tbuckley/cabot-search huggingface dataset:
Abstract 3514: AZD6621: Improving the therapeutic index for prostate cancer T cell engagers with a next-generation CD8-guided format
Authors: Suzanne Sitnikova, Natalie Burrows, Nikolaos Ioannou, Even Walseng, Chunning Yang, Nadia Luheshi, Yariv Mazor, Mark Cobbold, Saso Cemerski, Simon Dovedi
Journal: Cancer Research (2025)

Abstract Prostate cancer is the second most common malignancy in males with a 5-year survival rate for metastatic castration-resistant prostate cancer of only 37%. Six-transmembrane epithelial antigen of the prostate 2 (STEAP2) is a metalloreductase with plasma membrane expression that is restricted to the prostate but is highly overexpressed across all stages of prostate adenocarcinoma. This expression profile makes STEAP2 an ideal target for a T cell engager (TCE). Despite promising efficacy, the toxicity profile of current TCEs remains challenging with patients often experiencing cytokine release syndrome and on-target, off-tumor adverse effects. This dose-limiting toxicity profile restricts their therapeutic window and with it the potential for combination therapy. We sought to improve this therapeutic index in 3 ways: 1) targeting the tumor-restricted STEAP2 antigen, 2) affinity-optimizing the CD3 binding domain and 3) integrating a CD8 binding domain to preferentially engage CD8+ T cells over CD4+ T cells, as the latter have been shown to contribute to the risk of cytokine release syndrome. Here we provide preclinical in vitro and in vivo evidence demonstrating that this design can potentially increase the therapeutic index when compared to a conventional TCE. We demonstrate that AZD6621 mediates potent, STEAP2-dependent cytotoxicity in vitro with cytotoxicity EC50 values below 10 pM. AZD6621 also induces preferential activation of CD8+ T cells over CD4+ T cells, with an approximately 5-fold increase in maximal activation of CD8+ T cells, as well as significantly reduced cytokine release compared to a conventional TCE. AZD6621 mediates complete anti-tumor regressions as a monotherapy in the STEAP2-expressing 22Rv1 subcutaneous xenograft model in humanized mice. Anti-tumor activity of AZD6621 in vivo was also observed in a C4-2 intratibial xenograft model. Furthermore, when matched for anti-tumor activity in an intravenous 22Rv1 xenograft model, systemic cytokine levels were significantly reduced in AZD6621-treated mice compared to a conventional TCE. These data provide reason to believe that AZD6621 can improve the therapeutic index of conventional TCEs via CD8-guided, affinity-optimized CD3 engagement of STEAP2 on prostate cancer cells and support a first-in-human clinical trial planned to start in 2025. Citation Format: Suzanne Sitnikova, Natalie Burrows, Nikolaos Ioannou, Even Walseng, Chunning Yang, Nadia Luheshi, Yariv Mazor, Mark Cobbold, Saso Cemerski, Simon Dovedi. AZD6621: Improving the therapeutic index for prostate cancer T cell engagers with a next-generation CD8-guided format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3514.
Abstract 4299: Validation of the antitumor compound 3797 in human and murine glioblastoma models
Authors: Lara Gonzalez-Rendo, David Moreiras-Alvarez, Martín Baleiron-Rodriguez, Laura Porres-Ventin, Jose A. Zumalave, María Isabel Loza-García, Víctor M. Arce, Jose A. Costoya
Journal: Cancer Research (2025)

Abstract Multiple studies have highlighted the critical role of the RB-E2F pathway in the control of cell proliferation, therefore, decreasing E2F hyperactivity could be a valuable therapeutic strategy in cancer. Based on this, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells that show hyperactivation of this pathway, in other words, tumor cells. Preliminary data obtained in the group show that poly (ADP-ribose) polymerase-1 (PARP1) is a transcriptional co-activator of E2F1 and, because of this, loss of PARP results in cell cycle regulation and reduced tumor growth. Furthermore, taking into consideration that most oncogenic processes are associated with cell cycle dysregulation, disruption of the PARP1-E2F1 interaction could provide a new therapeutic target for various tumor types. By searching for compounds that can interfere with the PARP1/E2F1 interaction, our group has obtained a library of 85 compounds generated by in silico screening of millions of commercially available compounds using a drug discovery platform. After initial in vitro screening, we have identified 12 molecules capable of inhibiting this interaction. The one that performed best was selected for validation using 2D and 3D models of human and murine glioblastoma. For this purpose, we carried out cell viability and migration assays to assess the effect of the compound on two murine and one human glioma cell lines. In all cell lines, cell growth was decreased by treatment, as revealed by violet crystal staining. In addition, wound closure response was inhibited in treated cells as compared with controls. Finally, the therapeutic efficacy of compound 3797 was tested in organoids originated from those tumor cell lines, using the lactate dehydrogenase (LDH) assay, which assess the cell metabolic activity. In keeping with results obtained in 2D cultures, LDH assay showed that compound 3797 decreases the growth rate in organoids derived from glioblastoma cell lines. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Lara Gonzalez-Rendo, David Moreiras-Alvarez, Martín Baleiron-Rodriguez, Laura Porres-Ventin, Jose A. Zumalave, María Isabel Loza-García, Víctor M. Arce, Jose A. Costoya. Validation of the antitumor compound 3797 in human and murine glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4299.
Abstract 2167: AKT inhibition enhances antitumor efficacy of radiation and immune checkpoint blockade in triple-negative breast cancer by modulating tumor-infiltrating myeloid cells
Authors: Nawon Park, Seung Hyuck Jeon, Yoomin Kim, Seongmin Kim, In Ah Kim
Journal: Cancer Research (2025)

