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  • American Association for Cancer Research (AACR)  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 1
    Online Resource
    Online Resource
    Abstract C82: Induction of resistances to crizotinib in lung patient derived xenograft
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C82-C82
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C82-C82
    Abstract: Background. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, and its mutation, over-expression and gene fusion have been associated with various cancers. EML4-ALK fusion has been confirmed to be an oncogenic driver for a small subset of the lung cancers (∼4% of NSCLC)1, and becomes an excellent drug target that led to the development of the first effective therapy, crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase, for this disease 2,3. However, like any other cancer therapy so far, the treatment always led to the development of resistance, rendering them ineffective in the end4. Understanding the mechanisms causing these resistances can potentially facilitate overcoming the resistance and extend patients' life5,6. However, lack of experimental model hinders this understanding. Method. We have recently established a large collection of patient derived xenografts (∼350 PDXs)7, and we screened some of them for alk gene fusions. We then tested the positive model for sensitivity to crizothinib, and keep it under several rounds of crizotinib treatments to select resistant model. The induced resistant model was subjected to genomic analysis to identify the changes that might potentially be responsible for the resistance. Results. We identified one model, NSCLC LU1656, containing EML4-ALK fusion with elevated ALK expression. It has also been shown to respond well to crizotinib in vivo. The continued treatment eventually led to the development of resistance to crizotinib (LU2445), a situation that might occur in patients in the clinic under the same treatment. We have performed transcriptome sequencing of the parental sensitive tumor (LU1656) and the selected resistant tumor (LU2445). So far, we found both models expressed similar high levels of expression of ALK, but no additional mutations in ALK gene. There are other alterations either genetically or epigenetically, some seemingly related to the ALK signaling pathways. However, their role in resistance still need to be confirmed. Conclusions. Induced crizotinib resistance in ALK-fusion lung PDX can be useful to investigate crizotinib resistant mechanism and future drugs overcoming the resistance. References 1. Koivunen, J.P., et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 4275-4283 (2008). 2. Kwak, E.L., et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363, 1693-1703 (2010). 3. Takeuchi, K., et al. RET, ROS1 and ALK fusions in lung cancer. Nature medicine 18, 378-381 (2012). 4. Katayama, R., et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Science translational medicine 4, 120ra117 (2012). 5. Katayama, R., et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clinical cancer research : an official journal of the American Association for Cancer Research 20, 5686-5696 (2014). 6. Friboulet, L., et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer discovery 4, 662-673 (2014). 7. Yang, M., et al. Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naive Asian NSCLC patients. Int J Cancer 132, E74-84 (2013). Citation Format: Jianyun Deng, Zhun Wang, Jie Cai, Sheng Guo, Jean-Pierre Wery, Henry Li. Induction of resistances to crizotinib in lung patient derived xenograft. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C82.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-C82
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 2
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    Abstract 4997: Novel anti-PD-L1/IL-15 bifunctional immunotherapeutics potentiates antitumor immunity
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4997-4997
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4997-4997
