bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6314: Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch
Authors: Kim Ki Hyun , Kim Soohwan , Lee Eun-Hoe , Lim Soo-Yoon , Kim Sung Min , Kim E-Young , Lee Hyun-Jong , Kim Seong Yeol , Yoon Min , Lee Young-Ha , Hwang In-Sik , Lee Yoon , Kim Jong-Hoon , Lee Jong-Seo , Chung Junho 
Published: March 2024

Abstract
Chimeric antigen receptor (CAR) T cells targeting CD19 or the B cell maturation antigen (BCMA) have demonstrated impressive initial clinical responses. However, on follow-up assessment, a notable fraction of the patients with significant initial clinical response eventually experienced relapse. CAR T cell therapies targeting solid tumors have shown an even lower rate of clinical response as well as shorter remission periods. A prior study has shown that re-injection of the anti-HER2 CAR T cells was effective in a rhabdomyosarcoma relapse patient (Cancer Res 79, LB147 (2019)), but the repeated production of CAR T cells is costly, thus raising questions about its feasibility in practice. Previously, we developed a cotinine-based CAR T cell system (zCART) comprised of a tumor antigen-specific affibody conjugated with cotinine and an anti-cotinine scFv CAR, and demonstrated the anti-tumor activity of an anti-HER2 zCART treatment in both in vitro and in vivo settings. In this study, we tested the efficacy of anti-HER2 zCART treatment in vivo using an intraperitoneal (IP) tumor model with a single infusion of zCART cells. The anti-HER2 switch was injected daily for 7 days. When the HER2 positive tumor relapsed, the mice were re-treated with the same dose of anti-HER2 switch treatment for an additional 7 days. We observed that re-injection of only the anti-HER2 switch and not combined with zCART cells effectively and potently inhibited relapse of HER2 positive tumors. Furthermore, the efficacy of the anti-HER2 switch re-injection treatment was maintained in one additional relapse. In summary, the zCART system has potential to treat cancer relapse following CAR T cell therapy without the need for an additional production round of CAR T cells.
Citation Format: Ki Hyun Kim, Soohwan Kim, Eun-Hoe Lee, Soo-Yoon Lim, Sung Min Kim, E-Young Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Young-Ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, Junho Chung. Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch [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 6314.
Abstract 6362: The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate tumors
Authors: Wu Guojin , Liang Jiabei , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying 
Published: March 2024

Abstract
Cancer immunotherapy with 4-1BB agonists has faced limitations in further clinical development due to dose-limiting toxicity. PSMA, highly expressed in normal prostate tissue and prostate cancer, is a clinically validated target for prostate cancer treatment. In this study, we developed a bispecific antibody (BsAb), KA-3002, targeting PSMA and human 4-1BB, with the aim of restricting 4-1BB stimulation to the interior of tumors. KA-3002 was developed based on our nanobody antibody discovery platform. KA-3002, in IgG1 format, features mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It contains two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PSMA with two Fabs at the N-terminal. KA-3002 exhibits high avidity binding to prostate tumor cells expressing PSMA (EC50&lt;1nM) and also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PSMA with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3002 effectively suppresses the growth of 22Rv1 tumors, which highly express PSMA. The antibody also demonstrates a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. KA-3002 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3002, developed with our nanobody antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of prostate cancer.
Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate tumors [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 6362.
Abstract 6365: The bispecific antibody KA-3008, targeting both EGFR and B7H3, increases internalization and minimizes on-target, off-tumor toxicity
Authors: Wu Guojin , Ding Li , Peng Hao , Hao Feng , He Feng , Ning Jinying 
Published: March 2024

