tbuckley/cabot-search huggingface dataset:
Abstract LB001: Discovery of a monoclonal antibody that binds CD16a to inhibit the shedding and promote anti-tumor immunity
Authors: Bruna Taciane da Silva Bortoleti, Sophia Quasem, Stefanie Maurer, Xiaoxuan Zhong, Ruan Pimenta, Luiza Ribeiro de Lima Brandão, Matthew Hernandez, Melanie Fraidenburg, Pedro Henrique Alves da Silva, Raymond Alvarez, Benjamin K. Chen, Thomas Marron, Lucas Ferrari de Andrade
Journal: Cancer Research (2025)

Abstract CD16a is the Fc receptor that triggers antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells. Several antibody therapies bind CD16a to induce anti-tumor immune responses. However, CD16a undergoes cleavage-mediated downregulation by ADAM17, a protease with broad specificity to over one-hundred different types of proteins. “CD16a shedding” is a therapeutic target because it decreases the number of CD16a molecules available for antibody engagement. To overcome the ADAM17’s broad specificity, we developed a monoclonal antibody (F9H4) that binds CD16a to inhibit the cleavage. F9H4 is extremely effective in inhibiting the shedding and retaining CD16a on the NK cell surface. When combined with cetuximab for CD16a engagement, F9H4 increased ADCC against human lung cancer cell lines. F9H4+cetuximab inhibited the development of tumors in the lungs of immunodeficient mice that were inoculated with human lung cancer cell line and NK cells. Notably, a major advantage of F9H4 is that it inhibits the shedding in a CD16a specific manner and thereby it enabled physiologically relevant studies in immunocompetent hosts. Consistent with that notion, we applied F9H4 to Fc gamma receptor-humanized (hFcR) mice, which are immunocompetent. F9H4+cetuximab inhibited tumor growth in hFcR mice, and such effect was NK cell mediated. Cetuximab induced the CD16a shedding by blood NK cells in vivo, but F9H4 inhibited it. To generate insights about the clinical significance of CD16a shedding, we applied the tissue explant technology to tumor samples from patients. Through that, we discovered that cetuximab induced whereas F9H4 inhibited the CD16a shedding by primary tumor-infiltrating leukocytes from untreated patients with early-stage non-small cell lung cancer. Finally, we developed an Fc-enhanced version of cetuximab, by point mutations in the Fc region, and discovered that it synergized with F9H4 to promote ADCC. Therefore, F9H4 represents a new means to promote NK cell-driven immunity and applicable to cancer immunotherapy pre-clinical research. Citation Format: Bruna Taciane da Silva Bortoleti, Sophia Quasem, Stefanie Maurer, Xiaoxuan Zhong, Ruan Pimenta, Luiza Ribeiro de Lima Brandão, Matthew Hernandez, Melanie Fraidenburg, Pedro Henrique Alves da Silva, Raymond Alvarez, Benjamin K. Chen, Thomas Marron, Lucas Ferrari de Andrade. Discovery of a monoclonal antibody that binds CD16a to inhibit the shedding and promote anti-tumor immunity [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 LB001.