    Abstract: Target-based immunocytokine approaches have been reported to be efficacious in the control of tumor growth in preclinical and clinical studies. By targeting cytokines-activated immune effectors to local tumor sites, an antibody-based immunocytokine is able to achieve antitumor immunity in the tumor microenvironment while reducing cytokines-mediated systemic side effects. Recently, immune checkpoint antagonists to PD-1/PD-L1 have shown success in certain clinical settings across multiple cancer types. However, the full potential of the checkpoint inhibitor is limited due to impaired overall antitumor immunity. It is therefore desirable to develop immunotherapeutics with the capacity of simultaneously inhibiting immunosuppressive pathways and stimulating immune effector cells to potentiate innate and adaptive immune responses against tumor growth. To this end, we generated a bifunctional fusion protein, KD033, composed of an antibody specific for PD-L1 and IL-15 as a novel immunocytokine for achieving better immunotherapeutic efficacy against tumors. Previously, we demonstrated that KD033 has an enhanced immunological activity and stronger antitumor efficacy in some syngeneic mouse tumor models in comparison to single agents. In the present report, we show that the mechanisms of actions of the bifunctional protein in the enhancement of antitumor immune responses results from an increase in Th1 cytokine secretion, the expansion and cytotoxicity of CD8 T-cells and NK cells and a decrease in immunosuppressive cells, i.e. regulatory T cells and myeloid derived suppressive cells in a number of preclinical experimental models. In the preclinical studies, KD033 regimens, with the unique immunological properties, led to stronger anti-tumor efficacy in controlling primary tumor growth and prolonging the survival of tumor bearing mice in a number of mouse tumor models including PDX and GEMM tumor models. Importantly, the PD-L1-targeted IL-15 bifunctional protein had significantly less cytokine-related toxicity when compared to non-targeted full IgG antibody-IL-15 fusion protein in vivo. These results further elucidate the capacity of targeting IL-15-stimulated innate and adaptive immune effector cells into tumor microenvironment, thereby effectively controlling tumor progression while having minimized adverse effect in vivo. These encouraging preclinical results of the novel immunotherapeutics suggest further advancement of this innovative therapeutic candidate towards clinical development for cancer treatment. Citation Format: Yan Wu, Zhaojing Zhong, Stella Martomo, Dan Lu, Haifan Zhang, Zhanna Polonskaya, Xenia Luna, Zhikai Zhang, Zhun Wang, Leo Liu, Jeegar Patel, James Tonra, Henry Li, Larry Witte, Sam Waksal, Zhenping Zhu. Novel anti-PD-L1/IL-15 bifunctional immunotherapeutics potentiates antitumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4997.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4997
    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 A30: Modeling an immunotherapy of NK mechanism on a NSCLC patient derived xenograft
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 16_Supplement ( 2016-08-15), p. A30-A30
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. A30-A30
    Abstract: The recent clinical successes of immune checkpoint inhibitors have fueled the intense interest in novel immuno-oncology (I/O) therapeutics. The lack of relevant animal models remains a major hurdle in understanding the mechanism of action and evaluating the efficacy of such therapeutics. Patient derived xenograft (PDX), considered to most closely mimic patient tumors in both histo- and molecular pathology1,2, is however rarely used in I/O studies because it grow only in immune-compromised hosts. In reality, many PDXs grow well in nude mice where certain immune functions remain intact, excluding T-cells/T-cell functions. Therefore, PDX could still potentially be of practical use for studying T-cell independent I/O therapy. This study set out to evaluate a biologics for the treatment of a patient derived xenograft disease, by activating mouse natural killer (NK). NK and CD8 T cells are two major immune effector cell types that mediate cytotoxicity to tumor cells in vivo. One of the immunomodulatory agents, an anti-PD-L1 antibody-based IL-15 immunocytokine, was recently tested as a novel I/O treatment of cancer3. This molecule was engineered to be cross-species for both human and mouse PD-L1 and IL-15 that antagonize PD1/PD-L1 checkpoint-mediated immune suppression and also target the PD-L1-expressing tumor with IL-15 stimulated NK and CD8 T effector cells into local tumor sites, thus synergizing tumor-located anti-tumor immunity. In fact, our previous studies have demonstrated a greatly enhanced anti-tumor activity in the PDL-1-expressing syngeneic mouse tumor models via the mobilization of tumor infiltrating lymphocyte (TILs), over the PD-L1 antibody alone3. Since IL-15 also stimulates NKs in addition to T-cells, we reasoned that this bifunctional agent could also have potential activity against a PD-L1-expressing PDX in nude mice where NK remains functional. LU1901 is previously described NSCLC-PDX1, and was confirmed to express high level of PD-L1 by