Abstract
EGFR and B7H3 are highly expressed in various solid tumors, as well as in different normal tissues. Targeting EGFR or B7H3 alone with inhibitory monoclonal antibodies or antibody-drug conjugates (ADCs) may result in on-target, off-tumor toxicity. In this study, we developed a bispecific antibody (BsAb) named KA-3008, targeting both EGFR and B7H3 using our common light chain antibody discovery platform. KA-3008, in IgG1 format, features a regular antibody structure with an identical light chain, developed through knob-into-hole technology. Compared to its parent antibodies, its affinities for both EGFR and B7H3 decrease by more than ten times. It binds to cell lines expressing EGFR or B7H3 alone with an EC50 of more than 10nM, while it binds to cell lines expressing both EGFR and B7H3 with an EC50 of less than 1nM. KA-3008 also blocks the binding of EGF to EGFR and increases internalization when binding to both EGFR and B7H3 compared to binding to EGFR or B7H3 alone. In human tumor mouse models, KA-3008 effectively suppresses the growth of NCI-H1568 tumors expressing both EGFR and B7H3, but does not affect the growth of MS751 tumors that only highly express EGFR with low expression of B7H3. Additionally, KA-3008 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this BsAb with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3008 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3008, developed with our common light chain antibody discovery platform, is stable and holds potential for the development of ADCs targeting both EGFR and B7H3.
Citation Format: Guojin Wu, Li Ding, Hao Peng, Feng Hao, Feng He, Jinying Ning. The bispecific antibody KA-3008, targeting both EGFR and B7H3, increases internalization and minimizes on-target, off-tumor toxicity [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 6365.
Abstract 6465: A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients
Authors: Gaebe Karolina , Erickson Anders W. , Chen Sarah , Sahgal Arjun , Lok Benjamin H. , Chan Kelvin K. , Das Sunit 
Published: March 2024

Abstract
Introduction: Patients with small cell lung cancer (SCLC) have historically been characterized by poor overall survival (OS) and high risk for brain metastases (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking.
Methods: The aim of this study was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. This retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 2010 and March 2018. Data were analyzed between June 2022 and July 2023. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient cohorts stratified by disease stage, BM diagnosis, or first-line intracranial treatment modality.
Results: 8705 patients were included. Median age at diagnosis was 68 years (range 18-103). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n=2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) and had median OS of 9.76 months (95% CI, 9.36-10.22). 102, 1654, and 880 patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS was equivocal between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 1.18, 95% CI, 0.75-1.81) and those who received PCI prior to BM development (HR, 0.77, 95% CI, 0.53-1.13).
Conclusions: Survival for patients with SCLC remains poor, and many patients present with BMs. With careful selection, patients with SCLC may benefit from SRS treatment.
Citation Format: Karolina Gaebe, Anders W. Erickson, Sarah Chen, Arjun Sahgal, Benjamin H. Lok, Kelvin K. Chan, Sunit Das. A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients [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 6465.
Abstract 6476: Solving the real-world data challenge: A hybrid resourcing model to curate RWD at scale
Authors: Rudolph Julia , Kehl Kenneth L. , Bernstein Melanie 
Published: March 2024

Abstract
Introduction: As cancer treatments become more complex, the need for structured real-world data (RWD) to support clinical research is critical. However, researchers often lack resources to curate data in-house. Organizations are challenged with timely data curation at the quality and scale needed for real world applications.
Methods: As members of the AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) Biopharma Collaborative (BPC), Memorial Sloan Kettering Cancer Center (MSK) and Dana-Farber Cancer Institute (DFCI) partnered with Vasta Global, an Omega Healthcare company, to build a model for curating RWD at scale, allowing for cost-effective RWD curation while leveraging expert resources and best practices. The approach includes managing a hybrid onshore and offshore team with clear communication and recurring check-ins, cross-training curators on different EHRs to reallocate Vasta Global resources and maintain project pace, building program-specific clinical data curation training, establishing QA and delivery methods, standardizing data curation, assigning productivity standards, aligning data quality practices and benchmarks, and developing data visualizations and analytics to show progress and insights.
Results: In Phase 1 of the AACR GENIE BPC, data was curated from four sites: MSK, DFCI, Vanderbilt Ingram Cancer Center (VICC) in Nashville, and Princess Margaret Cancer Centre, University Health Network (UHN) in Toronto. During Phase 1, MSK and DFCI, with Vasta Global’s assistance, delivered high-quality RWD for 6,475 patients (NSCLC = 1,591; CRC = 1,264; Bladder = 639; Breast = 957; Pancreas 989; and Prostate = 1,035). All data for these cohorts will be publicly available by Spring 2024 in the AACR Project GENIE cBioPortal. MSK and DFCI generated usable and fit-for-purpose RWD to help advance oncology clinical decision-making and data sharing.
Conclusion: Accelerating RWD curation will empower the oncology community to leverage data-driven insights and advance treatment opportunities for cancer patients. Working alongside lead sites, a partner like Vasta Global enables researchers to leverage extensive expertise in the BPC data model, allowing for consistency and scalability of the BPC program. In this hybrid model, research partners can curate RWD in a cost-effective way, while remaining focused on core research responsibilities.
Citation Format: Julia Rudolph, Kenneth L. Kehl, Melanie Bernstein. Solving the real-world data challenge: A hybrid resourcing model to curate RWD at scale [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 6476.
Abstract 649: SOX11 regulates BCR signaling via the PAX5/CD19 axis in MCL
Authors: Dutta Rudra Prasad , Lee Heng-Huan , Leshchenko Violetta V , Shukla Ravi Prakash , Liu Yang , Jin Jian , Wang Michael , Parekh Samir 
Published: March 2024