Abstract Although radiotherapy (RT) and immune checkpoint blockade (ICB) are effective for treatment of triple-negative breast cancer (TNBC), significant portion of patients do not experience a clinical benefit, partly due to activation of immunosuppressive cells. Capivasertib, an AKT inhibitor, is approved for use in advanced luminal breast cancer, but its immunomodulatory role in breast cancer remains still unclear. Given the ability of PI3K/AKT/mTOR inhibition to regulate immunosuppressive myeloid cells, we hypothesized that capivasertib could enhance the efficacy of RT and ICB in TNBC. In this study, we investigated the antitumor effects and phenotypes of immune cells in 4T1 syngeneic mouse TNBC model treated with RT, dual ICB (PD-L1 and CTLA-4 blockade), and capivasertib. A dual-tumor model was used to examine abscopal effects, with one tumor receiving RT and the other remaining unirradiated. We found that the quadruple therapy (i.e. RT + anti-PD-L1 + anti-CTLA-4 + capivasertib) resulted in greatest growth delay of both irradiated (primary) and unirradiated (secondary) tumors, along with the lowest number of metastatic lung nodules. Notably, compared to the RT + anti-PD-L1 + anti-CTLA-4 treatment, the quadruple therapy significantly reduced tumor-infiltrating macrophages, with an increase in inflammatory M1 macrophages and a decrease in immunosuppressive M2 macrophages. Moreover, CD86+ mature dendritic cells within tumor microenvironment were increased by addition of capivasertib to RT + anti-PD-L1 + anti-CTLA-4 treatment. These changes were not observed within the spleen and tumor-draining lymph node. Proportion and phenotypes of myeloid-derived suppressor cells (MDSCs) and T cells in tumor were not significantly changed by the quadruple therapy. These findings suggest that capivasertib, when combined with RT and ICB, led to less immunosuppressive tumor microenvironment by modulating tumor-infiltrating myeloid cells. Taken together, this combination strategy could be a viable approach to overcome therapeutic resistance of ICB in TNBC patients. (Work supported by grants from KHIDI &amp; AstraZeneca, and the National Research Foundation of Korea #2023R1A2C3003782) Citation Format: Nawon Park, Seung Hyuck Jeon, Yoomin Kim, Seongmin Kim, In Ah Kim. AKT inhibition enhances antitumor efficacy of radiation and immune checkpoint blockade in triple-negative breast cancer by modulating tumor-infiltrating myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2167.
Abstract 5848: Oxygen-releasing cryogel reinforce dendritic cell function and T-cell mediated tumor immunity in hypoxic microenvironments
Authors: Khushbu Bhatt
Journal: Cancer Research (2025)