both RNAseq and flow analysis, after screening of a large panel of PDXs. We implanted LU1901 in Balb/c nude mice, and started to treat the mice by the bifunctional agent when the tumor reached to 150 mm3. Our result clearly demonstrated a significant inhibition of LU1901 growth by the bifunctional agent in nude mice, in the apparent absence of T-cells. When the treated tumors were examined at the termination, significantly infiltrate NK cells were found inside the treated tumors, as measured by both flow cytometry and immunohistochemistry (IHC). The number of infiltrating NK also statistically correlates to the amplitude of the tumor responses. Together, our data suggest that one of important mechanisms of action of this bifunctional agent relies on the tumor-targeting NK activation, and also that PDX could be a useful model suitable for in vivo efficacy analysis of T-cell independent immunotherapy. References 1. Yang, M., et al. Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naive Asian NSCLC patients. International journal of cancer. Journal international du cancer 132, E74-84 (2013). 2. Guo, S., Wubin Qian, Jie Cai, Likun Zhang, Jean-Pierre Wery, Qi-Xiang Li. Molecular pathology of patient tumors, patient derived xenografts and cancer cell lines EORTC-NCI-AACR. (2015). 3. Yan Wu, Zhaojing Zhong, Stella Martomo, Dan Lu, Zhanna Polonskaya, Xenia Luna, Haifan Zhang, Zhikai Zhang, Zhun Wang*, Leo Liu*, Jeegar Patel, James Tonra, Henry Li*, Larry Witte, Sam Waksal, Zhenping Zhu. Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity. EORTC-NCI-AACR Abstract (2015). Citation Format: Henry Q. Li, Zhun Wang, Xiaoyu An, Jinping Liu, Likun Zhang, Jean-Pierre Wery, Yan Wu, James Tonra, Sam Waksal, Zhenping Zhu. Modeling an immunotherapy of NK mechanism on a NSCLC patient derived xenograft. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A30.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.PDX16-A30
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
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  • 4
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    Abstract 1472: Building comprehensive and fully annotated patient tumor derived xenogragft (PDX) library mirroring cancer patient population
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1472-1472
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1472-1472
    Abstract: Patient derived xenografts (PDXs) mirrors patients’ pathology and genetic profiles, thus valued as predictive experimental models for studying oncogenesis and personalized treatments. Cancer is not a single disease but diseases of complex genetic components and oncogenic processes. Limited number of PDX models with minimal genetic characterization is insufficient to meet current research needs. For this, we have built the largest and most comprehensive PDX library with full genetic profiles. By far, our PDX library contains over 1,100 models derived from patients of both Asian and Western origins, covering over 20 major cancer types, including large panels (over 100 models each) of NSLCL(1), CRC(2), gastric(3), HCC(4), and pancreatic, and smaller panels ( & lt;100) of esophageal, H & N, ovarian, cholangiocarcinoma, breast, brain, etc. Our PDX models come with original patient and pathology diagnosis information, and verified at the level of histopathology and genetic fingerprints. These models have tumor growth and standard of care (SOC) treatment information. They are fully profiled using GeneChip based technology (U219, SNP6.0, miRNA), NGS (RNAseq and WES), and hotspot mutation, etc (HuPrime® 1.0), with HLA typing readily available to enable immuno-oncology research. Comparing our PDXs’ genomic profiles with published patient genomic profiles in literature (4) and TCGA data source (Guo et al., 2015 AACR Annual) revealed high degree of similarity. Subsets of models have been comprehensively characterized for special relevance to specific clinical characteristics and specific drug targeting mechanisms (HuPrime® 2.0). These subsets include all clinically observed EGFR mutated NSCLC(1, 5, 6); c-MET activation diseases(7); FGFR driven diseases; RET-fusion driven CRC(8); FLT3-LTD driven AML (9), IDH mutated AML(9) and CRC; RSPO-fusion driven CRC; BCL-ABL fusion disease, HER driven gastric and breast cancers, and ALK fusion NSCLC, etc. We have also established numeric drug resistant models to various SOCs of both chemotherapy and target therapies. The resistance could be de novo (1) or induced (10). These resistant models can be great tools to investigate drug resistant mechanisms and approaches to overcome them. Many PDXs can also been tested