tbuckley/cabot-search huggingface dataset:
Abstract 4005: HER2 TKIs enhance the anti-tumor activity of HER2-targeting CAR-T and CAR-NK cells against NSCLC
Authors: Yan Yang, Monique B. Nilsson, Alissa Poteete, Junqin He, Qian Huang, John V. Heymach
Journal: Cancer Research (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 5742: Therapeutic efficacy of CA102N in pancreatic cancer
Authors: Louis Lin, Shuling Tu, Eskouhie Tchaparian
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer to treat due to its aggressive nature and late-stage diagnosis. Considering the lack of effective therapies, there is an urgent need to develop new and effective therapeutics to improve the prognosis of patients. CA102N is a carrier-mediated novel anticancer product where hyaluronic acid is conjugated to Nimesulide-NH2. CA102N is currently under development for the treatment of solid tumors, including colorectal cancer. CA102N was safe and well tolerated in the first-in-human trial in patients with locally advanced or metastatic solid tumors. In the present study, the in vitro anticancer activity of CA102N was investigated in K-ras mutant PANC-1 pancreatic cancer cells. The antitumor efficacy was also tested in vivo in the PANC-1 mice model. Results demonstrated that CA102N inhibits cell growth, cell migration, angiogenesis, and cell proliferation in both K-ras mutant PANC-1 pancreatic cancer cells or tumors. Administration of CA102N in PANC-1 xenografts resulted in a dose-dependent and statistically significant decrease in tumor growth at 9.8 mg/kg and 14.7 mg/kg Nim equivalents, respectively, compared to the vehicle control group. A significant decrease (80%) in liver metastasis was also noted in the PANC-1 orthotopic mice model at 19.6 mg/kg Nim equivalents dose level. Mechanistically, CA102N was found to suppress the PI3k/Akt/mTOR and Raf/MEK/ERK signaling pathways, in addition to reducing the expressions of the N6-methyladenosine (m6A) reader and writer proteins, OCT3/4 transcription factor and RAS levels in vivo. CA102N also modified the tumor stroma and improved drug permeability in vivo. Based on this compelling data, CA102N shows promise as a potential treatment for pancreatic cancer. Combination therapies and regimens are currently being explored in in vivo models as a strategy for clinical development. Citation Format: Louis Lin, Shuling Tu, Eskouhie Tchaparian. Therapeutic efficacy of CA102N in pancreatic cancer [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 5742.
Abstract 947: A nanodroplet cell processing platform for identifying synergistic drug combinations for neuroblastoma treatment in TH-MYCN transgenic mice
Authors: Yen-Tzu Liao, Zhi-Kai Yu, Ching-Te Kuo, Wen-Ming Hsu, Yi-Xun Huang, Hsinyu Lee
Journal: Cancer Research (2024)

Abstract Neuroblastoma is the most common pediatric extracranial solid tumor and contributes to more than 15% of child mortality. It is characterized by extreme heterogeneity and high-risk tumors often resulting in poor prognosis. Currently, chemotherapy is a prevailing standard treatment for neuroblastoma. However, it is plagued by multiple challenges such as drug resistance and debilitating side effects. Synergistic drug combination is proposed as an innovative approach to potentially improve clinical outcomes of single-agent chemotherapy. We propose a novel approach to screen for effective chemo-synergistic drug combinations using Bioinspired nanodroplet processing (BioNDP) screening platform. This platform overcomes the limitations of conventional drug screening approaches, including the requirement for large cell numbers and the low translation rate from bench to bedside. In this study, we utilize TH-MYCN transgenic mice, a well-known genetically engineered mouse model of neuroblastoma that recapitulates critical genetic and clinical aspects of high-risk MYCN-amplified neuroblastoma. With its genetically homogeneous background and spontaneous tumor development, TH-MYCN mice offer a valuable comparison to traditional xenograft mouse models. We have also developed an optimal procedure of primary murine tumor isolation using both negative and positive selection approaches. The purity of the isolated cells was verified with GD2 expression, one of well-known marker of neuroblastoma. In addition, we have successfully identified an effective drug combination of cyclophosphamide, doxorubicin, and vincristine, using primary neuroblastoma tumor samples derived from TH-MYCN transgenic mice as a target. The in vitro synergistic effect of primary mouse tumor cell cytotoxicity was confirmed by using luminescent cell viability assay. Further in vivo experiments have demonstrated the therapeutic efficacy of this selected drug combination in suppressing tumor growth and improving survival rate in all TH-MYCN transgenic mice treated. To sum up, we aim to establish a future patient-centric paradigm by which minimal primary cell samples from a personalized biopsy of patients may undergo drug screening, leading to the identification of a tailored drug combination. The BioNDP platform we developed may become a pivotal resource for personalized therapy to ensure a faster and more efficient treatment strategy for patients. Citation Format: Yen-Tzu Liao, Zhi-Kai Yu, Ching-Te Kuo, Wen-Ming Hsu, Yi-Xun Huang, Hsinyu Lee. A nanodroplet cell processing platform for identifying synergistic drug combinations for neuroblastoma treatment in TH-MYCN transgenic mice [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 947.
