bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 390: Direct interaction of Pin1 with HIF-prolyl hydroxylase 2: Implications for breast cancer cell growth and survival
Authors: Quispe Yanymee Nimesia Guillen , Kim Su-Jung , Saeidi Soma , Choi Gyo-Jin , Chelakkot Chaithanya , Zhou Tianchi , Bang Sang-Beom , Kim Tae-Won , Shin Young-Kee , Surh Young-Joon 
Published: March 2024

Abstract
Prolyl hydroxylase domain 2 (PHD2) is the main hypoxia-inducible factor (HIF)-prolyl hydroxylase. PHD2 in normoxia hydroxylates specific proline residues in HIF-1α and HIF-2α, which facilitates their ubiquitination and proteasomal degradation. Although the activity of PHD2 is reduced in hypoxia, significant levels of residual activity of this monooxygenase are still detected under hypoxic conditions. However, its role under hypoxia is poorly understood. Peptidyl-prolyl isomerase (Pin1) binds to target proteins containing phosphorylated serine or threonine residues followed by proline (pS/T-P). As PHD2 harbors several pS/T-P motifs, it may be a potential substrate of Pin1. We found for the first time interaction between Pin1 and PHD2 in human breast cancer MDA-MB-231 cells in normoxic and hypoxic conditions. Additionally, the breast cancer tissue array showed elevated expression of PHD2 as well as Pin1 in tumors compared to adjacent normal tissues. LC-MS/MS spectrometry identified three amino acid residues (S125, T168, and S174) of PHD2 undergoing phosphorylation. Among these, serine 125 was found to be the principal site required for Pin1 binding. As a novel binding partner of Pin1, oncogenic PHD2 can be explored as a therapeutic target for the treatment of breast cancer.
Citation Format: Yanymee Nimesia Guillen Quispe, Su-Jung Kim, Soma Saeidi, Gyo-Jin Choi, Chaithanya Chelakkot, Tianchi Zhou, Sang-Beom Bang, Tae-Won Kim, Young-Kee Shin, Young-Joon Surh. Direct interaction of Pin1 with HIF-prolyl hydroxylase 2: Implications for breast cancer cell growth and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 390.
Abstract 3926: ARF6-dependent endocytic trafficking of the interferon-gamma receptor drives adaptive immune resistance and response to immune checkpoint blockade
Authors: Wee Yinshen , Wang Junhua , Wilson Emily C. , Rich Coulson P. , Rogers Aaron , Tong Zhongzong , DeGroot Evelyn , Gopal Y.N. Vashisht , Davies Michael , Ekiz Huseyin Atakan , Tay Joshua K.H. , Stubben Chris , Boucher Kenneth M. , Oviedo Juan M. , Fairfax Keke C. , Williams Matthew A. , Holmen Sheri L. , Wolff Roger K. , Grossmann Allie H. 
Published: March 2024

Abstract
Interferon-gamma (IFNγ)-driven adaptive immune resistance (AIR) in cancer begins at the plasma membrane where cytokine signaling is initiated. Cytotoxic CD8+ T cells secrete IFNγ, eliciting tumor-intrinsic IFNγ signaling and expression of immunosuppressive genes, which are critical for effective therapeutic response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade (ICB). Although the IFNγ receptor (IFNγR) is expressed in all cell types, its surface density can determine a cell’s responsiveness to ligand. Mechanistic control over this process remains a mystery. Herein we report that the endocytic trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR during primary tumor progression and in the setting of ICB therapy. The IFNγR1 subunit of the receptor is constitutively internalized in a ligand-independent manner. ARF6 is necessary for endocytic recycling of IFNγR1 and determines the steady-state surface density of the receptor. Loss of ARF6 results in lysosomal degradation of the receptor and controls IFNγR1 protein levels in melanoma, non-small cell lung cancer, colorectal cancer, and triple-negative breast cancer. IFNγ activates ARF6 in parallel with JAK1-STAT1 signaling, suggesting a positive feedback loop that allows tumor cells to dynamically respond to immune attack. Silencing ARF6 reduces tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to systemic ICB therapy. Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent adaptive immunity, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor shapes clinical outcomes of ICB therapy.
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Citation Format: Yinshen Wee, Junhua Wang, Emily C. Wilson, Coulson P. Rich, Aaron Rogers, Zhongzong Tong, Evelyn DeGroot, Y.N. Vashisht Gopal, Michael Davies, Huseyin Atakan Ekiz, Joshua K.H. Tay, Chris Stubben, Kenneth M. Boucher, Juan M. Oviedo, Keke C. Fairfax, Matthew A. Williams, Sheri L. Holmen, Roger K. Wolff, Allie H. Grossmann. ARF6-dependent endocytic trafficking of the interferon-gamma receptor drives adaptive immune resistance and response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3926.
Abstract 4003: TBK1 inhibition enhances CAR-T cell efficacy against patient-derived organotypic tumor spheroids
Authors: Maggs Luke , Sun Yi , Cattaneo Giulia , Ventin Marco , Chen Feng , Rasmussen Martin Q. , Wang Xinhui , Ferrone Cristina R. , Ferrone Soldano , Jenkins Russell W. 
Published: March 2024

