13 results on '"Colin Snyder"'
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2. Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy
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Amrita Basu, Ganesan Ramamoorthi, Gabriella Albert, Corey Gallen, Amber Beyer, Colin Snyder, Gary Koski, Mary L. Disis, Brian J. Czerniecki, and Krithika Kodumudi
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T helper ,CD4 ,neoantigen ,tumor associated antigen ,immunotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Current success of immunotherapy in cancer has drawn attention to the subsets of TH cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic TH subsets in the tumor milieu further contributes to the complexity of regulation of TH cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory TH9 and Tfh cells, immunosuppressive Treg cells, and the duality of TH17 function contribute to tip the balance of anti- vs pro-tumorigenic TH responses in the tumor. We highlight the developing knowledge of CD4+ TH1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4+ TH1 immunity, and how opposing action of TH cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4+ TH cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic TH subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.
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- 2021
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3. Sequential Anti-PD1 Therapy Following Dendritic Cell Vaccination Improves Survival in a HER2 Mammary Carcinoma Model and Identifies a Critical Role for CD4 T Cells in Mediating the Response
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Krithika N. Kodumudi, Ganesan Ramamoorthi, Colin Snyder, Amrita Basu, Yongsheng Jia, Sabrina Awshah, Amber P. Beyer, Doris Wiener, Lian Lam, Hongtao Zhang, Mark I. Greene, Ricardo L. B. Costa, and Brian J. Czerniecki
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breast cancer ,dendritic cells ,PD-1 ,PD-L1 ,HER2 ,immune checkpoints ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2+ breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC.
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- 2019
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4. 248 Intrathecal delivery of dendritic cell vaccine eradicates tumor growth and protects against leptomeningeal disease re-inoculation in immunocompetent HER2+ and triple negative breast cancer LMD xenograft models
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Vincent Law, Krithika Kodumudi, Colin Snyder, Brian Czerniecki, and Peter Forsyth
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- 2022
5. Photocatalytic Oxidation of Dissolved Mn2+ by TiO2 and the Formation of Tunnel Structured Manganese Oxides
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Wenqian Xu, Colin Snyder, Yuanzhi Tang, Mengqiang Zhu, Haesung Jung, Yan Li, Anhuai Lu, and Ke Wen
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Atmospheric Science ,chemistry ,Space and Planetary Science ,Geochemistry and Petrology ,Inorganic chemistry ,Photocatalysis ,chemistry.chemical_element ,Manganese ,010501 environmental sciences ,010502 geochemistry & geophysics ,01 natural sciences ,0105 earth and related environmental sciences - Published
- 2021
6. Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway
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Gary K. Koski, Amrita Basu, Payal Grover, Qianxing Mo, Hatem Soliman, Brian J. Czerniecki, Hyo S. Han, Mark I. Greene, Doris Wiener, Colin Snyder, Hongtao Zhang, Yong-Zi Chen, Jose R. Conejo-Garcia, Ricardo Costa, Ganesan Ramamoorthi, Zhongsheng Tong, Krithika Kodumudi, Catherine A. Lee, Shari Pilon-Thomas, and Yongsheng Jia
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Senescence ,Chaperonins ,Receptor, ErbB-2 ,Breast Neoplasms ,Cell Cycle Proteins ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Interferon ,Cell Line, Tumor ,Heat shock protein ,Drug Discovery ,Genetics ,medicine ,Humans ,Interferon gamma ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Cellular Senescence ,030304 developmental biology ,Pharmacology ,0303 health sciences ,biology ,Chemistry ,Vaccination ,Th1 Cells ,Cullin Proteins ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,Ubiquitin-Proteasomal Pathway ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Cancer research ,Cytokines ,Molecular Medicine ,Female ,CUL5 ,medicine.drug - Abstract
HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
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- 2021
7. Abstract 3197: Adoptive T cell therapy using IL-7 and IL-15 expanded HER2-specific CD4 T cells for metastatic breast cancer
