Response 1 % of Patients with a GUCY2C-Specific T-cell Response (N/N) 2 CRC 3 Recurrences (%; N/N);Median RFS 1x10 11 9 33% (5/15) 50% (4/8); 512 days 1x10 12 92 94% (15/16) 17% (1/6); not reached 5x10 12 218 100% (15/15) 0% (0/7); not reached P < 0.0001 P < 0.0001 P = 0.051 1 Median SFCs/5×10 5 PBMCs ; 2 at 4 weeks after 1 st vaccination ; 3 excluding stage IV patients .

1094 Background: AVZO-021 is a potent, once-daily, oral CDK2i with high selectivity against CDK1, thus minimizing off-target toxicity. Initial Phase 1 data from the ongoing first-in-human Phase 1/2 study of AVZO-021 (NCT05867251) showed clinical responses and a favorable tolerability profile. Methods: The ongoing Phase 1 portion of the study is evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of AVZO-021 alone and in combination with fulvestrant. As of January 20, 2026, the safety population included all patients treated with AVZO-021 monotherapy (n=50) or in combination with fulvestrant (n=13). Efficacy evaluable population included patients treated at ≥150 mg once daily (QD) with HR+/HER2- breast cancer or CCNE1-amplified solid tumors with at least 1 post-baseline scan (n=23 in monotherapy and n=12 in combination with fulvestrant). Results: The median age was 63 years for monotherapy patients and 60 years for combination with fulvestrant. Overall, 95% of patients were female, 78% had BC, 10% had ovarian/fallopian tube cancer, and 5% had endometrial/uterine cancer. AVZO-021 monotherapy patients had a median of 3 prior lines of systemic therapy and those in combination therapy had a median of 4 prior lines, in the metastatic setting. All patients with HR+/HER2- BC received prior CDK4/6i and hormonal therapy. Most common (>25%) all-grade treatment-emergent adverse events (TEAEs) were nausea (51%), fatigue (43%), anemia (33%), and vomiting (32%); 13 patients required dose reductions due to TEAEs and 2 patients discontinued due to TEAEs (1 unrelated Grade 3 intestinal obstruction, 1 related Grade 4 neutropenia). Four patients with HR+/HER2- BC and CCNE1-amplified solid tumors had confirmed partial responses and remain ongoing, demonstrating prolonged clinical benefit. Additionally, 23 patients had stable disease for a disease control rate of 77%. Continuous CDK2 target coverage and significant decreases in ctDNA were observed at ≥90 mg QD monotherapy and in combination with fulvestrant. Conclusions: With longer follow-up, AVZO-021 as monotherapy and in combination with fulvestrant continues to show an encouraging tolerability profile and clinically meaningful efficacy. Gastrointestinal and hematologic adverse events continue to be of low incidence and severity allowing for prolonged treatment and potential safe combination with AVZO-023, a highly potent and selective CDK4i currently enrolling patients with HR+/HER2- BC in combination with fulvestrant. Clinical trial information: NCT05867251 .

Purpose: Acquired resistance to anti-PD-1 therapy remains a major barrier to achieving durable responses in patients with solid tumors. The aryl hydrocarbon receptor (AHR) is a downstream mediator of intratumoral immunosuppression. We evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with advanced solid tumors and urothelial carcinoma.Patients and Methods: This was a first-in-human, open-label phase 1/1b study. Patients with advanced solid tumors refractory to standard therapies were enrolled in a dose-escalation study of IK-175 monotherapy or IK-175 plus nivolumab. An expansion cohort enrolled patients with advanced urothelial carcinoma previously treated with anti-PD-1 therapies. Primary objectives were safety, tolerability, and determination of recommended phase 2 doses. Secondary objectives included pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.Results: IK-175 was well tolerated, and the recommended phase 2 dose was established. Target engagement was confirmed by ex vivo AHR activation assays and dose-dependent modulation of AHR-regulated genes in tumor biopsies. Clinical responses, including one complete response and durable stable disease, were observed in patients with urothelial carcinoma refractory to prior checkpoint blockade. No new safety signals were identified in combination with nivolumab.Conclusions: IK-175, alone and with nivolumab, demonstrated a favorable safety profile, evidence of target engagement, and preliminary clinical activity in immune-refractory urothelial carcinoma. These data support continued development of AHR inhibitors to overcome adaptive immune resistance in solid tumors.