Abstract
Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR)-T cells in the treatment of solid tumors. Here, we set out to evaluate novel therapeutic strategies to improve the efficacy of B7-H3 (CD276) directed (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS). PDOTS are generated from fresh patient tumor tissue and contain tumor cells, autologous immune cells and stromal cells, therefore recapitulating key features of the tumor microenvironment (TME), enabling the study of tumor-immune dynamics. We confirmed activity of B7-H3.CAR-T in PDOTS, although a strong correlation between B7-H3 expression and CAR-T efficacy was not observed. Mechanistic studies subsequently demonstrated dynamic upregulation of co-inhibitory receptors on CAR-T cells following target cell encounter leading to CAR-T cell dysfunction and limiting CAR-T efficacy in B7-H3 expressing tumors. PD-1 blockade restored CAR-T activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR-T efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR-T activity in monotypic and organotypic tumor spheroids, prevented CAR-T cell dysfunction, and enhanced T cell proliferation. Inhibition or deletion of TBK1 also enhanced sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR-T cells using PDOTS, and suggest that targeting TBK1 is a novel strategy to enhance CAR-T efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.
Citation Format: Luke Maggs, Yi Sun, Giulia Cattaneo, Marco Ventin, Feng Chen, Martin Q. Rasmussen, Xinhui Wang, Cristina R. Ferrone, Soldano Ferrone, Russell W. Jenkins. TBK1 inhibition enhances CAR-T cell efficacy against patient-derived organotypic tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4003.
Abstract 4005: HER2 TKIs enhance the anti-tumor activity of HER2-targeting CAR-T and CAR-NK cells against NSCLC
Authors: Yang Yan , Nilsson Monique B. , Poteete Alissa , He Junqin , Huang Qian , Heymach John V. 
Published: March 2024

Abstract
Approximately 3% of non-small cell lung cancer (NSCLC) cases harbor ERBB2/HER2 mutations. Notably, the majority of actionable HER2 mutations in NSCLC are in-frame insertions in exon 20. Current HER2-targeting approaches, including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, have shown promising response rates. To explore novel strategies for targeting HER2-positive NSCLC, we investigated chimeric antigen receptor (CAR)-based therapies to enhance the anti-tumor activity of immune effector cells. We engineered a series of HER2 CAR constructs utilizing scFvs derived from trastuzumab, pertuzumab, and FRP5, recognizing distinct domains of HER2. These scFvs were integrated into second-generation BB3z (with 4-1BB and CD3z intracellular domains) and third-generation 28BB3z (with CD28, 4-1BB, and CD3z intracellular domains) CAR backbones, which were subsequently transduced into activated T and natural killer (NK) cells to generate CAR-T and CAR-NK cells, respectively. High transduction efficiencies were achieved, with over 80% in CAR-T cells and over 50% in CAR-NK cells. We next evaluated their activity against a panel of NSCLC cell lines expressing varying levels of HER2 in vitro using firefly luciferase assays. All HER2 CAR-T cells demonstrated more than 90% killing against H2170 (HER2 high) and H322 (HER2 medium) at an effector:target (E:T) ratio of 10:1, whereas HER2 CAR-T cells yielded a killing effect of 35% against A549 (HER2 low) cells. HER2-targeting CAR-NK cells also displayed potent cytotoxicity against HER2-expressing NSCLC cells. Moreover, we observed that treatment of HER2 mutant and HER2 amplified NSCLC cells with low doses of HER2 tyrosine kinase inhibitors (TKIs) such as poziotinib enhanced the expression of HER2 on the cell surface. This upregulation resulted in enhanced activation of HER2 CAR-T and CAR-NK cells in coculture experiments as measured by CD107a expression on effector cells. Additionally, treatment with the HER2 TKI poziotinib potentiated the killing activity mediated by HER2 CAR-T and CAR-NK cells. Using a HER2 YVMA duplication patient-derived xenograft (PDX) NSCLC model, we observed that the in vivo combination of poziotinib with HER2 CAR-NK cells exhibited superior anti-tumor activity as compared to poziotinib treatment alone. In conclusion, HER2 CAR-T and CAR-NK cells effectively target HER2-mutant and HER2-positive NSCLC, and their combination with HER2 TKIs enhances vulnerability to HER2-targeting strategies.
Citation Format: Yan Yang, Monique B. Nilsson, Alissa Poteete, Junqin He, Qian Huang, John V. Heymach. HER2 TKIs enhance the anti-tumor activity of HER2-targeting CAR-T and CAR-NK cells against NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4005.
Abstract 4025: A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis
Authors: Li Xiao-Yun , Xie Si-Yi , Chen Qiu-Yan , Mai Hai-Qiang , Tang Lin-Quan 
Published: March 2024

