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  • American Association for Cancer Research (AACR)  (27)
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  • 1
    Online Resource
    Online Resource
    Abstract 2857: Patient-derived cells (PDCs) and organoids (PDOs) as platforms for screening novel therapeutics for NSCLC
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2857-2857
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2857-2857
    Abstract: Purpose: Patient-derived cells (PDCs) and organoids (PDOs) are constructed from patient tissue to mimic the biological features of patients. In cancer research, PDC/PDOs have been crucial as they can recapitulate tumor mutations. As heterogeneity between traditional cell lines and the human body leads to clinical trial failure, PDC/PDOs are widely used for predicting the preclinical drug efficacy. The aim of this study is to show that the PDC/PDOs can be used as effective tools for screening novel therapies on non-small cell lung cancer (NSCLC). Experimental design: PDC/PDO models from malignant effusions were established as following. We succeeded the establishment with samples which are positive for malignancy in cytology tests and tumor colony formation. Genotypes are analyzed by Sanger sequencing, Whole exome sequencing, or RNA-sequencing. Cell viability assay was performed using currently approved drugs or drugs in clinical development or their combinations. Results: A total of 46 PDCs and 150 PDOs was established from NSCLC patients, including models harboring sensitizing EGFR mutations, ALK fusions, ROS1 fusions, EGFR exon20 insertion, BRAF V600E, and those harboring various resistance mechanisms to EGFR-TKIs (T790M, C797S/C797G, MET amplification), to ALK-TKIs (G1202R), and to ROS1 TKI (G2032R). Osimertinib-resistant YU-1097 harboring EGFR resistance mutation (E19del/T790M/C797S) revealed sensitivity to BLU-945 (IC50, 108nM), a novel fourth-generation EGFR-TKI. A similar inhibition of cell viability was observed with repotrectinib (IC50, 21nM), a next-generation ROS1-TKI and lorlatinib (IC50, 9nM) in YU-1078 harboring CD74-ROS1, whereas more robust tumor regression was seen with repotrectinib in YU1078-derived xenograft model. Amivantamab, a EGFR-MET bispecific antibody, showed a robust activity in YU-1163 and YUO-036 in vitro and in vivo. YU-1077 harboring ALK G1202R solvent-front mutation showed sensitivity to NVL-655, a next-generation ALK-TKI, with a potency & gt; 10-fold than that of lorlatinib. YUO-010 with MET amplification following osimertinib was sensitive to RGEN 5093-M114, a METxMET bispecific antibody-drug conjugate. Conclusions: PDC/PDO models can be utilized for evaluating activity of novel agents and will accelerate novel drug development in NSCLC. Citation Format: Yunjoo Joo, Sewon Park, Ju-hyeon Lee, Mi Ran Yun, Mi Ra Yu, Chun-Bong Synn, Seung Yeon Oh, Eun Ji Lee, Dong Kwon Kim, Seul Lee, Kyumin Lim, Min Hee Hong, Sun Min Lim, Chang Gon Kim, Ji Yun Lee, Jii Bum Lee, Byoung Chul Cho. Patient-derived cells (PDCs) and organoids (PDOs) as platforms for screening novel therapeutics for NSCLC [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 2857.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2857
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract 3234: OCT-598, a novel EP2/EP4 dual antagonist, promotes anti-tumor immune responses in syngeneic mouse tumor models in combination with standard-of-care chemo- and immunotherapies
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3234-3234
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3234-3234
    Abstract: Prostaglandin E2 (PGE2) is widely recognized as one of the major bioactive lipids that, with the striking regenerative potential, promote drug-resistance in cancer cells as well as immune evasion in the tumor microenvironment (TME). Primarily driven by apoptotic cell death, PGE2 is thought to elicit wound-healing responses to help provide an immunosuppressive and proliferative niche that supports cancer stem cell repopulation and thereby therapy-resistance. While COX1/2 inhibitors that attenuate PGE2 production have shown promising anti-cancer effects in various (pre-)clinical settings, the gastrointestinal- and cardiotoxicities precluded their development as anti-cancer agents. It is anticipated that specific targeting of PGE2 signaling via its cognate receptors constitutes a safer and potentially more effective approach. Of the receptor subtypes EP1-4, Gα,s-coupled EP2 and EP4 are believed to be directly involved in immunosuppressive effects of PGE2.OCT-598 is a novel, highly potent and