Abstract Background: BT5528 is a BDC® comprising a bicyclic peptide targeting EphA2 linked to MMAE via a cleavable linker. EphA2 is overexpressed in various solid tumors and is correlated with poor clinical outcomes. Earlier EphA2-targeted therapies were associated with significant toxicity which limited efficacy analysis. BDCs have potential to limit toxicity by reducing non-tumor exposure due to low molecular weight and high selectivity. Favorable dose escalation (DE) safety data for BT5528 monotherapy supported initiating the BT5528 + nivolumab (nivo) DE part (A-2) of the safety and efficacy study of BT5528 in pts with advanced solid tumors (NCT04180371). Methods: Eligible adults had recurrent metastatic solid tumors with tissue available for EphA2 expression testing and had exhausted all appropriate treatment options. Pts received BT5528 IV (2.2 or 4.4 mg/m2 once weekly, or 6.5 mg/m2 once every 2 weeks (wks) + nivo IV (480 mg once every 4 wks). Primary objectives: safety/tolerability. Secondary objectives: preliminary anti-tumor activity/pharmacokinetic (PK) parameters. EphA2 immunohistochemistry was retrospective using Tumor Proportion Score >1 to determine positivity. Results: As of November 10, 2025, 21 pts were treated. Median age was 65 years; 57% had ECOG PS 1; median prior lines of therapy was 2 (range 1-7); 11/18 (61%) tumor samples were EphA2+. All 14 pts in the 6.5 mg/m2 cohort had metastatic urothelial carcinoma (mUC) and had previously progressed on a checkpoint inhibitor and 10 while on enfortumab vedotin. Median BT5528 treatment duration was 58.0 days in all pts; 81.5 days in the 6.5 mg/m2 cohort; 5 pts remain on treatment. The most common BT5528-related adverse events (TRAEs) were fatigue (29%), nausea (24%), diarrhea (19%), and vomiting (14%). Grade ≥3 TRAEs were fatigue (10%) and ALT/AST increase (5% each). TRAEs of clinical interest were skin reactions (24%) and peripheral neuropathy (10%), all Grade 1/2. No TRAEs of hemorrhage occurred. There was one dose-limiting toxicity of fatigue in the 6.5 mg/m2 cohort. The objective response rate in all pts was 14%. In the 6.5 mg/m2 cohort, 3/10 pts who had EphA2+ mUC achieved a confirmed partial response (cPR); of 3 pts who were EphA2+ and MMAE-naïve, 2 achieved a cPR. The clinical benefit rate (complete response + PR + stable disease ≥4 months) for all pts was 24% and 100% for the 3 EphA2+ MMAE-naïve pts in the 6.5 mg/m2 cohort. PK of BT5528 and MMAE are similar +/- nivo, indicating no apparent PK interaction. Conclusions: BT5528 + nivo demonstrated a generally well-tolerated safety profile across doses, with no new safety signals, in contrast to prior attempts to target EphA2, with no PK drug-drug interactions. Preliminary anti-tumor activity was demonstrated in pts with mUC at a dose of BT5528 6.5 mg/m2 once every 2 wks + nivo 480 mg once every 4 wks, especially in MMAE-naive pts with EphA2+ tumors. Citation Format: Babar Bashir, Juan Martin-Liberal, Judy S. Wang, Raid Aljumaily, Bernard Doger de Spéville, Elena Garralda, Meredith McKean, Elisa Fontana, Hans Prenen, Daniel A. Peterson, Vienna Reichert, Xuemin Gu, Mengyao Li, Assunta De Rienzo, Alastair Greystoke. An EphA2-targeting Bicycle Drug Conjugate (BDC), BT5528, in combination with nivolumab in patients (pts) with advanced solid tumors: Results from a Phase 1/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT063.

PURPOSE Limited information exists regarding outcome severity among gynecologic cancer patients with SARS-CoV-2 infection. The objective of this study was to describe patient, cancer, and COVID-19 characteristics, and to identify factors associated with COVID-19 severity. METHODS Gynecologic cancer patients with SARS-CoV-2 infection were identified from the international COVID-19 and Cancer Consortium registry. We estimated odds ratios (ORs) for associations with severity of COVID-19 outcomes. Multivariable models included adjustment for age, race, cancer status, and time period of COVID-19 diagnosis. RESULTS Of 920 patients, 438 patients (48%) had endometrial, 249 (27%) had ovarian, 198 (22%) had cervical, and 44 (5%) had vulvar/vaginal cancers. Most were from the United States (86%) and non-Hispanic White (48%). Median age was 62 years (IQR, 52-71). When diagnosed with COVID-19, 457 (49%) patients were in remission and 343 (37%) had active disease. Outcomes included hospitalization in 452 patients (49%), intensive care unit admittance in 107 patients (12%), mechanical ventilation in 70 patients (8%), and death within 30 days of testing positive for SARS-CoV-2 in 91 patients (10%). In multivariable models, increasing age (adjusted OR, 1.35 [95% CI, 1.23 to 1.49]) and non-Hispanic Black race (adjusted OR, 1.75 [95% CI, 1.24 to 2.48]) were associated with increased COVID-19 severity, as were cardiac (adjusted OR, 1.85 [95% CI, 1.36 to 2.52]), pulmonary (adjusted OR, 1.58 [95% CI, 1.12 to 2.22]), and renal (adjusted OR, 2.18 [95% CI, 1.48 to 3.19]) comorbidities. Patients in remission <5 years had decreased COVID-19 severity (adjusted OR, 0.60 [95% CI, 0.42 to 0.87]). Other cancer characteristics associated with increased severity included progression (adjusted OR, 2.91 [95% CI, 1.92 to 4.40]), stage (adjusted OR, 1.57 [95% CI, 1.11 to 2.22]), and metastatic disease (adjusted OR, 1.60 [95% CI, 1.10 to 2.34]). CONCLUSION Patients with gynecologic cancer experience significant morbidity and mortality related to infection with SARS-CoV-2. Age, race, cancer status, comorbidities, and COVID-19 complications were associated with more severe COVID-19 outcomes.