Abstract
Immune checkpoint inhibitors (ICIs) have been widely used in recurrent or metastatic nasopharyngeal carcinoma (NPC), but the addition of ICIs to chemoradiotherapy in locoregionally advanced (LA) NPC requires further investigation. We conducted a phase II, single-arm trial to evaluate the efficacy and safety of neoadjuvant gemcitabine, cisplatin (GP) plus tislelizumab followed by concurrent chemoradiotherapy (CCRT) in LA-NPC. All participants received 3 cycles of GP chemotherapy plus tislelizumab (200 mg) followed by 3 cycles of cisplatin-based CCRT. The primary endpoint was the clinical complete response rate (CR) after neoadjuvant chemoimmunotherapy (NAT). The secondary endpoints include pathological CR rate, progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), etc. Pretreatment blood samples and paired (pre-/post-NAT) tissue biopsies were collected to perform full-spectrum peripheral T-cell profiling, PD-L1 and tertiary lymphoid structures (TLS) staining. Among all 63 participants, the CR rate after NAT reached 41.3% (95% CI, 28.8%-53.8%), far exceeding our hypothesized CR rate of 22%. The objective response rate (ORR) and pCR rate after NAT were 88.9% (95% CI, 80.9% to 96.9%) and 74.6% (95% CI, 62.1% to 84.7%), respectively. As of July 15th, 2023, after the median follow-up of 25 months, the 2-year PFS and OS were 98.4% and 100%. The incidence of grade 3-4 immunotherapy-related adverse events was 1.6%. The compliance of CCRT was not compromised. Patients who achieved CR had significantly more circulating CD4+ and CD8+ effector memory T cells (Tem), regulatory T cells (Treg) and follicular helper T cells (Tfh). The peripheral abundance of LAG3+ Tem and Tfh were independently predictive of NAT response. The number and maturation of TLS significantly increased after NAT in the CR group, but not in the Non-CR group. GP chemotherapy plus tislelizumab followed by CCRT was highly therapeutic and safe in treating LA-NPC, further randomized phase III studies are awaited.
Citation Format: Xiao-Yun Li, Si-Yi Xie, Qiu-Yan Chen, Hai-Qiang Mai, Lin-Quan Tang. A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4025.
Abstract 4077: T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability
Authors: van Geel Remon , Verhagen Mick , Post Elias , Vugs Willem , Popal Sorraya , van Berkel Sander , van Delft Floris 
Published: March 2024

Abstract
Engagement of T cell cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-immunocytokines, based on molecular architectures generated by a variant of DNA recombinant technologies, have recently entered the clinic. Earlier we have demonstrated how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan1, can be applied for attachment of various cytokines, including RLI or IL-15, without prior antibody engineering. The immunostimulatory activity of these GlycoConnect™ immune cell engagers (GC™-ICEs) can be modulated by tailoring linker design and payload stoichiometry. In this presentation, we demonstrate the GC™-ICE with either IL-15 or RLI can be applied to selective targeting of T cells, based on PD-1-selective binding and activation, using either protease-sensitive or non-cleavable linkers. We will show how such T cell targeting can be achieved leading to significant tumor volume reductions in syngeneic mouse models. Moreover, we have found that the GC-ICE™ can be applied without inducing systemic immune activation, thereby displaying a promising therapeutic index. In vitro and in vivo studies will be presented to showcase the biological activity of these GC™-ICEs in comparison to conventional immunocytokines obtained via genetic engineering.1Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14, DOI: 10.1080/19420862.2022.2078466.
Citation Format: Remon van Geel, Mick Verhagen, Elias Post, Willem Vugs, Sorraya Popal, Sander van Berkel, Floris van Delft. T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4077.
Abstract 4083: Pre-clinical development of IAMA-005, a long-acting cytokine fusion of modified IL-2 and IFN-α
Authors: Liu Liming , Han Zhen , Fan Yang , Pan Qi 
Published: March 2024

