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  • American Association for Cancer Research (AACR)  (119)
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  • 1
    Online Resource
    Online Resource
    Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 11 ( 2013-11-01), p. 1375-1386
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 11 ( 2013-11-01), p. 1375-1386
    Abstract: Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC. Implications: Tpl2 kinase activity has prognostic and therapeutic targeting potential in aggressive clear cell renal cell carcinoma. Mol Cancer Res; 11(11); 1375–86. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-13-0101-T
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Novel Morphologic and Genetic Analysis of Cancer Cells in a 3D Microenvironment Identifies STAT3 as a Regulator of Tumor Permeability Barrier Function
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 5 ( 2016-03-01), p. 1044-1054
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 5 ( 2016-03-01), p. 1044-1054
    Abstract: Tumor permeability is a critical determinant of drug delivery and sensitivity, but systematic methods to identify factors that perform permeability barrier functions in the tumor microenvironment are not yet available. Multicellular tumor spheroids have become tractable in vitro models to study the impact of a three-dimensional (3D) environment on cellular behavior. In this study, we characterized the spheroid-forming potential of cancer cells and correlated the resulting spheroid morphologies with genetic information to identify conserved cellular processes associated with spheroid structure. Spheroids generated from 100 different cancer cell lines were classified into four distinct groups based on morphology. In particular, round and compact spheroids exhibited highly hypoxic inner cores and permeability barriers against anticancer drugs. Through systematic and correlative analysis, we reveal JAK–STAT signaling as one of the signature pathways activated in round spheroids. Accordingly, STAT3 inhibition in spheroids generated from the established cancer cells and primary glioblastoma patient–derived cells altered the rounded morphology and increased drug sensitivity. Furthermore, combined administration of the STAT3 inhibitor and 5-fluorouracil to a mouse xenograft model markedly reduced tumor growth compared with monotherapy. Collectively, our findings demonstrate the ability to integrate 3D culture and genetic profiling to determine the factors underlying the integrity of the permeability barrier in the tumor microenvironment, and may help to identify and exploit novel mechanisms of drug resistance. Cancer Res; 76(5); 1044–54. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-2611
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Abstract 5189: Neoadjuvant and adjuvant anti-PD-1 based combination immunotherapy with a novel AXL inhibitor, SKI-G-801 in syngeneic tumor model: A combined analysis of immune profiling
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5189-5189
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5189-5189
    Abstract: Introduction: Neoadjuvant therapy suggests the systemic treatment of cancer prior to surgical therapy. The main purpose of neoadjuvant therapy is to improve surgical outcomes in patients for whom a primary surgical approach is difficult to practice. Recently, Anti-PD-1 has been applied to neoadjuvant and adjuvant therapy, but the anti-cancer responses are not sufficient to prevent tumor recurrence. According to our previous study, a novel AXL inhibitor, SKI-G-801 strongly inhibits metastasis of syngeneic tumor with immune responses. The primary goal of this study is to overcome limitation of anti-PD-1 based neoadjuvant and adjuvant therapy with SKI-G-801. Methods: 4T1 cancer bearing mouse models were established for neoadjuvant or adjuvant treatment. Mice were treated with single anti-PD-1 (BIW), SKI-G-801 (QD) or a combination for 6 days, followed by the surgical dissection of tumor tissue in a subcutaneous xenograft model. In five mice per group, their survival rates were monitored for 50 days. We used flow cytometry and immunohistochemistry for comprehensive immune profiling and tumor-infiltrating lymphocytes (TILs) from three mice per group surgically removed tumor tissues. Three tumors per group were stained, and CD3-positive cells per unit area (mm2) were analyzed using Vectra Polaris. Results: According to results, the median survival of control group (only surgical operation without treatment) was 16 days (N=5), whereas, the longest survival group was neoadjuvant-combination (median survival = 37 days). Two out of five mice were survived until end of experiment (D-50). Most of the groups had similar outcomes excluding neoadjuvant-combination group. The median survival of adjuvant-anti-PD-1 group was 30 days, and adjuvant-SKI-G-801 