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  • 1
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    Online Resource
    Type 17 immunity promotes the exhaustion of CD8 + T cells in cancer
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 6 ( 2021-06), p. e002603-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 6 ( 2021-06), p. e002603-
    Abstract: Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8 + tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8 + TILs in Il17a −/− mice, Il17a Cre R26 DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4 + T cells or CD11b + Gr-1 hi myeloid cells in vivo , respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset. Results Depletion of CD4 + T cells promotes the exhaustion of CD8 + T cells with a concomitant increase in IL-17-producing CD8 + T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8 + T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103 + KLRG1 − IL-7Rα hi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1 hi Tim3 + TOX + terminally exhausted CD8 + T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8 + T cells and also delays tumor growth in vivo . Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8 + T cell exhaustion signature gene sets in multiple cancers. Conclusion IL-17-producing cells promote terminal exhaustion of CD8 + T cells and tumor progression in vivo , which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8 + T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-002603
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 2
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    Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses
    MDPI AG ; 2020
    In:  Vaccines Vol. 8, No. 3 ( 2020-07-22), p. 403-
    Details
    In: Vaccines, MDPI AG, Vol. 8, No. 3 ( 2020-07-22), p. 403-
    Abstract: For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.
    Type of Medium: Online Resource
    ISSN: 2076-393X
    URL: Article
    DOI: 10.3390/vaccines8030403
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2703319-3
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  • 3
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    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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  • 4
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    Phase IIa study of BVAC-C in HPV type 16 or 18 positive recurrent cervical carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 5512-5512
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 5512-5512
    Abstract: 5512 Background: BVAC-C is a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, which was well tolerated in HPV positive recurrent cervical carcinoma in phase I study (J Clin Med. 2020 Jan 5;9(1):147). This phase IIa study sought to determine the antitumor activity of BVAC-C. Methods: Twenty-one patients with HPV 16 or 18 positive recurrent cervical cancer who had experienced recurrence after one prior platinum-based combination chemotherapy were enrolled. They were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks (1x10 8 cells/dose); Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks (5x10 7 cells/dose); Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks (5x10 7 cells/dose) with topotecan at 2, 6, 10, 14 weeks (0.75 mg/m2 for 3 days). Results: The overall response rate was 21% (Arm 1: 29% (2/7), Arm 2: 25% (1/4), Arm 3 : 0 % (0/3)) among the evaluable patients (N = 14), and the median duration of response was 18 months (range, 9 – 26 months). The disease control rate was 43% (Arm 1: 29% (2/7), Arm 2: 50% (2/4), Arm 3 : 67 % (2/3)) and the median duration of stable disease were 12 months (range, 6 - 26 months). The median progression-free survival in all patients was 4 months (95% CI, 2 to Infinite months). Immune responses of patients after vaccination were shown to be correlated with clinical responses of them. Consistent with Phase I study, all evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α), which might be mediated by the activation of natural killer cells and natural killer T cells, but also potent E6/E7-specific T cell responses upon vaccinations. Conclusions: BVAC-C demonstrated a durable antitumor activity with an immune response in HPV 16- or 18-positive recurrent cervical carcinoma patients who failed 1 st line platinum based chemotherapy. Clinical trial information: NCT02866006.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.5512
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Online Resource
    Efficacy and safety of BVAC-C in HPV type 16- or 18–positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study
    Frontiers Media SA ; 2024
    In:  Frontiers in Immunology Vol. 15 ( 2024-3-28)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 15 ( 2024-3-28)
    Abstract: BVAC-C, a B cell– and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV–positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16– or 18–positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1–not reported), the median PFS was 5.8 months (95% CI 4.2–10.3), and the median OS was 17.7 months (95% CI 12.0–not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration ClinicalTrials.gov , identifier NCT02866006.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2024.1371353
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 2606827-8
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  • 6
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    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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  • 7
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    Online Resource
    Immunomodulatory effects of topotecan augment the effectiveness of chemotherapy-immunotherapy combination
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 169.23-169.23
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 169.23-169.23
    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.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.169.23
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Online Resource
    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
    MDPI AG ; 2020
    In:  Journal of Clinical Medicine Vol. 9, No. 1 ( 2020-01-05), p. 147-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 1 ( 2020-01-05), p. 147-
    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.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm9010147
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662592-1
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  • 9
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    Development of broadly protective COVID-19 vaccine against up-to-date variants based on adenovirus type 5/35 vector platform.
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 159.06-159.06
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 159.06-159.06
    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron strain has evolved into a highly divergent variant with several sub-lineages. These new emerging variants could impair the protective efficacy of COVID-19 vaccines based on the ancestral spike, causing breakthrough infections and re-infections. Therefore, it is imperative to develop new multivalent vaccines that can provide broad protection against currently prevalent new variants. We previously developed AdCLD-CoV19-1 OMI, an Ad5/35 platform based non-replicating recombinant adenoviral vector that encodes the spike protein of BA.1, and currently performing clinical studies. We also constructed vaccines against emerging subvariants such as BA.5, BA.2.75, XBB, BQ.1.1, and BN.1 using the Ad5/35 platform and evaluated their immunogenicity by sera from vaccinated mice. To develop the bivalent vaccine, we selected a combination of BA.5 and BA.2.75 vaccines by antigenic cartography map based on cross-neutralizing activities. We found that a bivalent vaccine could induce broadly neutralizing antibodies against the predominant circulating strains and improved cross-neutralization capacity. These data suggest that the bivalent vaccine broadens immunity against current prevalent omicron subvariants. We further investigate combinations of next-generation multivalent vaccines to confer broad protection against new subvariants. Based on the results of preclinical studies, clinical trials of the polyvalent vaccines will be conducted. Supported by grant from the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2020M3A9I2107463)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.159.06
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 10
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    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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