orthotopically, including liver, brain, colon, pancreatic, ovarian, and breast etc. Models have great metastatic potential have also been identified, enabling study metastatic mechanism and identifying agents to block the metastasis. A number of PDXs can grow in humanized mice (HuPrime® 3.0), where human immunity has been reconstituted in the immune-compromised mouse background (11) to facilitate immune-oncology research. Our large library of different disease panels are particularly useful in conducting mouse clinical trial (MCT of HuTrialTM) (2, 5, 12), which can be used to discover predictive biomarker (2, 5, 13) and guide clinical study design. Citation Format: Jie Cai, Dawei Chen, Rajendra Kumari, Sheng Guo, Jie Yang, Mengmeng Yang, Andrew McKenzie, Zhun Wang, Xuesong Huang, Xiaoyu An, Jinping Liu, Jean-Pierre Wery, Henry Li. Building comprehensive and fully annotated patient tumor derived xenogragft (PDX) library mirroring cancer patient population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1472. doi:10.1158/1538-7445.AM2015-1472
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-1472
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 1432-1
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  • 5
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    Abstract 3219: Prior vaccination is critical to PD1/PDL-1 treatment efficacy in a mouse breast cancer allograft
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3219-3219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3219-3219
    Abstract: We previously generated the MuPrime® mBR6004 model, by engrafting the breast adenocarcinoma derived from MMTV-PyVT transgenic mice (GEMM)1 into the syngeneic FVB/N mice2,3. The allograft grows robustly, maintains the histopathology features of the original GEMM, and metastasizes to the lungs in all examined cases when implanted orthotopically2. Additionally, histopathology shows that the models is HER2++, but ER-/PR-. We profiled drug responses to standard of care (SoC)2 and checkpoint inhibitors3. Interestingly, among all checkpoints inhibitors tested, our model is insensitive to PD1/PDL-1 inhibitors, but responds to CTLA-4 inhibitors3. To further explore the underlying mechanism of response, we performed extensive tumor immuno-profiling for the presence of infiltrating immune cells, e.g. TIL, CTL, Treg, immune-suppressive macrophages, NK, etc3. We observed a good pharmacodynamic (PD) correlation between the presence of tumor infiltrating T-cells, particularly CD8+ TIL, and NK and a positive response to therapy, regardless the treatment type. Given this preliminary observation, we attempted animal vaccination with tumor lysates prior to tumor engraftment or treatments. Interestingly, while vaccination had minimal effects on the engraftment take rate (100% take for all animals) and on the growth kinetics of the engraftments, it had profound effects on the tumor response to anti-PD1/anti-PDL-1 antibody treatments, significantly enhancing tumor response to these agents in a model that was otherwise unresponsive. Our results suggest that the immunological status of the animal, at least with regard to the specific anti-tumor immunity, is critically important to determine the response to checkpoint inhibitors. Our observations suggest that vaccination is critical for the overall success of immunotherapy (I/O) treatments utilizing checkpoint inhibitors as well other treatment strategies. References 1. Guy, C.T., Cardiff, R.D. & Muller, W.J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Molecular and cellular biology 12, 954-961 (1992). 2. Annie Xiaoyu An1, Jinping Liu1, Jie Cai1, Jean Pierre Wery1, and Henry Q.X. Li1,. Building mouse tumor derived allogragfts for immune-oncology research. (2015). 3. Zhun Wang1, A.X.A., 2*, Jinping Liu1, Gavin Jiagui Qu1, Likun Zhang, Jie Cai1, Bin Chen1, Davy Xuesong Ouyang1, Jean Pierre Wery1, and Henry Q.X. Li1,2. Response to checkpoint inhibition by GEMM breast cancer allograft EORTC-AACR-NCI Abstract (2015). Citation Format: Zhun Wang, Xiaoyu An, Jinping Liu, Xuesong Ouyang, Jiagui Qu, Likun Zhang, Jie Cai, Jean-Pierre Wery, Henry Li. Prior vaccination is critical to PD1/PDL-1 treatment efficacy in a mouse breast cancer allograft. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3219.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3219
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract C173: Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C173-C173
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C173-C173