and neoadjuvant-anti-PD-1 group were 25 days. The Neoadjuvant-SKI-G-801 was recorded 23.5 days. Statistically, survival rate of neoadjuvant-combination therapy was significantly higher than of neoadjuvant-anti-PD-1 and neoadjuvant-SKI-G-801 (log-rank test, p & lt;0.01).The reason for neoadjuvant therapy is to improve immune responses before surgical operation. We investigated the effects of SKI-G-801 or anti-PD-1 alone and combination therapy on neoadjuvant treatment in the tumor microenvironment. IHC and flow cytometry were performed to elucidate tumor infiltrating immune cell populations with the tumor obtained by surgery. In IHC result, CD3+ cells population was significantly increased in SKI-G-801 alone and combination of neoadjuvant therapy compared to control group (p & lt;0.05, p & lt; 0.001, respectively), however, anti-PD-1 group was not significant. IFN-γ+ Tc cells, CD3+CD44+ memory Tc, and PD-1+Tc cells were significantly infiltrated into the tumor in the combination of neoadjuvant therapy (p & lt; 0.01). Conclusion: This study confirmed that a potential combination with aPD-1 and SKI-G-801 applies to neoadjuvant therapy, as evidenced by increased T cell infiltration and function. Our findings provide a rationale for further clinical investigations. Keywords: Axl inhibitor, Neoadjuvant therapy, Adjuvant therapy, Immunotherapy, Anti-PD-1 Citation Format: Ha Ni Jo, Wongeun Lee, Chun-Bong Synn, Hee Kyu Lee, Jae-Hwan Kim, Yeongseon Byeon, Sung Eun Kim, Ji Min Lee, Do Hee Kim, Jung-Ho Kim, Beung-Chul Ahn, Min Hee Hong, Hye Ryun Kim, Kyoung-Ho Pyo, Byoung Chul Cho. Neoadjuvant and adjuvant anti-PD-1 based combination immunotherapy with a novel AXL inhibitor, SKI-G-801 in syngeneic tumor model: A combined analysis of immune profiling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5189.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5189
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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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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  • 5
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    Abstract 6219: WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Abstract: As the representative targeted anticancer drug for colon cancer patients, cetuximab is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild type cancers. Even some patient with KRAS wt gene did not respond cetuximab. However, there is no treatment available for cetuximab-resistant patient group, which is almost 50% of KRAS WT gene holders. Recently, our team identified cetuximab primary resistant related proteins named as mtRTK (mutant receptor tyrosine kinase) by array analysis based cetuximab responder or non-responder colon cancer patient tissues. We investigated mtRTK’s oncogenic potential as a novel anti-cancer target. A large proportion of colon cancer patients (36.2% Caucasian, 56.9% Korean) expressed the mtRTK was identified, using the sequencing analysis of patient samples. Based on these results, our efforts have led to the discovery of WM-S1, mtRTK inhibitor, which is the first mtRTK inhibitor in clinical development. The potent enzyme inhibitor showed a high anticancer activity confirmed in Patient-Derived Cells (PDC) and Patient-Derived Xenograft (PDX) animal models expressing the mutation. In preclinical studies demonstrate that WM-S1 is well tolerated in rats and dogs. Furthermore, WM-S1 has potent anticancer activities for various solid tumor (NSCLC, cholangiocarcinoma, etc.) including activated mtKRAS colon cancer expressing the mtRTK. Currently we are investigating WM-S1 in a phase 1a trial in AUS, which is the first mtRTK inhibitor in clinical development. Meanwhile, the mtRTK inhibitor WM-S1 drives antitumor immunity (with anti-PD-L1) in NSCLC. Combinational approaches with immunotherapy showed that synergistic effect of WM-S1 and anti-PD1 monoclonal antibody, suppressing tumor growth by 75% in anti-PD1 resistance NSCLC-derived humanized mouse model. A phase 1b trial is expected to develop WM-S1 through not only indication expansion but also combination therapy with immuno-checkpoint inhibitors in the USA, AUS and KOR from Q2 2022. In conclusion, mtRTK is a potential oncogenic driver mutation in various solid tumor. A first-in-class anticancer agent WM-S1 targeting mtRTK can be promising therapeutic agents for cetuximab-resistant colon cancer patients regardless of KRAS mutation status and other cancers. Citation Format: Joseph Kim, Jai-Hee Moon, Kyung-Mi Lee, Hyun Ryu, Eun Hye Park, Sang Hee Kim, Jeong Seok Kim, Young Ok Ko, Yong Seok Kim, Hyo Jin Kim, Tae Young Kim Kim, Moon Seong Yoo, Soll Jin, Seongrak Kim, Yoon Sun Park, Min Ki Lee, Mi So Lee, Ji Hyun Go, Yu Geun Ji, Jun Hyung Lee, Haneul Lee, Min Hwa Kim, Eun Hee Ko, Yeo Jin Lee, Seung-Mi Kim, Joon-yee Jeong, Yeon-seoung Choi, Seung-geon Bae, Jinwoo Lee, Won Jun Lee, Min-Kyeong Kim, Ji min Shin, Dong-in Koh, Sun-Chul Hur, Chun-Ho Park, Hyun Ho Lee, Dong-Hoon Jin. WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer [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 6219.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6219