selective EP2/EP4 dual antagonist with Ki values of 23 nM and 0.2 nM vs EP2 and EP4, respectively. PGE2 inhibited normal differentiation of human monocytes into CD1a+CD16- dendritic cells under the presence of GM-CSF and IL-4 and promoted differentiation towards CD1a-CD16+ macrophages in vitro. However, EP2/EP4 dual inhibition by OCT-598 reversed this phenomenon to a greater extent than either EP2- or EP4-specific inhibitor alone. In vivo, OCT-598 effected tumor growth inhibition in multiple syngeneic mouse models as a single agent as well as in combination with an immune checkpoint blocker (ICB). Furthermore, the addition of OCT-598 to the lung cancer standard-of-care regimen (anti-PD-1 plus chemotherapy) in TC-1 mouse lung adenocarcinoma model gave rise to complete tumor regression. In conclusion, dual blockade of EP2 and EP4 by OCT-598 is shown to be a compelling strategy to reinforce antitumor effects by thwarting PGE2-mediated therapy resistance and immune evasion.Findings from this study provide a rationale for clinical development of OCT-598 as a therapeutic option for human malignant cancers. Citation Format: Youngrae Lee, Sujeong Baek, Dong Kwon Kim, Yeri Lee, Donggeon Kim, Seongin Jo, Sang Kyun Lim, Young Sook Shin, Soonsang Kwon, Seung Min Yang, Young Taek Kim, Seong-San Kang, Chun-Bong Synn, Kwangmin Na, Mi Hyun Kim, Heekyung Han, Yu Jin Han, Sungwoo Lee, Jae Hwan Kim, Mi Ran Yun, Youngseon Byeon, Young Seob Kim, Ji Yun Lee, Jii Bum Lee, Chang Gon Kim, Min Hee Hong, Sun Min Lim, Kyoung-Ho Pyo, Byoung Chul Cho, Taeyoung Yoon. OCT-598, a novel EP2/EP4 dual antagonist, promotes anti-tumor immune responses in syngeneic mouse tumor models in combination with standard-of-care chemo- and immunotherapies [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 3234.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3234
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Abstract 5935: Phenotype profiling of tumor microenvironment in EGFR mutant lung adenocarcinoma with multi-omics data
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5935-5935
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5935-5935
    Abstract: Introduction: EGFR mutations holds the major targets for drug in lung adenocarcinoma (LUAD). Despite the tremendous study of EGFR mutant (MT) LUAD, the comprehensive interpretation of the heterogeneous character of LUAD harboring EGFR MT remains a key challenge. Here, we investigated the heterogeneity of EGFR MT LUAD and explored the tumor microenvironment (TME) in EGFR MT LUAD. Method: We performed single-cell RNA sequencing (scRNA-seq) from 135 LUAD patients which consist of normal(n=24), EGFR wild (WT)(n=18), and MT(n=93). Also, we used whole genome sequencing and bulk-RNA sequencing to validate with scRNA-seq results. From 898,648 cells, main cell types were classified. To explore the various characteristics of MT LUAD tumor cells, we used two ways: i) We re-clustered epithelial cells populating the normal, WT, and MT. ii) We re-clustered only MT epithelial cells. In each analysis, we identified the tumor character in the clusters using differential expressed genes analysis, lineage tracing, clinical information, mutation, and trajectory analysis. Also, we extracted each main cell type except epithelial cells, and identified subtypes of main cell types. Finally, we revealed the interaction of cellular components in TME. Results: In the analysis of epithelial cells, we identified characteristics of specific EGFR MT by comparing of EGFR WT and MT tumors in clusters with similar biological features. The cluster represented by alveolar type 2 (AT2) known as initiation of LUAD was populating normal, WT, and MT. In this cluster, MT- and WT-associated pathway shared but differently significant between MT and WT in the pathway analysis. The cluster represented by proliferative is mostly comprised tumor cells and we found significantly increased the expression of MDK, CD24 in the MT of the cluster. In the analysis of only MT epithelial cells, 2 of clusters were stage-specific cluster: i) The cluster annotated as early stage cluster, ii) The cluster annotated as advanced stage cluster. Trajectory showed that there is a pseudotemporal continuum, following the stage from early stage cluster to advanced stage cluster. Also, based on the lineage tracing, 2 of clusters revealed lineage-specific clusters: i) The cluster annotated as AT2 was enriched from early stage cells, ii) The cluster annotated as basal cell known as origin of lung squamous cell carcinoma(LUSC) was enriched from advanced stage cells. Psedotemporal ordering of these cluster