    Abstract: Immune checkpoint antagonists to PD-1/PD-L1 and immunostimulating cytokines such as IL-15 have shown success to some extent in certain clinical settings across multiple cancer types. However, the full potential of the checkpoint inhibitor is limited due to impaired overall antitumor immunity, and cytokine as single agent has insufficient half-life and systemic toxicities due to the lack of target specificity. To overcome these challenging hurdles, we developed a bifunctional fusion protein, KD-033, composed of an antibody specific for PD-L1 and complex of IL-15Rα sushi domain/IL-15 as a novel immunotherapeutic agent for achieving better antitumor efficacy. Previously, we presented the generation and characteristics of a prototype of bifunctional fusion protein and its potential of in vivo antitumor activity. Here, we report a genetically modified fusion protein that has enhanced immunological activity and capability to achieve stronger antitumor efficacy in tumor models in comparison with either single agent. Our data indicate that the improved bifunctional fusion protein has favorable thermal stability and can be efficiently expressed in mammalian cells. The bifunctional fusion protein has higher affinity to PD-L1, silenced binding activity to Fc receptors and better ability to increase the secretion of Th1 cytokine, i.e. gamma IFN and the cytotoxicity of CD8 T-cells and NK cells to tumor cells as assessed in immunological assays. In preclinical study, KD033 had stronger anti-tumor efficacy in controlling primary tumor growth and prolonging the survival of tumor bearing mice in a number of mouse tumor models including those aggressive tumor models. Furthermore, the PD-L1 targeted bifunctional protein had significantly less cytokine-related toxicity when compared to non-targeted full IgG/IL-15Rα sushi domain/IL-15 fusion protein in vivo. These results demonstrate that KD033 has the capacity of targeting IL-15-stimulated innate and adaptive immune effectors into local tumor sites, thereby effectively controlling tumor progression while having minimized potential adverse effect in vivo. The preclinical studies of the novel immunotherapeutics warrant further investigation towards the clinical development of the bifunctional immunotherapeutic agent for cancer treatment. Citation Format: Yan Wu, Zhaojing Zhong, Stella Martomo, Dan Lu, Zhanna Polonskaya, Xenia Luna, Haifan Zhang, Zhikai Zhang, Zhun Wang, Leo Liu, Jeegar Patel, James Tonra, Henry Li, Larry Witte, Sam Waksal, Zhenping Zhu. Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C173.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-C173
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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    Abstract A11: HuGEMM-h/mPD1 mouse models for assessing anti-human PD1 therapeutics
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A11-A11
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A11-A11
    Abstract: Background. Blockage of immune checkpoints, e.g. by anti-PD1 antibody, becomes an important new cancer therapy1. Experimental models are important to evaluate new investigational therapy or new combination strategy. Syngeneic mouse tumor models have been widely utilized as an experimental model for testing surrogate immune-oncology (I/O) therapy by using its competent mouse immunity2, but cannot be used for testing human biologic therapeutics, due to the species specificity. The direct replacing mouse therapeutic target by human counterpart in mouse while maintaining the normal mouse immune-functions could be a potential practical preclinical approach to evaluate human biologic therapeutics in vivo. Methods. We have engineered a chimeric human/mouse PD1 gene (h/mPD1) composed of human exome 2 & 3 and mouse exome 1 & 4. We expressed the recombinant proteins and tested their bindings to their binding partner of PDL1 of both mouse and human origins, and also anti-human PD1 antibody. We knock-in the recombinant gene into C57Bl/6 mouse to create homozygous HuGEMM-h/mPD1 mouse, which is tested for growth of MC38 syngeneic mouse cell line tumor graft and for the growth inhibition by anti-human PDL1 antibody. Results. Our data demonstrated that chimeric protein h/mPD1 can interchangeably interact with mPDL1 or hPDL1 efficiently as efficiently as mouse PD1, and it also recognizes anti-human PD1 antibody as expected. The binding of anti-human PD1 antibody blocks its binding to mouse or human PDL1. The knock-in mice express the chimeric gene in the T-cells of the engineered mice both in vivo and ex vivo, however at significantly lower levels than mouse PD1 in the wild type C57BL/6 mice (1/10) under induction. When syngeneic MC38 cell line was subcutaneously engrafted in HuGEMM-h/mPD1 mice, the