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  • American Association for Cancer Research (AACR)  (36)
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  • 11
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    Online Resource
    Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET -Rearranged Lung Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 10 ( 2015-10-01), p. 2238-2248
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 10 ( 2015-10-01), p. 2238-2248
    Abstract: RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0–G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. Mol Cancer Ther; 14(10); 2238–48. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-15-0350
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 12
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    Abstract 1826: Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeutic antibody candidate with bispecific immuno-oncology target
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1826-1826
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1826-1826
    Abstract: Introduction: GI-101 was designed to address the significant unmet needs in immunotherapy for noninflamed tumor. The harmonized mechanisms of action consist of the extracellular domain of CD80 acting as a CTLA-4 inhibitor, together with a long-acting IL-2 variant that preferentially binds to the IL2Rβ. Therefore, GI-101 can play a role in the activation of cytotoxic immune cells and inhibition of CTLA-4-B7.1 axis-based immune suppression. Methods: The binding affinity of GI-101 to IL-2Rs, CTLA-4, and CD28 was performed by SPR and immune cell proliferation was analyzed by CFSE assay in vitro. GI-101 induced dose-dependent pharmacodynamics effects with consistent magnitude following repeat administration in monkeys. Direct anti-tumor effect of GI-101 was tested by single or combination treatment manner in multiple syngeneic and humanized models. Immune profiling in TME was analyzed by flow cytometry, IHC and IFN-γ ELISPOT assay. To mimic the standard care (SOC) in clinic, TC1 lung cancer model was involved in evaluating the efficacy of both 1st line and maintenance therapy of GI-101 with or without immuno-chemotherapy (Cisplatin, Pemetrexed, and anti-PD-1). Results: CD80 of GI-101 highly binds to CTLA-4 (Kd, 2.9nM), acting as a decoy ligand. IL-2 variant induces CD8+ T and NK cell proliferation. However, GI-101 had no evidence of toxicity related to IL-2 activity in the non-GLP monkey study, including vascular leakage syndrome and cytokine storm. GI-101 elicits improved restoration of immune functions in human PBMCs co-cultured setting with PD-L1/CTLA-4 co-expressed tumor cells. A dose-dependent (3 to 12 mg/kg) single inhibition of tumor growth was observed in CT26 syngeneic model. Immune profiling revealed a robust increase of M1 macrophages, CD8+ central memory T (Tcm) and NK cells but not Tregs in TME. Splenocyte tumor-specific immune cells were strongly proliferated when stimulated with CT26 neoantigens (gp70). IFN-γ+ T cells were significantly increased in draining lymph nodes from GI-101 treated mice. Furthermore, GI-101 was superior at inhibiting tumor growth when co-treated with anti-PD-1 in syngeneic (MC38, TC1, and B16F10) and MDA-MB-231 humanized mice models. Finally, the combination of GI-101 and immuno-chemotherapy showed not only suppressed tumor growth but also improved survival compared to immuno-chemotherapy alone. Conclusion: The complementary modes of action of GI-101 via checkpoint blockade and IL-2 activity to enhance the proliferation and activation of Tcm and NK cells are projected to translate into superior clinical efficacy and safety as indicated even in ‘cold tumor' models. GI-101 has promising potential to replace the first-generation ICBs as a monotherapy or in combination with other immunotherapies. Our findings provide a rationale for further clinical investigations. Citation Format: Kyoung-Ho Pyo, Young Jun Koh, Chun-Bong Synn, Jae Hwan Kim, Youngseon Byeon, Ha Ni Jo, Young Seob Kim, Wongeun Lee, Do Hee Kim, Seul Lee, Dong Kwon Kim, Eun ji Lee, Beung-Chul Ahn, Min Hee Hong, Myoung Ho Jang, Sun Min Lim, Hye Ryun Kim, Su Youn Nam, Byoung Chul Cho. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeutic antibody candidate with bispecific immuno-oncology target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1826.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1826
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 13
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    Phase II Clinical and Exploratory Biomarker Study of Dacomitinib in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 3 ( 2015-02-01), p. 544-552
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 3 ( 2015-02-01), p. 544-552
    Abstract: Purpose: The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). Experimental Design: Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16INK4A expression by IHC, and investigation of their relationship with clinical outcomes. Results: Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9–5.0] and 6.6 months (95% CI, 5.4–10.3). Adverse events were mostly grade 1–2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005). Conclusions: Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib. Clin Cancer Res; 21(3); 544–52. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1756
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 14
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    Abstract 5061: Molecular mapping of prostate cancer on whole mount prostatectomy specimens using deep neural networks to quantify genotypic heterogeneity
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5061-5061