revealed AT2 cluster transdifferentiate into basal cell cluster which implied the possibility of LUAD to LUSC transition by drug resistance. In the interaction of MT and WT TME, the number of signaling received epithelial cells from myeloid cells, endothelial cells, and fibroblasts as sender increased compared with the interaction of normal. Conclusion: We shed light on the ecosystem of TME according to clinical and biological feature of tumor in EGFR mutant LUAD. Citation Format: You Won Lee, Eun Ji Lee, Seung Yeon Oh, Kyoung-Ho Pyo, Seong Gu Heo, YoungJoon Park, Su-Jin Choi, Kyumin Lim, Ju-hyeon Lee, Jae Hwan Kim, Jii Bum Lee, Ji Yoon Lee, Sun Min Lim, Chang Gon Kim, Min Hee Hong, Mi Ran Yun, Byoung Chul Cho. Phenotype profiling of tumor microenvironment in EGFR mutant lung adenocarcinoma with multi-omics data. [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 5935.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5935
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Abstract 4029: JIN-A04, highly effective tyrosine kinase inhibitor targeting HER2 exon 20 insertion mutations in NSCLC
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4029-4029
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4029-4029
    Abstract: Introduction: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of lung cancer patients. 2% - 4% of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90 % of them exon 20 insertions. The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA (YVMA) mutation in the kinase domain. Currently, treatment options for this subset of patients are limited. JIN-A04 is an orally available tyrosine kinase inhibitor (TKI) targeting HER2 exon20 insertion mutations and has the potential to be a best-in-class drug candidate to address this unmet clinical need. Method: The inhibitory activity of JIN-A04 was evaluated by cell viability assay in both Ba/F3 cell lines expressed HER2 YVMA and HER2 P780_Y781insGSP (GSP) mutations. Also, Ba/F3 HER2 wild-type (WT) and normal cell lines for HUVEC (endothelial cells) and BEAS-2B (human bronchial epithelial cells) were used to assess cellular activity. In addition, to confirm mechanism action, western blotting analysis was performed on Ba/F3 YVMA and Ba/F3 GSP cell lines. Results: In cell viability assay, JIN-A04 strongly inhibited cellular activity against Ba/F3 cell lines engineering to express the mutants HER2 YVMA (IC50 = 11.1 nM) and GSP (IC50 = 1.4 nM). It was superior to Mobocertinib (IC50 = 27.1 nM for YVMA and IC50 = 3.3 nM for GSP) and comparable with Poziotinib (IC50 = 3.4 nM for YVMA and IC50 = 0.4 nM for GSP). In normal cell lines, JIN-A04 did not inhibit the activity of HUVEC (IC50 = & gt 1000 nM) and BEAS-2B (IC50 = & gt 1000 nM) cell lines, largely sparing HER2 WT activity (IC50 = & gt 1000 nM). In protein expression analysis, JIN-A04 was effectively inhibited in all signaling pathway of p-EGFR, p-AKT, p-ERK1/2, and p-S6 on Ba/F3 YVMA and Ba/F3 GSP cell lines at a low dose level. Conclusion: JIN-A04 is highly potent against HER2 exon 20 insertion mutations including YVMA and GSP, while largely sparing HER2 WT activity. Also, JIN-A04 demonstrated effective HER2 pathway inhibition. Based on these robust activities for HER2 exon 20 insertion, JIN-A04 is expected to provide a potent therapeutic opportunity for NSCLC patients with HER2 exon20 insertion mutations. Citation Format: Mi Ra Yu, Mi Ran Yun, Jii Bum Lee, Ji Yun Lee, So Won Aum, Su Jin Choi, Ju Yeon Park, Seung Yeon Oh, Eun Ji Lee, Krishna Babu Duggirala, Kwangho Lee, Min Hee Hong, Sun Min Lim, Anna Jo, Ethan Seah, Choonok Kim, Byoung Chul Cho. JIN-A04, highly effective tyrosine kinase inhibitor targeting HER2 exon 20 insertion mutations in NSCLC. [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 4029.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4029
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 15 ( 2021-08-01), p. 4397-4409
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 15 ( 2021-08-01), p. 4397-4409
    Abstract: Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets. Experimental Design: Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts. Results: PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions. Conclusions: We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-5026
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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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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  • 7