Abstract
Background: Mantle cell lymphoma (MCL) is an incurable lymphoid neoplasm, comprising about 6% of all non-Hodgkin lymphoma (NHL). The transcription factor SOX11 is overexpressed in the majority of MCL patients and linked to a more aggressive disease course and poorer clinical outcomes. In MCL, naïve B cells experience continuous proliferation because of the dysregulation of the B-cell receptor (BCR) pathway. Our previously published data (Kuo et. al., Blood 2018) identified that SOX11 aberrantly upregulated BCR signaling in transgenic mouse models. The current study describes the exact mechanism by which SOX11 regulates the BCR pathway using a combination of functional and pharmacological approaches.
Methods: To investigate the alterations in signaling pathways regulated by SOX11, we utilized a small molecule SOX11 inhibitor (Jatiani et. al., CCR 2021), performed CRISPR/CAS9 knockout of SOX11, 3X FLAG TAG overexpression, as well as conducted western blot and flow-cytometry experiments.
Results: Our prior published results (Kuo et. al., Oncogene 2015), as well as others (Vegliante et. al., Blood 2013), have shown that PAX5 is a direct target of SOX11. We confirmed PAX5 downregulation after SOX11 depletion in three human MCL cell lines (JEKO, MINO, Z138) using CRISPR-CAS9. Decrease of PAX5 expression was associated with reduction in CD19 expression and a concurrent reduction in phospho-BTK (Bruton tyrosine kinase). Conversely, overexpression of SOX11 could rescue PAX5/CD19 expression and restore p-BTK levels. Furthermore, the treatment of SOX11 expressing cells with small molecule SOX11-specific inhibitors resulted in a reduction in PAX5, CD19 and BCR activation (p-BTK).
Conclusion: Taken together, these findings delineate PAX5 as the direct target and PAX5/CD19 axis as the downstream pathway by which SOX11 regulates B-cell receptor (BCR) signaling in MCL. Notably, our treatment using a SOX11 inhibitor successfully replicated the effects observed with genetic knockdown. In conclusion, our findings provide valuable insights into the molecular mechanisms by which SOX11 contributes to MCL pathogenesis. The further development of pharmacological inhibitors targeting SOX11 holds promise as a beneficial therapeutic strategy for MCL patients, as these will block signaling upstream of current resistance mechanisms.
Citation Format: Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Yang Liu, Jian Jin, Michael Wang, Samir Parekh. SOX11 regulates BCR signaling via the PAX5/CD19 axis in MCL [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 649.
Abstract 6520: Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients
Authors: Goto Wataru , Matsuda Hanae , Henmi Saeko , Nishikawa Mariko , Kouchi Asuka , Kouhashi Rika , Yabumoto Akimichi , Takada Koji , Tauchi Yukie , Ogisawa Kana , Morisaki Tamami , Kashiwagi Shinichiro 
Published: March 2024