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5061-5061
    Abstract: Most primary prostate cancers are multifocal, with multiple genomically independent tumors identified in up to 80% of men undergoing radical prostatectomy for clinically localized disease. The heterogeneity in prostate cancer and the clinical significance of secondary tumors have been explored. However, studies to date have been limited to analyzing prostate biopsies or sections using dominant tumor foci only, not allowing for the evaluation of the inter and intra tumor molecular heterogeneity of the prostate cancer landscape. Recently, we identified mutually exclusive expression patterns of more than one driver molecular aberration in distinct tumor foci. Here, we present a quantitative analysis of tumors with distinct markers and correlate with clinical outcomes. We developed a model to quantify cancerous regions and genotype expression on immunohistochemical (IHC) slides. Our algorithm combines multiple modeling strategies, including deep neural networks and color deconvolution. Dual ERG/SPINK1 IHC staining was performed on whole mount prostatectomy slides. Patches from corresponding slides stained with Hematoxylin/eosin (H & E) were generated to train the model. A color devolution method was used to separate the patches into H & E and other stain channels. For evaluation, patches were generated from IHC slides, which were then transformed into Hematoxylin-only stained patches. Sample patches were analyzed for detection of cancerous regions at the pixel-level. The ratios of cancerous regions were calculated. Our segmentation results were compared with the area positive for ERG or SPINK1. For the ERG stain, the model demonstrated a sensitivity of 62.72% per pixel, whereas it was associated with a sensitivity of 48.37% per pixel for SPINK1. This represents a robust performance for a proof-of-concept model, and sensitivities are expected to improve significantly with additional annotations. To investigate the entire landscape of whole mount samples, training to include recognition of morphological variations such as HGPIN is underway and expected to also increase sensitivity. More detailed analysis will be shared at the time of presentation. We present here a quantitative analysis model that reveals unprecedented details on tumor heterogeneity with respect to molecular markers and tumor localization. To our knowledge, this is the first study on quantitative molecular mapping of cancer and biomarker expression using whole mount samples. The marker expression in each tumor foci can be correlated with clinicopathologic findings. Different molecular subtypes presented with more than one driver molecular aberration in distinct tumor foci may be associated with distinct clinical outcomes such as biochemical recurrence or metastasis, allowing for predicting disease progression and targeted approaches for effective prostate cancer management. Citation Format: Joonyoung Cho, In Hye Suh, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang, Nallasivam Palanisamy. Molecular mapping of prostate cancer on whole mount prostatectomy specimens using deep neural networks to quantify genotypic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5061.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5061
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 15
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    Abstract LB544: Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB544-LB544
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB544-LB544
    Abstract: Introduction: Acquired resistance to ALK-tyrosine kinase inhibitors (ALK-TKIs) treatment, particularly target-off resistance, remains a clinical challenge for ALK-rearranged non-small cell lung cancer (NSCLC). To explore novel vulnerabilities of ALK TKI-resistant cancer cells, we focused on their distinct metabolic pathways for growth and survival. Experimental Design: To investigate metabolic pathways in resistance mechanisms, we generated ALK-TKIs -acquired-resistant in vitro/vivo models. We screened metabolite mechanisms using metabolite assay kit, Seahorse Extracellular Flux Analyzer, real-time PCR, western blot, RNA-seq in resistant models. Results: Through an integrated transcriptomic and metabolic assay screening approach, we identified the enhanced reliance on glutamine metabolism in target-off ALK-TKIs-resistant cells. Specifically, resistant cells were characterized by upregulation of glutaminase 1 (GLS1), a mitochondrial enzyme hydrolyzing glutamine into glutamate, simultaneously with downregulation of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this metabolic state intensively accelerates glutaminolysis and subsequent mitochondrial glutamine-derived aspartate synthesis, resulting in TKI resistance by reinforcing antioxidant capacity with increase of NADPH and glutathione. Mechanistically, GLS1 inhibition elicited a marked reduction of cell growth with increase of reactive oxygen species (ROS) in resistant cells, which was restored by supplementation of exogenous aspartate. The antitumor activity of GLS1 inhibition against resistant tumor cells was further validated in in vivo experiments, patient-derived xenograft (PDX) and EML4-ALK transgenic mice. More importantly, glutaminase inhibitor CB-839 enhanced the therapeutic efficacy of anti-PD-L1 treatment in immune checkpoint blockade (ICB)-resistant EML4-ALK transgenic mice. Conclusion: Our findings highlight a new metabolic vulnerability of ALK-TKIs resistant tumors and provide a rationale for targeting GLS1 as a potential treatment option to overcome ALK-TKIs resistance. Citation Format: You Won Lee, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, Seong Gu Heo, Sun Min Lim, Min Hee Hong, Chang Gon Kim, Hye Ryun Kim, Mi Ran Yun, Byoung Chul Cho. Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB544.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB544
