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  • American Association for Cancer Research (AACR)  (10)
  • 1
    Online Resource
    Online Resource
    A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 15 ( 2007-08-01), p. 7477-7486
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 15 ( 2007-08-01), p. 7477-7486
    Abstract: Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu–specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and α-galactosylceramide (αGalCer)–loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or αGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer. [Cancer Res 2007;67(15):7477–86]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-4639
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 5 ( 2020-05-01), p. 698-709
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 5 ( 2020-05-01), p. 698-709
    Abstract: Although treatment with the glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21–producing follicular helper T (Tfh) cells play a crucial role in DTA-1–induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6fl/flCd4Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-19-0748
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 3
    Online Resource
    Online Resource
    Tumor Microenvironmental Conversion of Natural Killer Cells into Myeloid-Derived Suppressor Cells
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 18 ( 2013-09-15), p. 5669-5681
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 18 ( 2013-09-15), p. 5669-5681
    Abstract: How myeloid-derived suppressor cells (MDSC) emerge in the tumor environment remains unclear. Here, we report that GM-CSF can convert natural killer (NK) cells into MDSCs. When transferred into tumor-bearing mice, adoptively transferred NK cells lost their NK phenotype and were converted into Ly6ChighLy6Ghigh MDSC. This conversion was abolished by exposure to IL-2 either in vitro or in vivo. Notably, we found that of the 4 maturation stages based on CD11b/CD27 expression levels, only the CD11bhighCD27high NK cells could be converted into CD11b+Gr1+ MDSC ex vivo. Transfer of CD27high NK cells from tumor-bearing mice into tumor-bearing recipients was associated with conversion to MDSC in a manner associated with reduced numbers of CD11bhighCD27high and CD11bhighCD27low NK cell populations in the recipients. Our results identify a pathway of MDSC development from immature NK cells in tumor-bearing hosts, providing new insights into how tumor cells modulate their host immune microenvironment to escape immune surveillance. Cancer Res; 73(18); 5669–81. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-0545
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 3 ( 2019-03-01), p. 498-509
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 3 ( 2019-03-01), p. 498-509
    Abstract: GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF–induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2–PGE2 pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells in vitro and in vivo. GM-CSF–activated monocyte-derived dendritic cells converted tumor-specific naïve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-18-0518
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2732517-9
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  • 5
    Online Resource
    Online Resource
    Abstract CT123: Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT123-CT123
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT123-CT123
    Abstract: BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1×107, 4×107, or 1×108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2-11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway. Citation Format: Chel Hun Choi, Hyun Jin Choi, Jeong-Won Lee, Eun-Suk Kang, Duck Cho, Byung Kwan Park, Yong-Man Kim, Dae-Yeon Kim, Hyungseok Seo, Myunghwan Park, Wuhyun Kim, Ki-Young Choi, Taegwon Oh, Chang-Yuil Kang, Byoung-Gie Kim. Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer [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 CT123.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-CT123
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    Abstract 4239: Immunomodulatory effects of topotecan augment the effectiveness of chemotherapy-immunotherapy combination
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4239-4239
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4239-4239
    Abstract: Combination therapy is a cornerstone of anticancer therapy, suggesting potential therapeutic benefit to nonresponders to single-agent treatment. BVAC, a B-cell-and-monocyte-based vaccine loaded with alpha-galactosylceramide(α-GC) and tumor antigen as reported in our previous studies, can be successfully combined with other treatments. Here we found out a novel synergistic regimen in TC-1 tumor model which combines BVAC with topotecan, a chemotherapeutic agent as a topoisomerase I inhibitor. We demonstrated some significant alteration in the immunoprofiles of topotecan-treated mice. We observed increased tumor recruitment of monocytes and CD8+ T cells, and decreased frequencies in regulatory T cells in tumor. Accordingly, we are currently investigating how topotecan-induced changes in immune cell composition could lead to improvement of antitumor effect. These data indicate that topotecan not only has cytotoxicity to tumor but can contribute to modulating tumor immune microenvironment. We anticipate that this study could provide a rationale for combination of cancer vaccine and chemotherapy and define future optimal treatment regimens in cancer patients. Citation Format: Jeong-Mi Lee, Kwang-Soo Shin, Choong-Hyun Koh, Insu Jeon, Tae-Seung Kang, Boyeong Song, Chang-Yuil Kang. Immunomodulatory effects of topotecan augment the effectiveness of chemotherapy-immunotherapy combination [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 4239.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4239
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    CD1d-Restricted T Cells License B Cells to Generate Long-Lasting Cytotoxic Antitumor Immunity In vivo
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 13 ( 2006-07-01), p. 6843-6850
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 13 ( 2006-07-01), p. 6843-6850
    Abstract: Although resting B cells are known for being poorly immunogenic and for inducing T-cell tolerance, we have here attempted to test whether their immunogenicity could be enhanced by CD1d-restricted invariant T cells (iNKT) to a point where they could be used in cellular vaccines. We found that the addition of the iNKT ligand α-galactosylceramide (αGalCer) to peptide-loaded B cells overcame peptide-specific T-cell unresponsiveness and allowed for the generation of peptide-specific memory CTL immunity. This CTL was induced independently of CD4 T and natural killer cells but required iNKT and CD8 T cells. B cells directly primed CTL, and the αGalCer and the peptide must be presented on the same cell. Importantly, our B-cell–based vaccine is comparable in efficiency with dendritic cell–based vaccines, inducing similar CTL responses as well as providing an effective regimen for preventing and suppressing s.c. and metastatic tumors. Therefore, with the help of iNKT, peptide-pulsed B cells can establish long-lasting antitumor immunity and so show promise as the basis for an alternative cell-based vaccine. (Cancer Res 2006; 66(13): 6843-50)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-0889
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 18 ( 2018-09-15), p. 5315-5326
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 18 ( 2018-09-15), p. 5315-5326
    Abstract: PD-1–based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1–resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1–resistant tumors by restoring the effector function of tumor antigen–specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1–resistant cancer. Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315–26. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-0734
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    Online Resource
    Online Resource
    IL21 Therapy Combined with PD-1 and Tim-3 Blockade Provides Enhanced NK Cell Antitumor Activity against MHC Class I–Deficient Tumors
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Immunology Research Vol. 6, No. 6 ( 2018-06-01), p. 685-695
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 6, No. 6 ( 2018-06-01), p. 685-695
    Abstract: Increased expression of coinhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I–deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti–PD-1/anti–Tim-3 treatment suppressed tumor progression in mice bearing MHC class I–deficient tumors, and the suppression was further enhanced by recombinant IL21 (rIL21) treatments through an NK-cell–dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I–deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I–low/deficient tumors. Cancer Immunol Res; 6(6); 685–95. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-17-0708
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2732517-9
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  • 10
    Online Resource
    Online Resource
    Tumor-Derived Osteopontin Suppresses Antitumor Immunity by Promoting Extramedullary Myelopoiesis
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 22 ( 2014-11-15), p. 6705-6716
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 22 ( 2014-11-15), p. 6705-6716
    Abstract: Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2–MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor-derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment. Cancer Res; 74(22); 6705–16. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-1482
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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