Abstract 2477: Selective IL-21 and IFN-alpha immunocytokines engineered using the AlphaSeq platform
Authors: Charles Lin, Colleen Shikany, Leah Homad, Jessica Fint, Ruchi Bansal, Davis Goodnight, Jeff Adamo, Danielle Van Citters, Ryan Swanson, Randolph Lopez
Journal: Cancer Research (2024)

Abstract Although cytokine therapies have demonstrated curative effects in some cancer patients, clinical use remains limited due to undesired toxicity profiles accompanying systemic administration. Next generation cytokine approaches include conditional signaling focused on sites of interest, such as the tumor microenvironment or specific immune cell populations. Here, we share a novel approach for generating detuned cytokine therapeutic candidates using the AlphaSeq platform, which involves the re-engineering of yeast agglutination and mating to quantitatively measure protein-protein interactions at a library-on-library scale. Engineering interferon-alpha (IFNα) and interleukin-21 (IL-21), we show how AlphaSeq measures cytokine-receptor interactions and identifies cytokine variants with a broad range of affinities. A saturated mutational library was created for IFNα and IL-21and subsequently screened against a second library consisting of human IFNAR2 or human IL-21R, species orthologs and off-target receptors. AlphaSeq enabled identification of hundreds of detuned IFNα and IL-21 variants against both human and mouse receptors in parallel assays. Cytokine variants with lower affinity than parental IFNα or IL-21 were recombinantly expressed as Fc fusion proteins to orthogonally measure affinity with biolayer interferometry and characterize potency with an in vitro human PBMC phosflow assay, which showed strong correlation with AlphaSeq affinity measurements. Finally, detuned cytokine candidates were fused to anti-CD8 and other localizing antibodies to demonstrate cell population-specific signaling. Candidate molecules showed 1000-fold or greater potency in the targeted cell population than non-targeted populations. Our results show the AlphaSeq platform can accurately quantitate thousands of cytokine variant affinities simultaneously against multiple relevant receptors, enabling the selection of candidate immunocytokine antibody fusion proteins with targeted cell biased signaling. AlphaSeq’s rapid, comprehensive affinity determination is being used to develop clinically relevant IFNα and IL-21 therapeutic immunocytokines with accompanying preclinical data. Citation Format: Charles Lin, Colleen Shikany, Leah Homad, Jessica Fint, Ruchi Bansal, Davis Goodnight, Jeff Adamo, Danielle Van Citters, Ryan Swanson, Randolph Lopez. Selective IL-21 and IFN-alpha immunocytokines engineered using the AlphaSeq platform [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 2477.