Cancer immunotherapy faces significant barriers due to tumor heterogeneity and the hypoxic nature of the solid tumor microenvironment (TME). Hypoxia, defined by reduced oxygen (O2) tension, induces immunosuppression, impairing dendritic cell (DC) and T-cell function, which are critical for robust anti-tumor immunity. Here, we report on the evaluation of a novel hyaluronic acid (HA)-based cryogel scaffold, termed O2-cryogels, engineered to counteract hypoxia by releasing O2 through encapsulated calcium peroxide (CaO2) particles and catalase enzyme. Our results demonstrate that O2-cryogels effectively alleviate hypoxia-induced suppression of murine and human DC function. Specifically, they rescue critical DC processes such as antigen uptake, migratory activity, and the expression of activation and co-stimulatory molecules essential for T-cell priming. Moreover, O2-cryogels enhance the secretion of proinflammatory cytokines, mitigate hypoxia-induced phenotypic switching of mouse DCs to tolerogenic plasmacytoid DCs (pDCs), and suppress the upregulation of hypoxia-induced tolerance markers. These effects translate to restored allogenic T-cell proliferation and improved OT-I cell-mediated cytotoxicity against B16-OVA tumor cells under hypoxic conditions. This study highlights the ability of O2-cryogels to locally modulate oxygen levels, reinvigorate DC function, and enhance T-cell-mediated tumor cell killing, addressing a critical bottleneck in cancer immunotherapy. By targeting hypoxia, O2-cryogels offer a novel and promising approach to amplify the efficacy of immunotherapeutic strategies, paving the way for innovative treatments in hypoxia-driven solid tumors. Citation Format: Khushbu Bhatt. Oxygen-releasing cryogel reinforce dendritic cell function and T-cell mediated tumor immunity in hypoxic microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5848.
Abstract 3966: Divergent immune responses in pancreatic cancer driven by KRAS mutations
Authors: Andrew Wenger, Katherine Bacchi, Huanhuan Sun, Adrian Vega, Whitney Sisso, Erika Hissong, Lukas Dow, Despina Siolas
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted KrasG12R/+;Trp53KO mouse pancreatic tumors have a distinct immune profile in comparison to KrasG12D/+;Trp53KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available and real-world human PDAC datasets an enrichment of dendritic cells and other immune related cell pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an unique immunogenic role. Citation Format: Andrew Wenger, Katherine Bacchi, Huanhuan Sun, Adrian Vega, Whitney Sisso, Erika Hissong, Lukas Dow, Despina Siolas. Divergent immune responses in pancreatic cancer driven by KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3966.
Abstract 5833: Overcoming immune anergy by targeting tumor macrophages: Rearranging the tumor microenvironment
Authors: Frederick O. Cope, Simon A. Blackburn
Journal: Cancer Research (2025)

There are remarkable advances in immunotherapy which have transformed solid tumor therapy outcomes for many patients. Immunotherapy rationales include checkpoint inhibitor monoclonal antibodies (CIMA) or chimeric antigen receptor T cell therapy that have become primary treatment options and provide remarkably durable treatment responses that are generally not achieved with standard systemic non-targeted chemotherapy. A hallmark of solid tumors is their ability to induce immune anergy where the target tumor is able to evade immune surveillance. Within the solid tumor micro-environment, a critical element of this anergy maintenance is the presence of tumor-associated macrophages (TAMs). Indeed, the localization of TAMs in the tumor micro-environment is effectively co-opted into contributing toward tumor growth. We have developed two new immune-modulating therapeutic drugs that specifically address the role of TAMs in anergic immune responses. These include the synthetic CD-206 ligand PHY-001, a macrophage phenotype-shifting agent designed to act through CD-206-expressing M2-like TAMs. Its application to solid tumor microenvironments is indicated to result in a shift of TAMs to an antitumor M1-like phenotype. Alternative to TAM phenotype shifting is the induction of apoptosis of TAMs. This too, is effectively achieved through the CD-206 receptor with modification of PHY-001, such that loading of PHY-001 with an elemental anion, results in mitochondrial disruption and TAM apoptosis (Modified PHY001 --&amp;gt; PHY-003). Both agents have been target-tested (CD206) in vivo in humans using an approved isotopically labeled version of the molecule core. Either approach to the modification of TAMs releases the immune micro-environment from the existing anergic lock, resulting in significantly improved adaptive and innate tumor immune responses including increased cancer cell phagocytosis by a] reprogrammed existing TAMs or b] neo-localization of invading immunologically functional macrophages. These two new agents provide a novel approach to solid tumor immunotherapy where they may be used singly or in conjunction with other immunomodulating drugs. Such agents are a rational expansion in available approaches to solid tumor therapy. Citation Format: Frederick O. Cope, Simon A. Blackburn. Overcoming immune anergy by targeting tumor macrophages: Rearranging the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5833.
Abstract 2153: Preliminary analysis of immune cell profiling to neoadjuvant chemotherapy response in pancreatic cancer patients
Authors: Byeong-Gon Kim, Sung Jun Kim, Gyuryang Park, Tae Young Kim, Sung-Sik Han, Sang-Jae Park, Woo Jun Lee, Sun-Young Kong, Yun-Hee Kim, Jung Won Chun, Sang Myung Woo
Journal: Cancer Research (2025)