e15509 Background: Large language models (LLMs) are increasingly explored for oncology decision support, yet comparative evidence evaluating medical-specific versus general-purpose LLMs using expert-reviewed clinical cases is limited. We compared a medical-specific LLM (Google MedGemma 27B) with a general-purpose LLM (ChatGPT-5) using gastrointestinal (GI) and genitourinary (GU) oncology vignettes. Methods: This cross-sectional study evaluated 32 de-identified oncology vignettes (26 GI, 6 GU) created by a U.S. board-certified medical oncologist and informed by real-world cases. Vignettes included text-only information on the clinical context, description of pathology, tumor staging, biomarkers, and relevant comorbidities. Both LLMs were prompted to provide National Comprehensive Cancer Network(NCCN) guideline-based treatment recommendations, monitoring strategies, maintenance therapy considerations, and references, along with a self-reported confidence score (0–100). Board-certified U.S. medical oncologists independently reviewed outputs using a structured instrument; two disease specific expert oncologists evaluated each case. Outcomes included correctness and comprehensiveness (1–10 scales), hallucinations (factually fabricated or unsupported statements), NCCN traceability, potential patient harm, and clinician trust. Associations between accuracy and comprehensiveness were assessed using correlation coefficients. Inter-rater reliability was assessed using a two-way random-effects intraclass correlation coefficient (ICC). Results: ChatGPT-5 demonstrated higher mean correctness (8.65 vs 4.68) and comprehensiveness (8.68 vs 5.22) scores compared with MedGemma 27B. Accuracy and comprehensiveness were strongly correlated overall (Pearson r = 0.93, p < 0.001), with significant model-specific correlations (ChatGPT-5 r = 0.86, p < 0.001; MedGemma r = 0.77, p < 0.001). Hallucinations occurred less frequently with ChatGPT-5 (12.3% vs 65%), and NCCN-traceable recommendations were more common (75.4% vs 36.7%). Responses judged as potentially harmful occurred in 18.5% of ChatGPT-5 outputs versus 70% of MedGemma outputs. Clinician trust favored ChatGPT-5 (84.6% vs 15%). Inter-rater reliability improved with rater averaging (ICC(A,k): correctness 0.72; comprehensiveness 0.64). Conclusions: In expert-reviewed GI and GU oncology cases, ChatGPT-5 demonstrated higher clinical accuracy, comprehensiveness, and guideline alignment than a medical-specific LLM; however, a substantial rate of hallucinations and potentially harmful recommendations persisted across models. These findings underscore that, despite performance differences, current LLMs require rigorous clinician oversight and should not be used as standalone decision-support tools in oncology.