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 16
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    Abstract 161: Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 161-161
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 161-161
    Abstract: Purpose Cancer is one of the leading causes of death worldwide. Patient-derived tumor cells can serve as a powerful resource for studying pathophysiologic mechanisms and developing robust strategies for precision medicine. To address this problem, we launched the patient-derived organoids (PDOs) Hub to establish a comprehensive model of various tumor organoids from pancreatic, biliary tract, liver, colorectal, breast, gastric, ovarian, and oral cancers, with matching clinical data and molecular characteristics. Methods All specimens were collected from histologically confirmed cancer patients at the National Cancer Center. Samples obtained from surgery, biopsy, or body fluid (malignant ascites or pleural effusion) were collected for ex vivo culture of tumor cells. PDOs were managed according to our standard operating procedure (SOP), which included specimen delivery process, separation of cells from tissues, criteria for subculture, quality control (QC), production of genomic and histologic data, and the 384-well-based drug response evaluation system. Organoids were considered to be successfully cultured when they were maintained for five or more passages. Results A total of 263 PDOs were established from various cancer types, including oral cancer (N = 89), pancreatic cancer (N = 48), ovarian cancer (N = 32), breast cancer (N = 30), biliary tract cancer (N = 29), hepatocellular carcinoma (N = 17), gallbladder cancer (N = 8), gastric cancer (N = 7) and colorectal cancer (N = 3). PDOs broadly recapitulated the histologic and genetic characteristics of the patient’s tumor. These organoids available for long-term culture were cryopreserved, and a total of 2986 stocks have been accumulated. Drug screening tests were performed with 60 PDOs (pancreatic cancer, N = 36; breast cancer, N = 15; ovarian cancer, N = 6; gastric cancer, N = 3) using selected agents among the 47 drugs for each type of cancer. Profiles of cytotoxic agents were well correlated with the patient’s clinical responses to the matched drugs and tested investigational agents also showed promising antitumor activity. Conclusions We have established a model of several human cancer organoids. This will serve as the platform that can recapitulate the physiology and drug response profiles of human cancer and pave the way for screening innovative drugs, identifying novel targets, and stratifying patients for pertinent therapeutic options. (This work was supported by National Research Foundation of Korea grant, funded by the Korean government (MSIT) (No. 2020M3A9A5036362)) Citation Format: Yebeen Yu, Mi Rim Lee, Wonyoung Choi, Sumin Kang, Jeong Eun Gong, Soobeen Heo, Hye Ju Park, Sang Myung Woo, So-Youn Jung, Sung Weon Choi, Jong-Ho Lee, Myong Cheol Lim, Ji Yeon Baek, Bo Hyun Kim, Ji Hoon Kim, Yuri Cho, Sang-Jae Park, Yun-Hee Kim, Sun-Young Kong. Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 161.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-161
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 17
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    Abstract 713: Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 713-713
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 713-713
    Abstract: Purpose: Regulatory T (Treg) cells perform the immune suppressive function in cancer, but their suppressive mechanism in tumor microenvironment (TME) has not been clearly elucidated. We aim to identify the phenotype and functional mechanism of Treg cells in TME from cancer patients. Experimental Design: We collected 72 malignant effusion (ME) and peripheral blood (PB) specimens from stage IV cancer patients and 10 tumor tissue (TM) and PB from lung cancer patients who underwent surgery. Lymphocytes from ME, TM, and PB were analyzed for subtype of Tconv and Treg cells, and their expressions of immune checkpoint (IC) molecules including programmed death (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and T cell immunoglobulin containing molecule-3 (TIM-3) using by flow cytometry. To examine the functional role of PD-1 expressed Treg cells, TC-1 lung cancer mouse model was used. Result: Upregulation of PD-1 on Treg cells in TM and ME compared to PB was even more distinguishable than that on CD4+ and CD8+ Tconv cells. To clarify the characteristics of tumor infiltrating Treg cells, we comprehensively examined the characteristics of Treg cells from tumor, peri-tumor, and PB in lung cancer patients by analyzing the expression of IC molecules including PD-1, TIM-3, CTLA-4, and TIGIT, of which PD-1 is the highest expressed on tumor infiltrating Treg cells. To investigate the mechanism by which Treg cells mediate immune suppression, we compared the suppressive activity of Treg cells expressing high and low levels of PD-1 by co-culturing each population with naïve CD8+ T cells with or without αCD3/CD28 stimulation. This was more potently inhibited in co-cultures with PD-1high tumor infiltrating Treg cells than in those with PD-1low Treg cells. PD-1 blocked tumor infiltrating Treg cells demonstrated a significantly decreased suppressive function in the proliferation of CD8+ cells and their IFN-γ production. These results implicate that PD-1 expressed tumor infiltrating Treg confers the suppressive function of proliferation in CD8+ T cells through PD-1: PD-L1 interaction. Conclusion: Our study evidently demonstrated that upregulated PD-1 on tumor infiltrating Treg cells and their PD-1: PD-L1 interaction could be potential cause of T cell suppression, which might be helpful to completely understand their suppressive mechanism in cancer patients. Citation Format: Hye Ryun Kim, Hyo Jin Park, Jimin Son, Hyo Sup Shim, Byoung Chul Cho, Sun Young Rha, Sang-Jun Ha. Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 713.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-713