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Namrata Gautam, Krithika Kodumudi, Colin Snyder, Amber Beyer, Ricardo Costa, Heather Han, and Brian Czerniecki
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Cancer Research ,Oncology - Abstract
BACKGROUND: Adoptive cell therapy (ACT) has had limited success due to low T cell infiltration in breast cancer (BC) patients. We have shown that administration of class II HER2 peptide pulsed type I polarized dendritic cell (DC1) vaccines leads to increase in CD4 T cells in the periphery of BC patients. In this study, we investigated the feasibility of expanding CD4 T cells from peripheral blood mononuclear cells (PBMC) of HER2-DC1 vaccinated BC patients. METHODS: PBMCs from BC patients receiving HER2-DC1 vaccines were used for CD4 T cell expansion. PBMCs were co-cultured with HER2-DC1 at 10:1 ratio for initial activation followed by expansion with cytokines- IL-2 and IL-7 or IL-15. Expanded T cells were assessed for immune marker phenotyping by flow cytometry and TCRvb analysis. For TCRvB analysis, pre, post DC1, IL-7 and IL-15 expanded CD4 T cells were pelleted for DNA isolation and sequenced using Immunoseq Analyzer platform. In addition, we investigated the in vivo efficacy of adoptively transferred mouse IL-7/IL-15 expanded Her2 specific CD4 T cells in HER2+ TUBO mouse model. RESULTS: Co-culturing of patient PBMCs with HER2-DC1 in the presence of cytokines IL-2, IL-7 and IL-15 expanded CD4 T cells ranging from 8-43 fold expansion in different samples with 92-98% CD4 phenotype. CD4 T cells expanded in IL-7 had stem like memory phenotype while IL-15 skewed to terminally differentiated CD4 T cells. IL-7 expanded T cells had significantly higher Tim3 and Ox40 expression, and effector memory proportion as compared to the IL-15 expanded T cells. Restimulation of expanded T cells with HER2 pulsed DCs showed HER2 specificity as measured by increased interferon-gamma production We identified top five clones in PBMCs from DC1-HER2 vaccinated BC patients compared to baseline. We observed differential abundance of TCR clones under IL-7 and IL-15 conditions and identified unique clones for IL-7 and IL-15. ACT using a combination of IL-7 and IL-15 expanded mouse CD4 T cells led to 50% tumor regression in HER2+ model. CONCLUSION: These studies demonstrate that HER2 specific CD4 T cells can be successfully expanded from HER2-DC1 vaccinated patients. Post HER2 DC1 vaccine can generate a pool of antigen specific CD4 T cells and may offer a promising ACT for HER2 BC. Further studies are warranted to demonstrate the efficacy in the clinical setting. Citation Format: Namrata Gautam, Krithika Kodumudi, Colin Snyder, Amber Beyer, Ricardo Costa, Heather Han, Brian Czerniecki. Adoptive T cell therapy using IL-7 and IL-15 expanded HER2-specific CD4 T cells for metastatic breast cancer [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 3197.
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- 2023
8. Abstract 4056: Intratumoral delivery of autologous tumor antigen specific CD4 Th1 cells combined with dendritic cells eradicates HER2 mammary carcinoma
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Ganesan Ramamoorthi, Amy Aldrich, Colin Snyder, and Brian Czerniecki
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Cancer Research ,Oncology - Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression accounts for 30% of invasive breast cancer (BC) and is critically associated with aggressive disease, recurrence and metastasis. Adoptive cell therapy approaches using cytotoxic CD8 T cells and natural killer cells have been shown to trigger anti-tumor immunity in BC. However, the immunosuppressive tumor microenvironment (TME) can inhibit response to these therapies and diminish the presence and function of tumor-infiltrating lymphocytes. Recently, we have shown a critical role for anti-tumor CD4 Th1 cells in dendritic cells (DC) intratumoral (i.t.) delivery in combination with anti-HER2 therapy. This combination therapy enhanced systemic and local anti-tumor immunity and eradicated tumors in HER2 positive BC with a requirement for CD4 Th1 cells. Here we investigated the efficacy of i.t. delivery of both autologous anti-tumor CD4 Th1 cells and tumor antigen pulsed type 1 polarized dendritic cells (HER2-DC1) in a HER2 mammary carcinoma model. CD4 T cells were isolated from BALB/c mice that had completely regressed (pCR) from orthotopic TUBO tumors following HER2-DC1 i.t. or combination therapy with anti-HER2 antibody. CD4 Th1 cells were then expanded by co-culturing with HER2-DC1 in the presence of interleukin (IL)-2 and IL-7 cytokines. BALB/c mice bearing orthotopic TUBO tumors were treated weekly for six weeks with anti-tumor CD4 Th1 cells i.t., non-specific CD4 Th1 cells i.t., HER2-DC1 i.t. or