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract 1471: Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1471-1471
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1471-1471
    Abstract: Background: AXL has been identified to play multiple roles in the tumor microenvironment including the promotion of epithelial-mesenchymal transition and immune evasion. SKI-G-801, a small molecule inhibitor targeting phosphorylation of AXL, presented strong inhibition of cancer migration and invasion. Anti-PD-1(αPD-1) combined with paclitaxel(Pac)/carboplatin(Carbo) and pemetrexed(Pem)/cisplatin(Cis) are standard therapy in non-squamous and squamous lung cancer patients, respectively. Herein, we present that adding AXL inhibition with SKI-G-801 on αPD-1 plus chemotherapy suppressed tumor growth and improved overall survival and also enhanced anti-tumor T cell immunity in both non-squamous and squamous lung cancer models. Methods: C3PQ squamous and TC-1 non-squamous lung cancer bearing mouse models were established. In C3PQ squamous model, mice were treated with 2 cycles of induction Carbo + Pac + αPD-1 and 13 cycles of maintenance with αPD-1. In TC-1 non-squamous model, mice were treated with 3 cycles of induction with Cis + Pem + αPD-1 and 14 cycles of maintenance therapy. Both models included the groups of SKI-G-801 treatment from induction therapy and/or maintenance therapy. The tumor growth and survival were monitored for 60 days in both models. The tumor infiltrated lymphocytes were analyzed by flow cytometry. Results: In TC-1 non-squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pem/Cis chemotherapy followed by αPD-1 and Pem maintenance showed the superior overall survival to the others (vs. αPD-1+ Pem/Cis and αPD-1 + Pem maintenance; p & lt;0.001, vs. αPD-1 + Pem/Cis and αPD-1 + Pem + SKI-G-801 maintenance; p & lt;0.01, vs. αPD-1 + Pem/Cis and SKI-G-801 maintenance; p & lt;0.01). In C3PQ squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pac/Carbo followed by αPD-1 prolonged the overall survival compared the others (vs. αPD-1+Pac/Carbo and αPD-1 maintenance; p & lt;0.05, vs. αPD-1 + Pac/Carbo and αPD-1+ SKI-G-801 maintenance; p & lt;0.05, vs. αPD-1 + Pac/Carbo + SKI-G-801 maintenance; n.s.). In line with survival outcomes, upfront SKI-G-801 on αPD-1 combined with chemotherapy showed the strong tumor growth inhibition compared to the others. Especially, effector memory T cells (CD3+CD4+CD44+CD107-) and IFN-γ secretion level of CD8+ T cells were significantly increased in SKI-G-801 treated groups in C3PQ model (p & lt;0.05). Conclusion: Incorporation of SKI-G-801, a novel AXL inhibitor, with αPD-1 combined with chemotherapy significantly improved overall survival and anti-tumor activity in both non-squamous and squamous lung cancer model through enhancing cytotoxicity of CD8+ T cells and memory CD4+ T cells. These findings provide mechanistic insight into the activity of SKI-G-801 combined with standard therapy and support its clinical development in metastatic NSCLC as first line therapy. Citation Format: Kyoung-Ho Pyo, Wongeun Lee, Hee Kyu Lee, Dong Kwon Kim, Ha Ni Jo, Chun-Bong Synn, Jae Hwan Kim, Yeongseon Byeon, Young Seob Kim, Beung-Chul Ahn, Min Hee Hong, Sun Min Lim, Byoung Chul Cho, Hye Ryun Kim. Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity [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 1471.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1471
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract 3325: Intratumoral STING activation on artificially generated cutaneous metastasis of EML4-ALK lung cancer alters immunologic milieu of primary tumor
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3325-3325
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3325-3325
    Abstract: Introduction: Therapeutic monoclonal antibodies targeting immune checkpoints inhibitors (ICIs) are game changers in the treatment landscape of multiple solid tumors. However, response rate remains relatively low in most cases. Particularly, anti-PD-1 or PD-L1 therapies are not effective in EML4-ALK rearranged- and EGFR mutant-NSCLC patients due to their cold immune microenvironment. Recently, activation of stimulator of interferon genes (STING) has shown potential to enhance antitumor immunity through induction of various pro-inflammatory cytokines and chemokines. In this study, we attempted to induce inflamed tumor microenvironment by artificially generating skin metastasis using intratumoral STING activation in EML4-ALK transgenic mice. Methods: EML4-ALK transgenic mice were implanted with a new EML4-ALK tumor subcutaneously. The size of lung