Abstract
In 1990s, both IL-2 and IFN-α were approved as the first two immunotherapies for metastatic melanoma and renal cell carcinoma; IFN-α was also approved for hairy cell leukemia. Although the response rates are relatively low, along ~25%, those who responded have long term survival benefits. However, the severe toxicity especially in high dose prohibited their broad use in oncology. Recently, there have been tremendous interests in modifying these two cytokines in the efforts to reduce the toxicity and enhance the activity. One such effort is to enhance the binding of IL-2 to the intermediate affinity β/γ receptors, which are expressed and function on CD8 T cells and NK cells. Another effort is to reduce the binding of IL-2 to high affinity α/β/γ receptors which mostly expressed on Treg and stimulate the growth of Treg cells, which suppress immune responses. Recently, whether it’s better to target intermediate affinity or high affinity for cancer therapy has become controversial with some studies showing that high affinity receptor engagements are required for robust anti-tumor activity while others favoring intermediate affinity receptor engagement for better efficacy; However, the clinical comparison is still lacking to be sure which approach is better. Here we have developed a long-acting novel IL-2-Fc-IFN-α fusion molecule termed IAMA-005 that has mutations to reduce the toxicity effects of IL-2 and IFN-α. We have characterized this molecule preclinically both in vitro and in vivo. IAMA-005 has demonstrated a potent tumor cell killing activities in numerous cancer cell lines including BT-474, SK-OV-3, NCI-N87, OE19, HCC-1954, MDA-MB-231, MDA-MB-468. When combined with IAMA-004 (a Her2-CD47-CD16 tri-specific antibody) in vitro, the tumor cell killing activities were dramatically increased. In addition, IAMA-005 was also tested in patient-derived Ex-Vivo fluids (one malignant pleural effusion and one malignant asities) and demonstrated excellent tumor cell killing efficacies. In addition, the killing activities of IAMA-005 could be attributed to the specific part of the fusion molecule because of the TME immune cell compositions. The in vivo assays to demonstrate efficacy and safety are ongoing and will be presented in the poster. These results suggest that this fusion cytokine molecule may be used in monotherapy in certain indications and an excellent complementary therapeutic to antibody targeted therapies or immunotherapies when used in combination.
Citation Format: Liming Liu, Zhen Han, Yang Fan, Qi Pan. Pre-clinical development of IAMA-005, a long-acting cytokine fusion of modified IL-2 and IFN-α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4083.
Abstract 4090: Gut microbiota mimics as a source of cross-reactive tumor rejection antigens
Authors: Panneton Vincent , Gigoux Mathieu , Zebboudj Abderezak , Sadek Norah , Choi Hyejin , Mangarin Levi M. , George Mariam M. , Kulakowski Guillaume , Magalhaes Joao G. , Carpier Jean-Marie , Dugat Thibaud , Gaal Camille , Strozzi Francesco , Tibaldi Lorenzo , Chene Laurent , Wolchok Jedd D. , Balachandran Vinod P. , Merghoub Taha 
Published: March 2024

Abstract
The crosstalk between gut microbiome and anti-tumor immunity has recently gained attention in clinical settings. The administration of antibiotics during immune checkpoint blockade (ICB) therapies has been correlated with poorer outcomes in cancer patients, suggesting that microbiome alterations affect overall responses to ICB. The establishment of microbiota-specific T cell clones with tumor cross-reactivity potential was proposed as one of the mechanisms linking the microbiome to anti-tumor responses. Vaccine-based strategies aimed at reactivating these dormant pools of T cells to help eliminate tumors have been proposed as an alternate approach, but the parameters required for successful responses remain poorly understood. Here, we performed in silico selection of bacterial peptides derived from healthy mice based on their mimicry of either tumor-associated antigens (TAAs) or neoantigens expressed by murine melanoma cells and not healthy tissue. We show that in silico predicted peptide binding affinity to MHC I correlates with experimental MHC I binding, a key factor associated with strong immune responses. Moreover, we confirmed that a significant proportion of selected peptide candidates can provoke an immune reaction in a vaccination setting. From this group of peptides, we selected candidates which triggered cross-reactive immune responses against TAAs or neoantigens. Data from preliminary tumor challenge experiments with prophylactic peptide vaccination and ICB allowed us to define key parameters such as target gene expression levels which can predict the cross-reactive potential of bacterial peptides that mimic tumor antigens. These findings provide novel insights into the design of gut microbiome peptide-based tumor vaccines and pave the way for establishing combinatorial therapies with immunomodulatory drugs.
Citation Format: Vincent Panneton, Mathieu Gigoux, Abderezak Zebboudj, Norah Sadek, Hyejin Choi, Levi M. Mangarin, Mariam M. George, Guillaume Kulakowski, Joao G. Magalhaes, Jean-Marie Carpier, Thibaud Dugat, Camille Gaal, Francesco Strozzi, Lorenzo Tibaldi, Laurent Chene, Jedd D. Wolchok, Vinod P. Balachandran, Taha Merghoub. Gut microbiota mimics as a source of cross-reactive tumor rejection antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4090.