combination therapy. The i.t. delivery of anti-tumor CD4 Th1 cells combined with HER2-DC1 induced a strong anti-tumor response with survival benefit and complete tumor eradication in 50% of treated mice. Importantly, the i.t. delivery of anti-tumor CD4 Th1 cells were critical for providing priming signals to HER2-DC1 within the TME via CD40/CD40L engagement (licensing). This was supported by a strong anti-tumor response and complete tumor regression in 60% of orthotopic TUBO tumor bearing mice treated with CD40/CD40L licensed HER2-DC1 i.t. therapy compared to un-licensed HER2-DC1 i.t. therapy. Additionally, enhanced survival and functionality of human and mouse HER2-DC1 was observed following activation of CD40/CD40L signaling using anti-CD40 agonistic antibody in vitro. Collectively, these results suggest a new promising therapeutic strategy using DC1-anti-tumor CD4 Th1 adoptive cell therapy intratumoral delivery to induce DC1 priming and create robust anti-tumor immunity within the TME in BC. Citation Format: Ganesan Ramamoorthi, Amy Aldrich, Colin Snyder, Brian Czerniecki. Intratumoral delivery of autologous tumor antigen specific CD4 Th1 cells combined with dendritic cells eradicates HER2 mammary carcinoma. [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 4056.
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- 2023
9. EXTH-01. INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE RE-INOCULATION IN HER2+ AND TRIPLE NEGATIVE BREAST CANCER LMD XENOGRAFT MODELS
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Vincent Law, Krithika Kodomudi, Colin Snyder, Peter Forsyth, and Brian Czerniecki
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND Leptomeningeal disease (LMD) occurs in approximately 5% of patients with breast cancer and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in breast cancer patients. In pre-clinical and clinical trials, the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ breast cancer patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in breast cancer-associated LMD immunocompetent animal models. METHODS Luciferase-labeled HER2+ TUBO breast cancer cells were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir in patients) for the IT administration of DCVs into the CSF. RESULTS AND DISCUSSION breast cancer-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p< 0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ breast cancer-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-g and IL18 response upon DCV treatment. CONCLUSIONS Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in breast cancer patients with LMD.
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- 2022
10. BSCI-01 INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE (LMD) RE-INOCULATION IN IMMUNOCOMPETENT HER2+ AND TRIPLE NEGATIVE BREAST CANCER (TNBC) LMD XENOGRAFT MODELS
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Vincent Law, Krithika Kodumudi, Colin Snyder, Brian Czerniecki, and Peter Forsyth
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General Medicine - Abstract
BACKGROUND LMD occurs in ~5% of patients with breast cancer (BC) and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in BC patients. In pre-clinical and clinical trials the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ BC patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in BC-LMD immunocompetent animal models. MATERIALS AND METHODS Luciferase-labeled HER2+ TUBO BCs were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir clinically in patients) for the IT administration of DCVs into the cerebral spinal fluid (CSF). RESULTS AND DISCUSSION BC-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p CONCLUSION Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in BC patients with LMD.
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- 2022
11. Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma
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Ganesan Ramamoorthi, Krithika Kodumudi, Colin Snyder, Payal Grover, Hongtao Zhang, Mark I Greene, Amrita Basu, Corey Gallen, Doris Wiener, Ricardo L B Costa, Hyo S Han, Gary Koski, and Brian J Czerniecki
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Pharmacology ,Cancer Research ,Receptor, ErbB-2 ,Carcinoma ,Immunology ,Breast Neoplasms ,Dendritic Cells ,CD8-Positive T-Lymphocytes ,Mice ,Oncology ,Animals ,Humans ,Molecular Medicine ,Immunology and Allergy ,Female - Abstract
BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.MethodsBALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.ResultsHER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75–80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.ConclusionsHER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.