Abstract Background: Neoadjuvant chemotherapy (NAT) is used in the clinical setting to improve the chance of surgery for pancreatic cancer (PC) patients. Immune profiling shows great promise for improved prediction of response to chemotherapy, But the role of the immune system of PC remain unclear. This study aimed to identify immune biomarkers for improved prediction of response to chemotherapy. Materials and Methods: Blood samples were collected from 23 pancreatic cancer patients undergoing neoadjuvant chemotherapy (NAT) before (pre, n=23) and during the 2-month follow-up after treatment (post 2M, n=15). Peripheral blood mononuclear cells (PBMC) were isolated from whole blood samples using Ficoll buffer and flow cytometry analyzed using 18 colors-LSRFortessa for immune cell profile. The following fluorescent-labeled antibodies were used: Fixable viability stain 700, Fluorescein isothiocyanate anti-CD3, Brilliant violet (BV) 605 anti CD14, BV510 anti-HLA-DR, BV655 anti-CD123, BV421 anti-CD11c, Brilliant ultraviolet (BUV) anti-CD4, and BV711 anti-CD8. The immune cell profiling in peripheral blood mononuclear cells were analyzed by flow cytometry. Patients were classified as responders (compete response, partial response) or non-responders (stable disease, progressive disease) base on their response to NAT, and their immune cell profiles were compared. Results: The baseline characteristics of the two groups were similar. The median number of NAT cycles was 8 (range, 4-9) in responders and 8 (4-12) cycles in non-responders, respectively. Among various immune cell types, the myeloid dendritic cells (mDC) levels were significantly increased in responder of the NAT group (P = 0.025); however, the levels of CD4, CD8, monocyte, overall DC, and plasmacytoid DC were not significantly different. After NAT 2-month, a decrease in mDC levels was frequently observed in the non-responder group (75% vs. 43%), but the difference was not significant. Conclusion: Our study suggests that mDC in blood may be a useful biomarker for predicting NAT response and improving treatment responses in pancreatic cancer patients. Further research is required to fully assess the role of mDC in predicting NAT response.Funding: This work was supported in part by the National Cancer Center, Korea (No. 2410680). Citation Format: Byeong-Gon Kim, Sung Jun Kim, Gyuryang Park, Tae Young Kim, Sung-Sik Han, Sang-Jae Park, Woo Jun Lee, Sun-Young Kong, Yun-Hee Kim, Jung Won Chun, Sang Myung Woo. Preliminary analysis of immune cell profiling to neoadjuvant chemotherapy response in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2153.
Abstract 1808: Engineering lipid-polymer nanoparticles for siRNA delivery to breast cancer cells
Authors: Abdulelah Alhazza, Arthur Manda, Hamidreza Montazeri Aliabadi, Hasan Uludag
Journal: Cancer Research (2025)

Abstract RNA interference (RNAi) is a powerful tool that can specifically target the expression of virtually any protein without the expensive and time-consuming drug development studies. Despite the initial excitement and extensive efforts, the potential impact of RNAi approaches is yet to be materialized fully in clinical settings. This is mainly due to the challenges in delivering RNA molecules. Lipid nanoparticles (LNPs) have been the leading delivery system for nucleic acids, an achievement established by introducing the first FDA-approved small interfering RNA (siRNA) drug and COVID-19 vaccine to clinics. However, targeted delivery to a solid tumor still eludes the developed LNPs. On the other hand, polymers are among the oldest delivery systems for nucleic acids, and polyethyleneimine (PEI) was once considered the gold standard in nucleic acid delivery. In this study, we introduce a novel lipid-polymer nanoparticle (LPNP) platform, meticulously engineered for targeted delivery of siRNA to cells implicated in breast cancer. We hypothesized that specially designed low molecular weight PEIs can partially or completely replace the ionizable lipids for a more accommodating structure for additional moieties, which could lead to a safer and more efficient nucleic acid delivery. We first optimized the LNP formulations as a point of reference for cellular uptake, cytotoxicity, and protein silencing efficiency, employing sophisticated designs facilitated by the Design-Expert software. Leveraging the optimal LNP formulation, we integrated specifically designed cationic polymers as partial or complete replacements for the ionizable lipid. This methodological approach, incorporating optimal combined designs and response surface methodologies, refined the LPNPs to an optimal efficiency. Our results indicate that these refined LPNPs enhance the delivery of siRNA, leading to efficient gene silencing in targeted cancer cells. The improved delivery efficiency not only underscores the potential for specific therapeutic applications, but also suggests a broader utility for this platform in various cancer treatments. Citation Format: Abdulelah Alhazza, Arthur Manda, Hamidreza Montazeri Aliabadi, Hasan Uludag. Engineering lipid-polymer nanoparticles for siRNA delivery to breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1808.