Abstract 6262: Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid cancer
Authors: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Nabil Siraj, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya
Journal: Cancer Research (2024)

Abstract Background: Differentiated Thyroid Cancer (DTC) has an indolent nature and generally has favorable prognosis. AJCC TNM classification is the most adopted system to evaluate the biological behavior of DTC. Age cut-off of 55 years has been included in the eighth edition of TNM staging system since it led to better prediction of disease specific survival (DSS) of patients with DTC. However, optimal age cut-off in DTC patients from Middle Eastern ethnicity has not been fully explored. We evaluated the optimal age cut-off for the TNM staging system to predict DSS in Middle Eastern patients with DTC. Methods: We retrospectively analyzed a large cohort of 1721 adult DTC patients who underwent surgery between 1990 to 2018. The optimal age cut-off value was determined using several age cut-offs (between 20 and 85 years) to assess DSS. Harrel’s C-Index, Akaike information criterion (AIC) and Bayesian Information Criterion (BIC) were used to assess the statistical model performance of the TNM staging system (eighth edition), with different age cut-offs for prediction of DSS. The proportion of variation explained (PVE) was also calculated to compare predictability of DSS in patients with DTC. Results: The median age of patients at diagnosis was 39.9 years (IQR 31.0 - 51.7 years) and 75.5% (1299/1721) were female. Median follow up was 9.3 years and 10 years DSS was 97.1%. For DTC overall, an age cut-off of 50 years had the best statistical model performance. On receiver operating characteristic curve analysis, the optimal age cut-off for prediction of DSS was 50.5 years (area under the curve = 0.872, p &amp;lt; 0.0001). Conclusion: In this large cohort of Middle Eastern DTC patients, an age cut-off of 50 years was more appropriate for TNM staging to achieve better predictability for DSS. Therefore, implementation of different age cut-off for DTC in Middle Eastern patients could improve the predictive value for TNM staging system, and allow for better therapeutic and surveillance approach for these patients. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Nabil Siraj, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya. Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid cancer [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 6262.
Abstract 6107: Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer Database
Authors: Rachel C. Chang, Elise K. Brunsgaard, David Reid
Journal: Cancer Research (2024)

Abstract Introduction: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer whose incidence and survival outcomes demonstrate disparities based on patients’ socioeconomic status (SES). This study aims to evaluate the impact of SES on MCC diagnosis age, comorbidity burden, treatment modalities, and survival outcomes using the National Cancer Database. Methods: We conducted a retrospective analysis of 9742 patients diagnosed with MCC from 2016 to 2020 in the United States. To assess how socioeconomic status influences outcomes, a composite score was created by adding income and education quartile assignments (1, 2, 3, 4), to create new composite SES quartiles of 2-3, 4-5, 6-7, and 8. Patients were stratified into quartiles based on their SES (lowest Q1 to highest Q4). Binomial test was performed for categorical variables and ANOVA was performed for continuous. Survival differences were examined with Cox proportional hazards models and Kaplan-Meier curves. Results: Patients with lower SES presented with MCC at younger ages, with the average age of patients in the lowest SES Q1 being 73.8 years (95% CI 73.15-74.35) and the highest SES Q4 being 75.0 years (95% CI 74.48-75.46). Patients in SES Q1 also had higher Charson-Deyo scores, indicating more comorbidities than patients in SES Q4 (8.41% vs 5.8%, p &amp;lt; 0.001). They were also more likely to have advanced stage 4 MCC (9.67% vs 7.79%, p &amp;lt; 0.01) compared to patients in SES Q4. When treated with surgery, patients in SES Q1 were more likely to be treated with local tumor excision (14.39% vs 10.83%, p &amp;lt; 0.001) whereas patients in SES Q4 were more likely treated with Mohs surgery (5.02% vs 3.56%, p &amp;lt; 0.01). Survival probabilities for patients SES Q1 were worse at 1 year (82.99% vs 85.81%, p&amp;lt;0.001), 3 years (61.18% vs 68.49%, p &amp;lt; 0.001) and 5 years (45.99% vs 55.09%, p &amp;lt; 0.001) compared to patients in SES Q4. Conclusion: This study highlights disparities in age at diagnosis, comorbidities, treatment, and survival outcomes in MCC patients based on SES. Patients in lower SES quartiles are diagnosed younger, bear higher comorbidity burdens, and have worse rates of survival. Citation Format: Rachel C. Chang, Elise K. Brunsgaard, David Reid. Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer Database [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 6107.