primary tumor and subcutaneous tumor were each measured by micro-MRI and calipers, respectively. The treatment groups were divided into the control group, tumor-implanted group, and intratumor STING activation group (skin). On day 14, subcutaneous tumor, primary tumor (lung), and systemic immune organs were collected for further analysis. Results: STING agonist promotes pIRF3 signaling and massive immune cell recruitment in skin region, the subcutaneous tumor was dramatically reduced with hyperinflammation. In addition, primary tumor (lung) was observed with increased T cell population in tumor with necrotic regions. IFN-gamma expression was increased in bronchoalveolar fluid in STING activation group compared to control and tumor only groups (P & lt; 0.05). Tumor macrophages and NK cells were increased compared to control group (P & lt; 0.05, P = ns, respectively). We considered that skin consists of cutaneous innate immune cells, especially, macrophage. Increased T cells and macrophages were observed in STING activated tumor within 6 hours. The in vitro assay proved that macrophages highly express chemokines (CCL5, CCL2, and CCL12) which is recruiting T cells and myeloid cells. This initial immune activation results in increased tumor-specific T cell, especially, memory helper T cell (CD3+CD4+CD44+) in spleen, LN and MLN. We tested anti-IFN-beta antibody for neutralization of STING activity in vivo. The IFN-gamma expression of lymphocytes in MLN was reduced but not significant. Conclusion: This study confirmed that STING activation in cold tumor alters inflamed-immunologic milieu of primary tumor via hyper cutaneous immune activity with pivotal roles of macrophage. Our findings provide a rationale for further clinical investigations. Keywords: STING, cutaneous metastasis, EML4-ALK Citation Format: Chun-Bong Synn, Ji Min Lee, SunMin Lim, Do Hee Kim, Bianca-Ioana Gheorghiu, Jae-Hwan Kim, Wongeun Lee, Sung-Eun Kim, Sungwon Park, Beung-Chul Ahn, Ha Ni Jo, Min Hee Hong, Hye Ryun Kim, Kyoung-Ho Pyo, Byung Chul Cho. Intratumoral STING activation on artificially generated cutaneous metastasis of EML4-ALK lung cancer alters immunologic milieu of primary tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3325.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3325
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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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 2755: Single-cell RNA sequencing reveals priming professional antigen-presenting macrophages and chemokine expressing T cells in tumor microenvironment by AXL inhibitor, SKI-G-801
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2755-2755
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2755-2755
    Abstract: The mechanistic investigations have defined that AXL inhibition reprograms the immunological microenvironment leading to increased T cells and antigen-presenting cells. However, previous reports did not clearly demonstrate the linchpin mechanism of anti-tumor effects with AXL inhibitors. It may be possible to elucidate the immunological mechanism of AXL inhibitor based on a comprehensive analysis of cell type-specific transcriptomic changes using scRNA-seq. The human CD34-NSG mice were engrafted LUSC tumor. These mice were divided into four dose groups: Vehicle, SKI-G-801, pembrolizumab, and combination groups. The tumor-associated cells were collected for flow cytometry and scRNA-seq analysis, and FFPE sample of tumor tissue was analyzed by a multispectral imager. The combination group demonstrated the superior anti-cancer efficacy to vehicle, pembrolizumab, and SKI-G-801 groups (all p & lt;0.05). The scRNA-seq was performed with Seurat 4.0. The cells were separated into total 9 clusters. Following SKI-G-801 treatment, the T cells showed higher expressions of CD2, CCL5, CCL4, GZMA, and GZMB compared to both pembrolizumab and vehicle groups (both p & lt;0.05). The gene expressions of CD2 and GZMA were higher than pembrolizumab and vehicle groups (both p & lt;0.05). The CDR3 length differences of TCRs and diversity of T cell clones were higher increased in SKI-G-801, pembrolizumab and combination groups than vehicle group (p & lt;0.05). In the macrophage cluster, the HLA-A, HLA-DRA, HLA-DRB1, and IL-1B genes were commonly expressed in SKI-G-801 and combination group (p & lt;0.05). Mostly, the professional antigen-presenting macrophages (MHC class 2 protein complex high, p & lt;0.05) were increased in the combination group. The combination effects between pembrolizumab and SKI-G-801 can be addressed by enhanced antigen presenting machinery, T cell activation and unique T cell clones. These transcriptomic results were highly correlated with the results of multispectral imaging and flow cytometry. Tumor infiltrations of helper T cells and cytotoxic T cells significantly increased in combination and SKI-G-801 groups (p & lt; 