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    Abstract 5107: A novel AhR inhibitor ‘DA-4505’ improved the anti-cancer efficacy of surgical and chemotherapy via synergistic anti-tumor effects of aPD-1
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5107-5107
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5107-5107
    Abstract: Background: The Aryl hydrocarbon receptor (AhR) is one of the most predominant regulators of cancer metabolism. The AhR exerts important immunosuppressive functions by activating Treg cells and myeloid-derived suppressor cells and repressing CD8+ effector T cells. Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy via modulation of tumor immune surveillance compared to BAY2416964, an AHR antagonist drug candidate being studied in the clinical phase. Methods: To evaluate anti-tumor effects of DA-4505 and BAY2416964, the two AhR inhibitors were dosed at 10 mg/kg once daily alone or in combination with aPD-1 (10 mg/kg) in surgical and chemotherapy models, and a PDX model (YHIM2004). Tumor volume, relapse, and survival were evaluated, and immune profiles were analyzed with IHC, flow cytometry, and scRNAseq. Results: A significant tumor reduction appeared in the CT26 and 4T1 tumor models after the DA-4505 treatment compared to vehicle group (P & lt;0.05). In contrast, DA-4505 treatment did not induce significant tumor regression compared to vehicle group in tumor-bearing NOG mice, suggesting that anti-tumor effects of DA-4505 were driven by immunologic mechanisms. To evaluate the role of DA-4505 in conjunction with surgery, DA-4505 alone or in combination with anti-PD-1 was given prior to and following resection of the tumors in 4T1 tumor-bearing mice. Survival of mice treated with DA-4505 alone or DA-4505 combined with anti-PD-1 was significantly prolonged after resection compared to aPD-1 treatment group (P & lt;0.05). In addition, there were four mice that did not have a relapse by treating DA-4505 with or without aPD-1 after surgery (4/5). A tumor regression also appeared in the YHIM2004-engrafted humanized mouse study. A tumor reduction was shown by treating DA-4505 alone or in combination with pembrolizumab compared to vehicle group (P & lt;0.05). Next, we co-administered an AhR inhibitor and aPD-1 as a partner to improve the antitumor effects of chemotherapy. The DA-4505 add-on group showed tumor regression when compared with the combination therapy group treated with aPD-1 and chemotherapy (P & lt;0.0001). In addition, a significant increase in survival rate was shown in the group treated with a DA-4505 add-on compared to vehicle group (P & lt;0.001). Analysis of scRNAseq showed that M1 macrophage expressing CCL7 and CCL8 were increased in DA-4505 treated group compared to the vehicle and aPD-1 groups. This suggests that immune modulatory effect of DA-4505 may be due to enhanced recruitment of immune cells into the tumor site by macrophages with high chemotactic activity. Conclusion: The AhR inhibitor DA-4505 demonstrated an improvement in anti-tumor efficacy. In addition, it has shown a synergistic effect when combined with aPD-1. Discoveries from this study provide a preclinical rationale for future clinical implications in solid tumor. Citation Format: DongKwon Kim, Sujeong Baek, Seung Min Yang, Yu Jin Han, Seong-san Kang, Chun-Bong Synn, Mi Hyun Kim, Heekyung Han, Kwangmin Na, Young Taek Kim, Sungwoo Lee, Taedong Han, Hyounmie Doh, Jongho Cho, Dajeong Kim, Daewon Cha, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Mi Ran Yun, Ji Yun Lee, Jii Bum Lee, Chang Gon Kim, Min Hee Hong, Sun Min Lim, Byoung Chul Cho, Kyoung-Ho Pyo. A novel AhR inhibitor ‘DA-4505’ improved the anti-cancer efficacy of surgical and chemotherapy via synergistic anti-tumor effects of aPD-1. [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 5107.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5107
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Abstract 6433: A novel bacterial strain, CJRB-101, induces anti-cancer effects by repolarization of M2 to CXCL9 and CXCL10 dual expressing M1 macrophages in humanized non-small cell lung cancer mice models
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6433-6433
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6433-6433