tumor were found to grow significantly slower with increased T-cell infiltration, as compared to those in the wild type mice. MC38 tumor did not respond to anti-human PD1 antibody well either. These observations can apparently be attributed to the low level PD1 and the associated high autoimmunity that also inhibits tumor growth. Interestingly, a specific condition can be artificially created to enhance MC38 tumor growth in the chimeric mice, likely contributed by the enhanced h/mPD1 expression. The enhanced tumor growth seems to also be suppressible, at least partially, by anti-human PD1 antibody as shown in our preliminary study. Currently, we are re-engineering our chimeric gene (version 2) in order to increase their expression to the wild type gene level, so to create a model for more optimal drug evaluation. In the meantime, we are also engineering HuGEMM-hu-CKPT (e.g. CTLA4 PDL-1, OX40, 4-1BB, etc.) for evaluating other checkpoint inhibitors. Conclusions. Our data suggests the conditioned version 1-HuGEMM-h/mPD1 mouse can be explored to evaluate anti-human antibody. References 1. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer 12, 252-264 (2012). 2. Allard, B., Pommey, S., Smyth, M.J. & Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 5626-5635 (2013). Citation Format: Zhun Wang, Bin Cai, GANG Chen, Jinping Liu, Xiaoyu An, Zhengsheng Wang, Davy Ouyang, Jean-Pierre Wery, Jay Liu, Xin Dong, Henry Li. HuGEMM-h/mPD1 mouse models for assessing anti-human PD1 therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A11.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-A11
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
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    Abstract A200: CBT-502 (TQB2450), a novel anti-PD-L1 antibody, demonstrates favorable activity in MC-38/H-11 murine colon and A375 human melanoma animal models
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. A200-A200
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A200-A200
    Abstract: Background: CBT-502 (TQB2450) is a novel humanized IgG1 antibody against programmed cell death-ligand 1(PD-L1) developed by CBT Pharmaceuticals, Inc. CBT-502 shows significant sequence divergence in CDRs from other anti-PD-L1 antibodies in the market today, including atezolizumab, durvalumab, and avelumab. Several human cancer cells express high levels of PD-L1. PD-L1 binds to its receptor, PD-1, on activated T cells, and CD80, on dendritic cells and monocytes and inhibits cytotoxic T cells. Therapeutic blockade of PD-L1 reduces the growth of tumors in the presence of immune cells. In vitro, CBT-502 demonstrated binding affinity to human PD-L1 by SPR of 0.25 nM and cyno-PD-L1 of 0.24 nM. In cell based assay, CBT-502 effectively blocked the interaction of hPD-1 and hPD-L1 (IC50 47.97 pM) and blocked binding of PD-L1 with CD80 (IC50 1.09 nM). CBT-502 strongly activates T cells as measured by IFN-gamma production in a mixed lymphocyte reaction assay. Pharmacokinetic data in cynomologus monkeys showed a linear dose-dependent relationship. No adverse clinical or histopathologic findings were observed in toxicology screen (NOAEL=200 mg/kg). CBT-502 showed no Fc receptor affinity including FcgRIa, FcgRIIa-167His/Arg, FcgRIIIa-176Phe/Val, FcRn SPR and C1Q. In vivo antitumor activity was evaluated in two mouse models, A375 (melanoma) and MC-38/H-11 (colon), reported herein. Methods: Fifty C57BL/6 mice were intraperitoneally (IP) inoculated with 1x105 MC-38/H-11 cells, and the mice were randomly divided into five groups on Day 2 (D0) following inoculation. The test article group was intraperitoneally injected (IP) with 1.5, 5 and 15 mg/kg once every other day (Q2D) x 11 times while the positive control group (atezolizumab) was administered IP with 15 mg/kg, and the negative control group (human IgG) was injected with same volume at 15 mg/kg. Similarly, A375 human melanoma cells (5 x 106) were implanted subcutaneously in the flank region of highly immune-deficient mouse model (NCG mouse, n=36). The mouse immune system was replaced with human PBMC. Only mice with high CD45 ratio are included in the study. CBT-502 was dosed IP at 5 and 10 mg/kg once weekly (qw) and three times weekly (tiw), whereas atezolizumab was dosed 10 mg/kg (tiw). Results: In the MC-38/H-11 model, CBT-502 relative to atezolizumab demonstrated comparable tumor growth inhibition (TGI) rates, 91.7% vs. 93.8% in the 15 mg/kg dose group. CBT-502 showed potent in vivo antitumor activity in a dose-dependent manner in the A375 model. TGI % at 10 mg/kg tiw was 53.5% and 59.4% for CBT-502 and atezolizumab, respectively. There was no obvious loss of