Abstract CT169: Phase Ib/II open-label, randomized study of atezolizumab + regorafenib + AB928 or atezolizumab + regorafenib vs regorafenib for patients with microsatellite-stable, refractory metastatic colorectal cancer in MORPHEUS-CRC
Authors: James M. Cleary, Carlos Gomez-Roca, Francois Ghiringhelli, Joon Oh Park, Tae-You Kim, Brandon Beagle, Janelle Soong, Yibing Yan, Hans-Joachim Helms, Janet Lau, Edward Cha, Michel Ducreux
Journal: Cancer Research (2025)

Abstract Background: A major challenge in metastatic colorectal cancer (mCRC) is the development of immunotherapeutic strategies for patients (pts) with microsatellite-stable (MSS) tumors. High levels of adenosine contribute to the immunosuppressive tumor microenvironment of mCRC. Here, atezolizumab (atezo) was combined with regorafenib (rego; a multi-kinase inhibitor) ± AB928 (an inhibitor of the adenosine pathway) to see if these combinations could improve upon rego alone in mCRC. Methods: Pts with MSS mCRC who had disease progression following ≤2 separate lines of treatment (tx) were enrolled into MORPHEUS-CRC (NCT03555149). Pts received atezo (840 mg IV days [D]1, 15) + rego (120 mg PO D1-21) + AB928 (150 mg PO D1-28) (triplet) or atezo + rego (doublet) or control tx with rego (160 mg PO D1-21; comparator). The primary endpoints were ORR and safety. Secondary endpoints included PFS, OS, DOR, and DCR. Biomarker analyses were exploratory. Results: As of March 1, 2023, 15 pts were randomized into both the triplet and doublet arms and 24 pts into the comparator arm. One response was seen with the triplet and 1 with the doublet (see table for efficacy data). Both responders lacked liver metastases. Tx-related adverse events occurred in 100% (n=15), 93% (n=14) and 95% (n=18) of pts receiving triplet, doublet and comparator tx, respectively. Grade 5 AEs (unrelated to study tx) were seen in 1 doublet pt (tumor hemorrhage) and 2 comparator pts (sepsis). Correlations between PD-L1 levels, immune phenotype, KRAS status and efficacy were examined with no clear associations. Conclusion: Atezo + rego ± AB928 did not have sufficient clinical activity to merit further evaluation in an unselected mCRC population. Consistent with other reports of PD-(L)1-directed immunotherapy in mCRC, durable responses were observed in pts without liver metastases. Citation Format: James M. Cleary, Carlos Gomez-Roca, Francois Ghiringhelli, Joon Oh Park, Tae-You Kim, Brandon Beagle, Janelle Soong, Yibing Yan, Hans-Joachim Helms, Janet Lau, Edward Cha, Michel Ducreux. Phase Ib/II open-label, randomized study of atezolizumab + regorafenib + AB928 or atezolizumab + regorafenib vs regorafenib for patients with microsatellite-stable, refractory metastatic colorectal cancer in MORPHEUS-CRC [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 CT169.
Abstract CT167: Phase II study of Nimotuzumab combined with AG regimen in pancreatic cancer with liver metastases (PCLM): A prospective, single-arm trial
Authors: Dandan Wu, Yang Liu, Linlin Fu, Yinchao Zhang, Linze Xu, Jin Zhang, Huikai Li, Jihui Hao
Journal: Cancer Research (2025)

Abstract Background: Patients with PCLM represent approximately 70% of advanced pancreatic cancer cases in our department and often have limited surgical options due to the aggressive nature of their tumors. For patients with good performance status (ECOG PS 0-1), the NCCN guidelines recommend Gemcitabine plus Nab-paclitaxel (AG). While Nimotuzumab combined with Gemcitabine has shown survival benefits, there is limited clinical data on its efficacy when combined with AG for treating PCLM. This study aims to evaluate the safety and efficacy of adding Nimotuzumab to the AG regimen for PCLM. Methods: Patients with potentially resectable, treatment-naïve PCLM received Nimotuzumab (400 mg, iv, d1, qw) and AG chemotherapy (Gemcitabine 1000mg/m2, Nab-paclitaxel 125mg/m2, d1, d8, 21d cycle). After two cycles of treatment, patients eligible for surgery underwent resection, while others continued treatment until disease progression, unacceptable toxicity, or withdrawal. The primary endpoints were objective response rate (ORR) and disease control rate (DCR), with secondary endpoints including surgical conversion rate, R0 resection rate, pathological complete response (pCR) rate and adverse events (AEs). Results: As of October 29, 2024, data were collected from 26 PCLM patients. The median duration of Nimotuzumab treatment was 4 months (range: 1-13), with a median follow-up of 10 months. The average age was 62 years (range: 40-75), and 73.1% of patients were male, all with an ECOG PS of 0-1. In 22 patients with initial efficacy assessments, the ORR was 13.6% (3/22), and the DCR was 77.3% (3 PR, 14 SD). The CA19-9 response rate, with a &amp;gt;50% drop from baseline, was 54.5% (12/22). After 2-5 months of conversion therapy, 10 patients underwent surgery, resulting in a surgical resection rate of 45.5%, with no patients achieving pCR. The median progression-free survival (PFS) was 5 months, and median overall survival (OS) has not yet been reached. The most common adverse events were nausea and vomiting, which were resolved or improved with symptomatic treatment. No grade 4-5 TRAEs were observed. Conclusions: Combining Nimotuzumab with AG therapy can facilitate conversion to surgical resection in patients with PCLM, while maintaining a manageable safety profile. Clinical trial: NCT06405685. Citation Format: Dandan Wu, Yang Liu, Linlin Fu, Yinchao Zhang, Linze Xu, Jin Zhang, Huikai Li, Jihui Hao. Phase II study of Nimotuzumab combined with AG regimen in pancreatic cancer with liver metastases (PCLM): A prospective, single-arm trial [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 CT167.
Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection
Authors: Jun Xiao, Weiyun Li, Xin Zheng, Linlin Qi, Hui Wang, Chi Zhang, Xiaopeng Wan, Yuxiao Zheng, Ruiyue Zhong, Xin Zhou, Yao Lu, Zhiqi Li, Ying Qiu, Chang Liu, Fang Zhang, Yanbo Zhang, Xiaoyan Xu, Zhongzhou Yang, Hualan Chen, Qiwei Zhai, Bin Wei, Hongyan Wang
Journal: Immunity (2025)
Abstract CT111: A phase 1, first-in-human study of IB-T101, an OUTLAST™ CAR-T product for the treatment of CD70-positive clear cell renal carcinoma
Authors: Bo Liu, Warren Anderson, Mathew Esquivel, Adam Pecoraro, Kate Fagan-Solis, Yuning Lei, Jun Cui, Yarong Liu, Kevin Carbajal, Maximilian Richter, Matthias Schroff
Journal: Cancer Research (2025)

Abstract Relapsed/refractory clear cell renal cell carcinoma (ccRCC) presents an unmet medical need for patients as they are faced with limited treatment options and poor clinical outcomes. CD70, is commonly expressed in ccRCC and is an attractive target for chimeric antigen receptor T cell (CAR-T) therapy. IB-T101 is an autologous CAR-T targeting CD70 that has been expanded under OUTLAST™ conditioning. OUTLAST™ conditioning is easy to implement during cell expansion and results in CAR-T cells that exhibit an early memory T cell phenotype, are resistant to suppressive signals from the tumor microenvironment, and exhibit increased persistence. These attributes are expected to lead to superior clinical outcomes for IB-T101 CAR-T cells in an ccRCC solid tumor setting. Here we present an in-progress phase 1, first-in-human, open label, multi center investigator-initiated clinical trial aimed at evaluating the safety and efficacy of IB-T101 in ccRCC in patients that have relapsed on prior VEGF targeting therapies alone or in combination with an immune checkpoint inhibitor. Autologous patient T cells are transduced with a lentiviral vector encoding a CD70-targeting CAR and are CRISPR Cas9 gene edited to knock out endogenous CD70, followed by expansion under OUTLAST™ conditioning. Escalating doses of IB-T101 CAR-T cells (150 - 500 x 106) will be infused following lymphodepletion. Primary endpoints of the study will assess the safety and tolerability of IB-T101. Additional objectives of the study are to assess the anti-tumor activity and the pharmacokinetics of IB-T101. Correlative assessments will include pre-treatment biopsies to assess the level of CD70 expression in the tumor. Citation Format: Bo Liu, Warren Anderson, Mathew Esquivel, Adam Pecoraro, Kate Fagan-Solis, Yuning Lei, Jun Cui, Yarong Liu, Kevin Carbajal, Maximilian Richter, Matthias Schroff. A phase 1, first-in-human study of IB-T101, an OUTLAST™ CAR-T product for the treatment of CD70-positive clear cell renal carcinoma [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 CT111.