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 18
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    EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E–Mutant NSCLC Cell Lines
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 7 ( 2016-07-01), p. 1627-1636
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2016-07-01), p. 1627-1636
    Abstract: Although treatment of BRAF V600E–mutant non–small cell lung cancer (NSCLCV600E) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLCV600E, we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLCV600E to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR–RAS–CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF–CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo. Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLCV600E with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627–36. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-15-0375
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 19
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    Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 8 ( 2020-08-01), p. 1194-1209
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 8 ( 2020-08-01), p. 1194-1209
    Abstract: EGFR exon 20 insertion driver mutations (Exon20ins) in non–small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR–MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft models harboring diverse Exon20ins were used to characterize the antitumor mechanism of amivantamab. Amivantamab inhibited proliferation by effectively downmodulating EGFR–MET levels and inducing immune-directed antitumor activity with increased IFNγ secretion in various models. Importantly, in vivo efficacy of amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins-targeted TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work. These findings provide mechanistic insight into the activity of amivantamab and support its continued clinical development in Exon20ins patients, an area of high unmet medical need. Significance: Currently, there are no approved targeted therapies for EGFR Exon20ins–driven NSCLC. Preclinical data shown here, together with promising clinical activity in an ongoing phase I study, strongly support further clinical investigation of amivantamab in EGFR Exon20ins–driven NSCLC. This article is highlighted in the In This Issue feature, p. 1079
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-0116
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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  • 20
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    Abstract B032: CD161+ TRM cells counteract HPV-associated clinical benefits in oropharyngeal cancer immunotherapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Immunology Research Vol. 11, No. 12_Supplement ( 2023-12-01), p. B032-B032
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 11, No. 12_Supplement ( 2023-12-01), p. B032-B032
    Abstract: Oropharyngeal squamous cell carcinoma (OPSCC) is a prevalent subtype of head and neck cancer representing one of the largest diagnosed malignancies worldwide. A distinct subtype of OPSCC induced by Human Papilloma Virus (HPV) is well known to favor beneficial clinical outcomes in cancer treatment compared to HPV-negative OPSCCs. However, HPV-positive OPSCCs in the context of immunotherapy remains unclear, as no distinct benefits are observed in clinical trials. In this study, we performed single-cell RNA and T cell receptor sequencing analyses of 20 tumor samples to dissect the cellular and molecular factors associated with viral infection and immunotherapy outcome. We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. This finding suggests heterogeneity of malignant cells negates immunotherapy response in HPV-positive OPSCCs. We also observed a significantly larger proportion of CD4+ follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8+ resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed significant association with dampened antitumor activity in HPV-positive OPSCC patients, which may explain their clinical heterogeneity. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Validation in an independent cohort confirms enhanced tertiary lymphoid structure activity in HPV-positive OPSCCs. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade confirmed an inverse correlation between the density of CD161+ Trm and changes in tumor size. These results suggest that targeted inhibition of CD161 in Trm may augment immunotherapy efficacy in HPV-positive oropharyngeal cancers. Citation Format: Junha Cha, Dahee Kim, Gamin Kim, Jae-Won Cho, Euijeong Sung, Seungbyn Baek, Min Hee Hong, Chang Gon Kim, Nam Suk Sim, Hyun Jun Hong, Jung Eun Lee, Martin Hemberg, Seyeon Park, Sun Ock Yoon, Sang-Jun Ha, Yoon Woo Koh, Hye Ryun Kim, Insuk Lee. CD161+ TRM cells counteract HPV-associated clinical benefits in oropharyngeal cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B032.
    Type of Medium: Online Resource
    ISSN: 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM23-B032
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2732517-9
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