0.01, p & lt; 0.001 respectively). In multiplex IHC analysis, the proportion of CD4+ and CD8+ T cells were significantly increased in the tumor nest (both p & lt;0.05), but the Tregs were not changed in the tumor nest which observations were validated by further flow cytometry analysis. A novel AXL inhibitor, SKI-G-801 drives priming of professional antigen-presenting cells and tumor-infiltrating T cells, leading to immunological synapsis for tumor killing, which is significantly enhanced by the combination with pembrolizumab. These results suggest the inhibition of AXL signal pathway by SKI-G-801 could confer a solid rationale for clinical investigation of lung cancer cells. Citation Format: Kyung-Ho Pyo, Hee Kyu Lee, Ha Ni Jo, Wongeun Lee, Seong Gu Heo, Sang Bin Lim, Dong Kwon Kim, Chun-Bong Synn, Youngseon Byeon, Young Seob Kim, Beung-Chul Ahn, Min Hee Hong, Sun Min Lim, Hye Ryun Kim, Byoung Chul Cho. Single-cell RNA sequencing reveals priming professional antigen-presenting macrophages and chemokine expressing T cells in tumor microenvironment by AXL inhibitor, SKI-G-801 [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 2755.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2755
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 10
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    Abstract 479: ATM pathway upregulation of combination therapy with radiation and MSC-based IL-12M gene vaccine, Gx-051, in allograft animal model.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 479-479
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 479-479
    Abstract: PURPOSE: In spite of the powerful therapeutic effects of radiotherapy, the attempts to combined radiotherapy with others have so far kept going on to find better therapeutic protocol for patients in the head and neck cancer. Previously, we announced some part of anticancer effects of combined radiotherapy with Gx-051 named as mesenchymal stem cell (MSC) expressing modified interleukin-12 (MSCs/IL-12M). It is a novel component of human immune system to attack cancer cells by the recruitment of immune cells with a high specificity. Thus, in the present study, we have tried to reveal another therapeutic effect of combined radiation and immunotherapy, compared to the treatment with each single modality in allograft animal model. METHODS AND MATERIALS: AT-84 cells, one of murine head and neck carcinoma cells, were injected for allograft induction on C3H/HeN mice. All the mice were randomly divided into 4 groups; control (non-treated), radiation only-treated, Gx-051 only-treated, and irradiation with Gx-051-treated. Intra-tumoral injection of Gx-051 (adopted within 24hr after irradiation) as well as 8 Gy-local irradiation was carried out, totally 4 times (twice a week for 2 weeks). To clarify the anti-tumoral effect of radiation with Gx-051 administration, we provided reasonable evidences; tumor volume, levels of IL-12 and IFN-r, and the changes in signaling pathway related-protein expression level. RESULTS: In the present study, we could confirm that combined treatment with radiation and Gx-051 significantly enhanced the anti-tumor effect. The proliferation of cancer cell was markedly inhibited in all the treated groups compared to non-treated group (p & lt;0.05) as down-regulating of PCNA expression. Also, via mediating the expression of ATM and CDK2, the combined treatment group (radiotherapy with Gx-051) significantly enhanced the activation of ATM pathway-related proteins (p & lt;0.05). The tumor suppress gene, p53, was highly expressed and the one of typical oncogenes, Met, was suppressed in combined treatment group compared to others. In addition, expression of p38-MAPk as one of the cell stress markers was decreased in combined treatment group compared to others. CONCLUSIONS: We determined the combined radiotherapy with Gx-051 improved the responses to HNSCC by AT-84 via the activation of ATM pathway that influenced cell proliferation, apoptosis, and regulation of tumor suppress gene and oncogene. These results gave us the partial rationale to the further study about the combined therapy of radiation with Gx-051 for the advanced treatment of human HNSCC. This study was supported by grant of the Korean Health Technology R & D Project, Ministry of Health & Welfare (A091205) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012-0004140). Citation Format: Jiyoung Yeo, Eun-Ji Park, Kwang-Jae Cho, Kyung Min Kim, Young-chul Sung, Jun-Ook Park, In-chul Nam, Chung-su Kim, Min-Sik Kim. ATM pathway upregulation of combination therapy with radiation and MSC-based IL-12M gene vaccine, Gx-051, in allograft animal model. [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 479. doi:10.1158/1538-7445.AM2013-479
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-479
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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