Abstract CT107: A phase 1a/b, open-label, dose-escalation study of 225Ac-ABD147 for locally advanced or metastatic small cell lung cancer and large cell neuroendocrine carcinoma of the lung following platinum-based chemotherapy
Authors: Babak Saboury, Lisa Bodei, Gary A. Ulaner, Jowell Go, Guanying Wang, Charles M. Rudin
Journal: Cancer Research (2025)

Abstract Background: 225Ac-ABD147 is a targeted radioligand therapy that uses actinium-225 (225Ac), an alpha-emitting radionuclide, coordinated to a VHH-Fc -chelator conjugate ABD147. It targets with high affinity the delta-like ligand 3 (DLL3) receptor, commonly overexpressed on high-grade neuroendocrine tumors including Small Cell Lung Cancer (SCLC) and Large Cell Neuroendocrine Carcinoma (LCNEC) of the Lung but not on normal tissue. 111In-ABD147, a single-photon emission computerized tomography (SPECT) imaging agent, serves as a surrogate to assess tumor targeting and normal organ dosimetry. Preclinical studies have shown specific, high affinity binding of ABD147 to DLL3-expressing cancer cells, minimal uptake in normal tissues and preferential accumulation in tumor tissue. In vivo studies demonstrated significant antitumor activity and extended survival in SCLC xenograft models. Objectives: This open-label, Phase 1a/b, first-in-human study aims to evaluate the tolerability, biodistribution, pharmacokinetics (PK), and preliminary antitumor activity of 225Ac-ABD147 in patients with locally advanced or metastatic SCLC and LCNEC of the lung post platinum-based chemotherapy. Methods: Phase 1a involves escalating doses to determine the safety, tolerability, dosimetry, PK, and the dose for Phase 1b expansion. Phase 1b will assess safety and preliminary efficacy to recommend the Phase 2 dose (RP2D). Dosimetry assessments involve up to 10 patients for 111In-ABD147 and 3 to 6 patients for 225Ac-ABD147. Inclusion criteria include confirmed locally advanced or metastatic SCLC or LCNEC, completion of platinum-based chemotherapy (and a checkpoint inhibitor if approved as standard of care). Subjects must have measurable disease by RECIST v1.1. Exclusion criteria include primary resistant disease, hypersensitivity to 225Ac or 111In, active infection, uncontrolled bleeding, or non-healing wound and prior EBRT to &amp;gt;25% of the bone marrow. Phase 1a dose escalation is ongoing in the US. (NCT06736418) Citation Format: Babak Saboury, Lisa Bodei, Gary A. Ulaner, Jowell Go, Guanying Wang, Charles M. Rudin. A phase 1a/b, open-label, dose-escalation study of 225Ac-ABD147 for locally advanced or metastatic small cell lung cancer and large cell neuroendocrine carcinoma of the lung following platinum-based chemotherapy [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 CT107.
Abstract CT096: Mechanisms of acquired resistance and ctDNA clearance in <i>EGFR</i>-mutated advanced NSCLC following lazertinib treatment: Results from the phase 3 LASER301 study
Authors: Byoung Chul Cho, Ki Hyeong Lee, Chin Heng Fong, Anastasia Zimina, Yong Kek Pang, Sergey Orlov, Joo-Hang Kim, Jason K. Sa, YuKyung Kim, Mi-Jung Kwon, SeokYoung Choi, Dongmin Kim, Min Kim, Myung-Ju Ahn
Journal: Cancer Research (2025)

Abstract Background: Patients (pts) with treatment-naïve, EGFR-mutated (EGFRm), advanced non-small cell lung cancer (NSCLC) who received lazertinib (CNS-penetrant, third-generation EGFR tyrosine kinase inhibitor) in the LASER301 study had significantly longer median progression-free survival versus gefitinib. Here we report results on mechanisms of acquired resistance and circulating tumor DNA (ctDNA) clearance in pts who received lazertinib in LASER301. Methods: Next-generation sequencing (NGS; Guardant360; Guardant Health) of circulating cell-free DNA (cfDNA) was performed on paired blood samples collected at baseline and at disease progression from pts who received lazertinib to evaluate the emergence of potential resistance mechanisms. To evaluate ctDNA clearance, exon 19 deletion (Ex19Del) and L858R ctDNA in blood was analyzed at baseline and Week 6 (Cycle 3, Day 1) with droplet digital PCR and EGFRm testing (Droplex EGFR Mutation Test v2; Gencurix). ctDNA clearance was defined as undetectable EGFRm determined at Week 6 in pts with detectable EGFRm ctDNA at baseline. Results: NGS analysis included 168 pts, of which 82 pts had detectable plasma EGFRm at baseline and were eligible for acquired resistance analysis. The most frequently occurring alterations acquired at disease progression were EGFR C797S alteration (9%) as well as MET and ERBB2 amplifications (7% each; Table). For the ctDNA clearance analysis, 149 pts were included. At baseline, ctDNA was detected in 52% of pts (77/149), with Ex19Del detected in 64% (49/77) and L858R detected in 36% (28/77). At Week 6, ctDNA was cleared in 94% of pts (72/77). Conclusions: In eligible pts with advanced EGFRm NSCLC treated with lazertinib from LASER301, EGFR C797S was the most commonly detected alteration at the time of disease progression, representing a potential mechanism of acquired resistance. ctDNA clearance was achieved in the majority of these pts by Week 6. Citation Format: Byoung Chul Cho, Ki Hyeong Lee, Chin Heng Fong, Anastasia Zimina, Yong Kek Pang, Sergey Orlov, Joo-Hang Kim, Jason K. Sa, YuKyung Kim, Mi-Jung Kwon, SeokYoung Choi, Dongmin Kim, Min Kim, Myung-Ju Ahn. Mechanisms of acquired resistance and ctDNA clearance in EGFR-mutated advanced NSCLC following lazertinib treatment: Results from the phase 3 LASER301 study [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 CT096.