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- 2022
12. EXTH-04. INTRATHECAL (IT) DELIVERY OF TYPE I POLARIZED DENDRITIC CELL VACCINE (DC1) ERADICATES TUMOR GROWTH IN BREAST CANCER (BC) XENOGRAFT MODEL WITH BRAIN METASTASES (BM) AND LEPTOMENINGEAL DISEASE (LMD)
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Krithika Kodumudi, Vincent Law, Colin Snyder, Peter A. Forsyth, and Brian J. Czerniecki
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Cancer Research ,business.industry ,medicine.disease ,Intrathecal ,Preclinical Experimental Therapeutics ,Breast cancer ,Oncology ,Dendritic cell vaccine ,medicine ,Cancer research ,LEPTOMENINGEAL DISEASE ,Tumor growth ,Neurology (clinical) ,business ,skin and connective tissue diseases - Abstract
BACKGROUND Approx. 5% of BM will also develop LMD. Currently there is no effective treatment for BC-associated BM/LMD. As systemic therapies do not prevent the disease recurrence and eventual death, the better option would be direct-targeted approach. We have shown that there is a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune response in BC patients (pts). In a clinical setting, administration of class II HER2 peptide-pulsed Type I polarized dendritic cell vaccine (HER2-DC1) partially restored anti-HER2 Th1 immune responses with pathologic complete response in HER2+ BC patients. In this study, we examined the IT delivery of HER2/HER3- DC1 in BC-LMD model. METHODS Luciferase-labeled HER2+ TUBO BC cell line was injected into the cisterna magna of BALB/c mice to develop BM/LMD. We developed a technique, coined the “Top Hat” (TH) for mouse model that mimics the Ommaya reservoir in BC-pts. The TH essentially allows us to administer IT treatment directly into CSF. BC-BM/LMD bearing mice were given HER2- and Her3 peptide-pulsed Type I polarized DC1 through the TH. RESULTS AND DISCUSSION BM/LMD mice were randomized into following groups: 1) systemic Her2-DC1 2) IT Her2-DC1 3) IT Her2-/Her3-DC1. The median survival (MS) of control mice was 10 days and systemically treated mice was 19 days. IT Her2-DC1 animals did significantly better than both control and systemic treated groups (MS: 63 days; p< 0.0001) and overall survival (OS): 44%. Interestingly, mice given IT Her2-/Her3-DC1 had the best OS (78%). Surviving animals were eventually disease free. Mice that had complete tumor regression were immune to subsequent rechallenge with TUBO cells. Immune cell infiltration in the of CSF, spinal cord and tissues of experimental mice are currently ongoing. CONCLUSIONS Our preclinical data supports the clinical relevance of using intrathecal delivery of DC1 vaccine as a potential treatment for BM and LMD of BC-pts.
- Published
- 2020
13. Disseminated cancer cells in breast cancer: Mechanism of dissemination and dormancy and emerging insights on therapeutic opportunities
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Amber Beyer, Krithika Kodumudi, Amrita Basu, Colin Snyder, Corey Gallen, Doris Wiener, Nadia Nocera Zachariah, Brian J. Czerniecki, Ricardo Costa, Ganesan Ramamoorthi, and Gabriella Albert
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Clinical Decision-Making ,Breast Neoplasms ,Targeted therapy ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Tumor Microenvironment ,Medicine ,Humans ,Neoplasm Metastasis ,business.industry ,Mechanism (biology) ,Disease Management ,Immunotherapy ,medicine.disease ,Primary tumor ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Disease Progression ,Dormancy ,Female ,business ,Homing (hematopoietic) - Abstract
Metastatic spread in breast cancer patients is the major driver of cancer-related deaths. A unique subset of cells disseminated from pre-invasive or primary tumor lesions are recognized as the main seeds for metastatic outgrowth. Disseminated cancer cells (DCCs) can migrate to distant organs and settle in a dormant state for a prolonged period until they emerge to overt metastases. Understanding the biology of breast cancer cells dissemination, dormancy and reactivation to form overt metastases has become an important focus. In this review, we discuss the recent advancements of molecular pathways involving breast cancer cell dissemination, role of chemokine-chemokine receptor networks in DCCs migration, DCCs phenotypic heterogeneity and unique genes signatures in tumor dormancy, microenvironmental regulation and specific niches that favors DCCs homing and dormancy. In addition, we also discuss recent findings relating to the role of immune response on DCC dissemination and dormancy. With recent advances in the field of immunotherapy/targeted therapy and its beneficial effects in cancer treatment, this review will focus on their impact on DCCs, reversal of stemness, tumor dormancy and metastatic relapse.
- Published
- 2020
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