Abstract
Background: Recently, some basic research has reported that the tumor immune microenvironment (TIME) is related to the therapeutic efficacy and prognosis of breast cancer patients, and that the regulation of metabolism can affect TIME and enhance antitumor immunity. Suppression of aromatase expression from adipose tissue is the standard adjuvant endocrine therapy for postmenopausal hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, but few studies have examined the impact of controlling lipid metabolism on TIME and cancer prognosis.
Materials and Methods: Except for patients with ductal carcinoma in situ, 531 postmenopausal HR-positive/HER2-negative breast cancer patients treated with curative surgery between 2011 and 2017 were examined. Serum lipid levels and systemic immune-related markers were evaluated by blood samples, and tumor-infiltrating lymphocytes (TILs) in cancer tissue samples were investigated by immunohistochemistry. We also examined the relationship between lipid metabolism, TIME, and prognosis, respectively.
Results: Good serum lipid control group was significantly correlated with low neutrophil- to-lymphocyte ratio (NLR) (p = 0.024) and high TILs (p = 0.039). The median follow-up time for the assessment of prognosis was 5.5 years, and 67 patients had recurrence. Only patients treated with aromatase inhibitor as adjuvant endocrine therapy showed significantly better recurrence-free survival (RFS) in the good lipid control group (p = 0.025, log-rank). Also, multivariate analyses showed that good serum lipid control was an independent prognostic factor for recurrence (HRs = 4.722, 95%CI: 1.006-22.161, p = 0.049). Patients with high CD8/FOXP3 ratio (CFR) had significantly better RFS (p=0.027, log-rank) and tended to have good lipid control.
Conclusions: Good control of serum lipid metabolism may inhibit the acquisition of resistance to endocrine therapy by improving TIME and induce favorable outcome in postmenopausal HR-positive/HER2-negative breast cancer patients.
Citation Format: Wataru Goto, Hanae Matsuda, Saeko Henmi, Mariko Nishikawa, Asuka Kouchi, Rika Kouhashi, Akimichi Yabumoto, Koji Takada, Yukie Tauchi, Kana Ogisawa, Tamami Morisaki, Shinichiro Kashiwagi. Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients [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 6520.
Abstract 6532: Blockade of CD24 sensitizes pancreatic cancer to Kras inhibitors
Authors: Wei Yongkun , Liu Minghui , Yen Er-Yen , Yao Jun , Nguyen Phuoc T. , Wang Xiaofei , Yang Zecheng , Yousef Abdelrahman , Pan Dean , Jin Yanqing , Theady Madelaine S. , Park Jangho , Cai Yiming , Takeda Mitsunobu , Vasquez Matthew , Zhou Yong , Zhao Hong , Viale Andrea , Wang Huamin , Zhao Dan , DePinho Ronald A. , Yao Wantong , Ying Haoqiang 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by KRAS oncogene. KRAS, long considered an undruggable target, has been targeted by drugs including a KRASG12C inhibitor (G12Ci), AMG 510, which is approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC). AMG 510 also exhibited promising anticancer activity in human PDAC, with 21% response rate and over 70% patients experiencing certain level of tumor control. However, targeting KRAS oncogenes faces the major challenge of therapy resistance, which severely limited its survival benefit. While multiple studies have elucidated potential resistance mechanisms to G12Ci in lung cancer, the molecular mechanisms underlying resistance in PDAC remains elusive. Here, using KRASG12C-driven mouse PDAC model, we found that similar to the clinical observation, KRASG12C tumors exhibit only partial response to AMG 510 treatment. CyTOF analysis indicates that such tumor persistence following G12Ci treatment occurs even in the presence of conversion from a ‘cold’ pro-tumor immune microenvironment to a ‘hot’ anti-tumor immune environment, as evidenced by the prominent increase in both cytotoxic T cells and M1-like macrophages. Interestingly, we discovered that the expression of CD24, which was recently identified as a new ‘do not eat me’ signal, is significantly upregulated on the surface of persist tumor cells after G12Ci treatment which suppresses the function of anti-tumor macrophages. Anti-CD24 blocking mAb enhanced macrophage-mediated phagocytosis in vitro and significantly sensitizes KRASG12C tumors to AMG 510 treatment in vivo in a macrophage-dependent manner. Similar findings were observed in KRASG12D-driven PDAC model. Our findings identified a novel immune combination to improve the outcome of KRAS targeted therapy in PDAC.
Citation Format: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Madelaine S. Theady, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Yong Zhou, Hong Zhao, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying. Blockade of CD24 sensitizes pancreatic cancer to Kras inhibitors [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 6532.