    Abstract: Backgrounds: Live biotherapeutic products (LBPs) emerged as potential therapeutics to overcome the limitation of ICIs. This research shows that CJRB-101, a novel bacterial strain, can improve anti-tumor effects in synergy with pembrolizumab in non-small cell lung cancer (NSCLC). Objectives and Methods: Tumors from NSCLC patients (anti-PD-1 refractory and resistant) were transplanted into Hu-CD34-NSG to establish humanized patient-derived xenograft (PDX) mice models. Five models (YHIM-2003, 2004, 2009, 2010 and 2014) were treated with CJRB-101 at low (5 × 107 CFU) or high (109 CFU) doses, or with pembrolizumab (10 mg/kg, i.p., Q5D) or in combination. Tumor growth inhibition (TGI) rate was measured. Tumor microenvironment (TME) was analyzed using multiplex IHC, flow cytometry and single cell RNA sequencing. Ex-vivo assays were performed to validate in silico findings. Results: Tumor in PDX models was unresponsive to pembrolizumab alone, however, in combination with CJRB-101 effectively suppressed tumor growth. The synergy was highlighted in YHIM-2009 where TGI was 10-fold higher (56%) than pembrolizumab group (5%). Immune profiling revealed that macrophages may be responsible for the anti-tumor effects of CJRB-101. IHC showed significantly increased antigen presenting specialized DCs (CD16+CD68−CD11c+) and granzyme B+ CD8+ T cells in the tumor by CJRB-101 compared to pembrolizumab (p & lt;0.01). This suggested that CJRB-101 induced infiltration of cytotoxic CD8 T cells into the tumor nest by enhancing antigen presenting machinery. Trajectory analysis showed that CJRB-101 induced repolarization of M2 to M1 macrophages, characterized by high expression of CXCL9/10. CXCL9+/10+ M1 macrophages were comparatively more abundant in the combination group (23.11%) than the pembrolizumab group (0.91%). CXCL9/CXCL10 expression in macrophages was higher in the CJRB-101 group compared to the pembrolizumab group (p & lt;0.0001). The combination group (10.84%) had a higher relative abundance of CD8+ T cells compared to the pembrolizumab group (1.58%) and higher IFNγ expression in CD8+ T cells compared to the pembrolizumab group (p=0.0152), suggesting that CJRB-101 repolarized macrophages and recruited active CD8+ T cells. Co-culture assays using bone marrow-derived macrophages validated that CJRB-101 drove differentiation towards F4/80+ or MHC II+ expressing M1 macrophage (p & lt;0.0001) and repolarized existing M2 (CD206+) to M1 (p=0.0002). Conclusion: Combination treatment of CJRB-101 with anti-PD-1 showed synergistic anti-tumor effects via repolarization of M2 to M1 macrophages, leading to activation of CD8+ T cells in TME. Especially, CXCL9+/10+ M1 macrophage playing a key role in TGI induced by CJRB-101 in NSCLC models. Findings from this study provided rationale for clinical investigation of CJRB-101. Citation Format: Arim Min, Chun-bong Synn, Seong-san Kang, Bo-eun Kwon, Junwon Yang, Hyunkyung Park, Jieun Im, Hyunjeong Kim, Sujeong Beak, Dong Kwon Kim, Jii Bum Lee, Hyeonseok Oh, Seung Min Yang, Yu Jin Han, Mi hyun Kim, Heekyung Han, Kwangmin Na, Young Taek Kim, Sungwoo Lee, Mi Ran Yun, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Ji Yun Lee, Chang Gon Kim, Min Hee Hong, Sun Min Lim, Kyoung-Ho Pyo, Byoung Chul Cho. A novel bacterial strain, CJRB-101, induces anti-cancer effects by repolarization of M2 to CXCL9 and CXCL10 dual expressing M1 macrophages in humanized non-small cell lung cancer mice models [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 6433.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6433
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 5865: Combinatorial activity of amivantamab and pembrolizumab in head and neck squamous cell carcinoma and lung squamous cell carcinoma expressing wild-type EGFR and MET
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5865-5865
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5865-5865
    Abstract: Introduction: Unmet needs exist for immunotherapy targeting PD-1/PD-L1 in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC) due to its suboptimal response. Amivantamab, a bispecific antibody targeting epidermal growth factor receptor (EGFR) and c-Met, has been demonstrated to induce antibody-dependent cytotoxicity and trogocytosis in tumor cells. We hypothesized that combination of amivantamab with pembrolizumab may synergistically enhance antitumor immunity. In this study, we present comprehensive immunomodulatory and synergistic antitumor efficacy of amivantamab and pembrolizumab in humanized HNSCC and LUSC mice models. Methods: EGFR and MET-expressing tumors from a HNSCC and a LUSC patient were transplanted into Hu-CD34-NSG to establish humanized patient-derived xenograft (PDX) models. Tumor-bearing PDXs were treated with vehicle, pembrolizumab (10mpk, Q5D, n=10), amivantamab (10mpk, BIW, n=10), or a combination of pembrolizumab and amivantamab (n=10). Analysis of immune modulatory responses within the tumor microenvironment (TME) using multiplexed IHC, flow cytometry, and single cell RNA sequencing was