body weight (BW) with CBT-502 administration, although a slight reduction in BW was observed with atezolizumab 10 mg/kg tiw. Conclusions: CBT-502 preclinical pharmacodynamics and toxicology studies demonstrated pharmacologic activity and is well tolerated at effective doses with a wide margin of safety. In vivo efficacy and safety data in the A375 model compared favorably to atezolizumab, with the MC38 model confirming activity of CBT-502. With these encouraging nonclinical data, CBT Pharmaceuticals and China partner CTTQ plan to develop and evaluate CBT-502 in multiple solid tumors, anticipated in 2018. Citation Format: Zhao Wei, Ling Yang, Yingchun Li, Jiansheng Lu, Xiquan Zhang, Xin Tian, Jiping Zha, Ziyong Sun, Junzhuan Qiu, Zhun Wang, Mamatha Reddy, Gavin S. Choy, Sanjeev Redkar. CBT-502 (TQB2450), a novel anti-PD-L1 antibody, demonstrates favorable activity in MC-38/H-11 murine colon and A375 human melanoma animal models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A200.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-A200
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    miR-125b Is Methylated and Functions as a Tumor Suppressor by Regulating the ETS1 Proto-oncogene in Human Invasive Breast Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 10 ( 2011-05-15), p. 3552-3562
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 10 ( 2011-05-15), p. 3552-3562
    Abstract: The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G1 cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease. Cancer Res; 71(10); 3552–62. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-2435
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    Abstract 2008: Intestinal microbiota may dynamically facilitate the anti-PD-L1 immunotherapy
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2008-2008
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2008-2008
    Abstract: Cancer immunotherapies, e.g. the antibody against programmed death ligand 1 (PD-L1), a checkpoint inhibitor, have witnessed great successes in treating certain cancers in recent years. Recent data have also demonstrated that gut microbiota are important modulators on anticancer immunotherapy1,2. Heterogeneity in patient outcome seems to suggest complex communications between microbiota and host antitumor immunity. To this end, we tested an engineered chimeric MC38 mouse cell line, hPDL1-MC38-HuCELL™ via human PD-L1 knock-in procedure, where MC38 CRC syngeneic cell is derived from C57BL/6. After treatment of PD-L1 antibodies (cD7A8 and BMS PD-L1 of different dose regimens), we observed significantly different drug responses among the mice from three different Chinese rodent suppliers: the mice from Vendor 1 showed no tumor progression after treatment with a variety of doses while no favorable response was observed in mice from Vendor 2 and Vendor 3. To deeply study the gut microbiota of these mice, we performed 16S ribosomal RNA sequencing on untreated mice from three groups (5 replicates for each). Global diversity analysis by Quantitative Insights Into Microbial Ecology (QIIME) tool revealed a clear separation in the three sources of mice: the microbiota composition of Vendor 2 and Vendor 1 are relatively closer to each other whereas the Vendor 3 mice are different, suggesting that the main difference seen between Vendor 1/2 and 3 in the original composition of gut microbiota is not the key impact for the observed anti-PD-L1 efficacy, and there should be other complex dynamics impacted anti-PD-L1 treatment, which remains unknown. Moreover, a group of 27 taxa were identified with significant difference in abundance (Kruskal-Wallis test, p-value & lt; 0.05) across the groups, such as Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae, which confirmed the previous data1. In conclusion, intestinal microbiota dynamically facilitate anti-PD-L1 efficacy and reversely anti-PD-L1 treatment could influence reconstruction of gut microbiota. References 1. Sivan A, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084-9. 2. Vétizou M, et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350(6264):1079-84. 3. Caporaso JG, et al., QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335-6. Citation Format: Jia Xue, Zhun Wang, Sheng Guo, Jie Cai, Davy Ouyang, Bin Cai, Gang Chen, Jie Liu, Xin Dong, Henry Li. Intestinal microbiota may dynamically facilitate the anti-PD-L1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2008. doi:10.1158/1538-7445.AM2017-2008
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2008
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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