Replication stress (RS) is a critical cancer vulnerability. ART0380 is an inhibitor of Ataxia-Telangiectasia and Rad3-related (ATR), the primary orchestrator of the cellular response to RS. This is the first clinical report of a development approach wherein tumor cells experience a triple combination of biological insults: induced RS by irinotecan, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and prevention of rescue from RS by ATR inhibition (NCT04657068). Patients (pts) with advanced cancers who had no satisfactory alternative treatment option received escalating doses of ART0380 (25mg to 400mg) on days 1-3 and 8-10 in combination with low dose irinotecan (60mg/m2 or 85mg/m2) on days 1 and 8 of a 21-day cycle. Pts in dose expansion were selected based on ATM protein expression. Key objectives included safety, tolerability, and preliminary efficacy. At the data cut-off (01Nov24), 87 patients were dosed with ART0380 + irinotecan. The recommended phase 2 dose (RP2D) was established as 200mg ART0380 on days 1-3 and 8-10 and 60mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. At the RP2D (N=58), the median prior lines of therapy was 3 (range 1-7) with 59% of pts receiving prior irinotecan. The most common treatment related adverse events were neutropenia (53%), anemia (41%), fatigue (33%) and diarrhea (31%). Grade≥3 related diarrhea, nausea and vomiting each occurred in 1 pt. By intent-to-treat (ITT) analysis, the confirmed objective response rate (ORR) was higher in pts with ATM protein loss by immunohistochemistry compared to those with tumors that expressed ATM protein (see Table 1). Further analyses with longer follow-up will be available for conference presentation. ART0380 and low dose irinotecan is well tolerated and suitable for long-term dosing. Clinically meaningful activity has been demonstrated and further refined via biomarker selection (45% confirmed RECIST response rate in patients with ATM negative cancers). Susanna Ulahannan, Jason T. Henry, Kathleen N. Moore, Gerald S. Falchook, Meredith S. Pelster, Elisa Fontana, Bryony Harrop, Nicola Little, Helen Millward, Amelia Fielding, Sara Busacca, Emre Karakoc, Suraj Menon, Sarah V. Holt, Niall Martin, Graeme C. Smith, Desiree Headley, Ian C. Smith, Bert H. O'Neil, Babar Bashir. First results of ART0380 (an ATR kinase inhibitor) with low dose irinotecan in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT267.

Data on COVID-19 outcomes in Asian Americans and Pacific Islanders (AAPI) are lacking. We analyzed data from 6,244 patients from the COVID-19 and Cancer Consortium, including 6.0% AAPI patients, to examine disparities in outcomes following acute COVID-19. Despite AAPI patients having lower median BMI than non-Hispanic White (NHW) patients and higher diabetes rates, both groups showed similar 30-day mortality and COVID-19 outcomes. In multivariable analyses, morbid obesity (BMI >35 kg/m2) in AAPI patients was associated with significantly higher 30-day mortality (OR 4.96; 95% CI 1.78 - 13.88) and COVID-19 severity (OR 2.6; 95% CI 1.26 - 5.35); underscoring the differential impact of obesity in AAPI patients.

Abstract Background: Collectively, cancers of the esophagus, stomach, pancreas, and colorectum (“GI cancers”) are the leading cause of cancer-related death. Despite standard of care, 30-90% of GI cancer patients experience tumor recurrence. In colorectal cancer (CRC), guanylyl cyclase C (GUCY2C), a transmembrane heat-stable enterotoxin receptor, is overexpressed in more than 95% of colorectal tumors and in subsets of gastroesophageal and pancreatic tumors. We are conducting a Phase 2A, dose-finding, single-center, open-label, randomized trial (NCT04111172) to evaluate the safety and immunogenic activity of three dose levels of the Ad5.F35-GUCY2C-PADRE vaccine in adult patients with select solid tumors (colorectal, pancreatic, or gastroesophageal) who are at high risk of relapse following definitive surgery and adjuvant therapy. To further investigate the immunogenicity of the GUCY2C-targeting vaccine across diverse patient populations and facilitate downstream laboratory-based studies—such as autologous T cell expansion, TCR sequencing and cloning, and in vivo patient-derived xenograft (PDX) models—we explored the feasibility of a protocol for the stimulation and expansion of antigen-specific T cells derived from peripheral blood mononuclear cells (PBMCs). Methods: PBMCs from healthy donors were used as a pilot to optimize this protocol and assess its efficacy. PBMCs were cultured in vitro for approximately 10 days with adjuvants, cytokine cocktails, and antigen-specific peptides. The enriched T-cell populations were then evaluated for antigen-specific targeting using flow cytometry and ELISPOT analysis. Results and Conclusion: The stimulation protocol successfully expanded both CD4+ and CD8+ effector T cells. The final T cell population was predominantly CD8+ T cells, which secreted IFNγ following CEF (CMV, EBV, Influenza), but not MOG (self-antigen myelin oligodendrocyte glycoprotein) peptide stimulation, indicating antigen-specific reactivity of the expanded T cells. Further studies, including cytotoxicity assays and antigen-presenting cell (APC)-based longitudinal expansion, are necessary to support the high-throughput application of this protocol for future preclinical and clinical investigations. Citation Format: Zhengyang Sun, Jagmohan Singh, Miao Cao, Anne Glowacki, Tingting Zhan, Babar Bashir, Scott A Waldman, Adam E Snook. An antigen-specific t cell stimulation and expansion platform for immunological investigation of the Ad5.F35-GUCY2C-PADRE vaccine in gastrointestinal cancers [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B067.