performed. Results: Combination of amivantamab and pembrolizumab showed a significant reduction of tumor volume (p & lt;0.001) compared to vehicle or single treatment in both models. Additionally, significantly longer survival was observed for combination treated compared to the vehicle treated groups (p & lt;0.0001). Multispectral imaging of tumor indicated that granzyme B-producing CD8+ T cells were significantly increased within the tumor in the combination group (p & lt;0.01). Further analysis of T cell subsets suggested that central memory type CD8+ T cells were increased upon combination treatment. This group also demonstrated significantly higher CEA-tetramer positive CD8+ T cells in the tumor (p & lt;0.01), suggesting that cytotoxic T cells recognizing tumor specific antigens enhanced antitumor immune response. Single cell RNA sequencing analysis of HNSCC showed that an EGFRhighMEThigh cluster was enriched in the TME after pembrolizumab treatment. This subcluster had elevated glycolysis and lactic acid pathway-related genes compared to EGFRlowMETlow cluster. Lactate transporter, MCT4 (SLC16A3) and LDHA genes were dramatically increased in the EGFRhighMEThigh cluster. Elevated lactic acid pathway may lead to immune evasion in the tumor, dampening the activity of pembrolizumab. Interestingly, combination treatment with amivantamab could reduce EGFRhighMEThigh cluster, and could effectively control tumor via creating favorable immune TME. Conclusion: Our study demonstrated combinatorial benefits of amivantamab and pembrolizumab by effectively remodeling TME, providing a preclinical rationale to clinically combine amivantamab and PD-1 blockade treatments. Citation Format: Sun Min Lim, Chun-Bong Synn, Seong-san Kang, DongKwon Kim, Soo-Hwan Lee, Sujeong Baek, Seung Min Yang, Yu Jin Han, Mi hyun Kim, Heekyung Han, Kwangmin Na, Young Taek Kim, Sungwoo Lee, Mi Ran Yun, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Jii Bum Lee, Ji Yun Lee, Chang Gon Kim, Min Hee Hong, Kyoung-Ho Pyo, Joshua Curtin, Bharvin Patel, Isabelle Bergiers. Combinatorial activity of amivantamab and pembrolizumab in head and neck squamous cell carcinoma and lung squamous cell carcinoma expressing wild-type EGFR and MET [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 5865.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5865
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 4662: Prognostic value of total lesion glycolysis from 18F-fluorodeoxyglucose positron emission tomography patients with gastric neuroendocrine carcinoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4662-4662
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4662-4662
    Abstract: Background: Gastric neuroendocrine carcinomas (NET) are very rare, aggressive tumors of the stomach. The objective of this study was to examine the predictive role of pretreatment fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)-assessed metabolic parameter of the whole-body and primary tumors in patients with gastric NET Method: We conducted a retrospective review of the 25 patients with histopathologically confirmed poorly differentiated NETs of the stomach at our hospital between January 2005 and December 2012. All of the patients underwent 18F-FDG-PET examination at diagnosis. Metabolic parameters [SUVmax, SUVmean, and total lesion glycolysis (TLG)] on pretreatment 18F-FDG-PET were analyzed for survival. Results: Median follow up duration was 39.4 months (95% CI, 20.0-58.1 months) and median overall survival (OS) was 25.7 months (95% CI, 14.1-37.2 months). When subjects were divided into two groups according to TLG with a cutoff value of 500, the high TLG group showed significantly shorter OS compared to the low TLG group (p=0.006). However, SUVmean and SUVmax had no significant association OS (p = 0.258, and p = 0.52, respectively). Conclusions: Our findings suggest that TLG may be more useful than SUVmean and SUVmax for predicting OS in patient with NET. The TLG measurement on 18F-FDG-PET imaging could be routinely recommended to advanced gastric cancer with neuroendocrine carcinoma Citation Format: Minkyu Jung, Beodeul Kang, Ji Soo Park, Sun Min Lim, Hyo Song Kim, Sun Young Rha, Joong Bae Ahn, Hyun Cheol Chung, Mijin Yun, Arthur Cho. Prognostic value of total lesion glycolysis from 18F-fluorodeoxyglucose positron emission tomography patients with gastric neuroendocrine carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2014-4662
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4662
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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