Abstract CT142: The first-in-human trial of USP28 inhibitor CT1113
Authors: Jie Jin, Xingnong Ye, Huafeng Wang, Xiang Shen, Jin Peng, Pumin Zhang
Journal: Cancer Research (2025)

Abstract The deubiquitinase USP28 plays an important role in maintaining the expression levels of a large number of onco-proteins prominent among which is c-MYC. Previous work has shown the potential of USP28 as a pan-cancer therapeutic target. We identified a potent and specific inhibitor of the deubiquitinase, CT1113, which showed excellent preclinical anti-tumor activities. The inhibitor can induce c-MYC degradation in cancer cell lines with all different tissue-origins and in xenograft tumors. We therefore launched a first-in-human phase I trial of CT1113 in patients with relapsed/refractory acute myeloid leukemia (R/R AML). The compound showed excellent safety and PK profiles. Importantly, preliminary efficacy was observed, validating USP28 as a therapeutic target. A phase II trial has been planned. Citation Format: Jie Jin, Xingnong Ye, Huafeng Wang, Xiang Shen, Jin Peng, Pumin Zhang. The first-in-human trial of USP28 inhibitor CT1113 [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 CT142.
Abstract CT069: A phase I study of the first-in-class anti-fatty acid oxidation agent, KN510713, in patients with advanced solid cancers
Authors: Sang Myung Woo, Wonyoung Choi, Jung Won Chun, Sung Hoon Sim, Ho Lee, Woo Jin Lee, Joon Hee Kang, Hyun Chul Kim, Sungyeun Bae, SeungHwan Lee, Soo-Youl Kim
Journal: Cancer Research (2025)

Abstract Purpose: We discovered that cancer cells rely heavily on fatty acid oxidation (FAO) for ATP production, unlike normal cells. This led to the development of the FAO inhibitor KN510713. This study explored the effects of KN510713 on mitochondria and evaluated its safety, tolerability, and pharmacokinetics in patients with relapsed or refractory solid tumors, mainly focusing on advanced pancreatic cancer. Experimental Design: Patients were enrolled in escalating dose cohorts to receive the combination of KN510 and KN713 for 4 weeks per cycle in a 3 + 3 design. Patients continued treatment until disease progression. Adverse effects (AEs) and dose-limiting toxicities (DLTs) were monitored. Pharmacokinetics were assessed after the 1st and 21st doses. Results: Among the 12 subjects who received the investigational product at least once, 39 AEs occurred in 11 subjects. Of these, 16 AEs were assessed to have a relationship with the KN510713. Among the AEs that occurred in the subjects, except for 2 severe cases (Hypersensitivity, Constipation), all others were mild to moderate, and no subjects dropped out of the clinical trial due to the AEs. There was 1 serious adverse event (Constipation), and the most common AEs were Influenza-like illness with 6 events in 5 subjects, followed by Diarrhoea with 4 events in 3 subjects. Since no DLTs occurred, the highest tested dose of KN510 120 mg/day + KN713 120 mg/day was well-tolerated. Pharmacokinetic analysis showed dose-proportional increases in plasma concentrations of KN510 and KN713 across all cohorts with proper pharmacokinetic profiles allowing for once-daily dosing. No significant drug-drug interactions were observed between KN510 and KN713. Of the 12 evaluable, heavily pretreated patients, 4 achieved stable disease, and one patient with pancreatic cancer achieved prolonged stabilization for 6 months. Conclusion: Our findings indicate that KN510713 was well-tolerated up to the highest dose tested, with no DLTs observed.(ClinicalTrials.gov identifier: NCT06012708) Citation Format: Sang Myung Woo, Wonyoung Choi, Jung Won Chun, Sung Hoon Sim, Ho Lee, Woo Jin Lee, Joon Hee Kang, Hyun Chul Kim, Sungyeun Bae, SeungHwan Lee, Soo-Youl Kim. A phase I study of the first-in-class anti-fatty acid oxidation agent, KN510713, in patients with advanced solid cancers [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 CT069.