Abstract 3264: Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer
Authors: Neeraj Joshi, Ramona Graves Deal, Galina Bogatcheva, James N. Higginbotham, Marisol Ramirez, Benjamin P. Brown, Qi Liu, Jens Meiler, Bhuminder Singh
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in the United States (US). Individuals with surgically unresectable stage four CRC have a five-year overall survival rate of 13%. Targeting of the receptor tyrosine kinase (RTK), EGF receptor (EGFR) with therapeutic monoclonal antibodies (cetuximab, panitumumab) is approved for use in wild-type (WT) KRAS/NRAS/BRAF (RAS/RAF) advanced CRC. However, these antibodies as a single agent have response rates of 12-17% and expected progression-free survivals of only 3-4 months. Accordingly, resistance may be present at the outset (de novo resistance) or develop during treatment (acquired resistance). Here, we report the identification of an EGFR ectodomain missense mutation acquired in vitro in response to treatment with anti-epidermal growth factor receptor (EGFR) antibody cetuximab. Using 2D and 3D drug sensitivity assays, our results demonstrate that this EGFR ectodomain mutation in addition to being resistant to cetuximab and panitumumab, also could not be targeted by the oligoclonal antibody cocktail MM-151. To determine whether this EGFR ectodomain mutation is necessary and sufficient to impart cetuximab resistance, we engineered CRC lines to inducibly overexpress mutant EGFR and showed that this was sufficient to induce cetuximab resistance. Further structural, and functional characterization is underway for this ectodomain mutation that confers resistance to cetuximab and will be shared during the meeting. These findings necessitate the need for additional treatment strategies for a subset of subjects with mCRC who do not respond to treatment with cetuximab/panitumumab and MM-151. Citation Format: Neeraj Joshi, Ramona Graves Deal, Galina Bogatcheva, James N. Higginbotham, Marisol Ramirez, Benjamin P. Brown, Qi Liu, Jens Meiler, Bhuminder Singh. Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer [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 3264.
Abstract 353: Investigate the role of homoharringtonine in treating B-cell acute lymphoblastic leukemia
Authors: Emilie An An Jiao, Kei Ching Yuen, Bai Lin Li, Chun Fung Sin
Journal: Cancer Research (2024)

Abstract B lymphoblastic leukemia (B-ALL) is an aggressive and highly lethal hematolymphoid malignancy and it is the most common cancer in children. Although the incidence of B-ALL in adult is lower than that in children, adult patients with B-ALL have a poor prognosis. Relapse/refractory disease is still the main cause of death in B-ALL patients. Homoharringtonine (HHT) is a plant alkaloid that was approved to treat chronic myeloid leukemia (CML) by FDA. Herein, we aimed to investigate the anti-leukemic activity of HHT in B-ALL. Cell viability was reduced in a time and dose-dependent manner upon treatment with HHT. Moreover, HHT was able to induce apoptosis in B-ALL cell lines by downregulating the MCL-1 protein level after 24 hours of treatment. Cell cycle analysis indicated G1 phase arrest, and western blot analysis demonstrated downregulation of CDK-4 and CDK-6. A proteomics study using label-free protein quantitation revealed enrichment of proteins involved in fatty acid oxidation, and further analysis showed downregulation of acyl-CoA desaturase after HHT treatment. Additionally, HHT significantly reduced the leukemic burden and prolonged survival in NSG mice injected with the PALL-2 cell line. Overall, the findings suggest that HHT is effective in treating B-ALL by inducing cell cycle arrest, with a potential inhibitory effect on fatty acid oxidation. Further studies will be conducted to evaluate the mechanism of modulation of fatty acid oxidation. Citation Format: Emilie An An Jiao, Kei Ching Yuen, Bai Lin Li, Chun Fung Sin. Investigate the role of homoharringtonine in treating B-cell acute lymphoblastic leukemia [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 353.