scholarly journals JQ1 Synergize with Anti-CD47 Antibody to Enhance the Function of Macrophages and Repress the Progression of Burkitt Lymphoma

2021 ◽  
Author(s):  
Shunan Wang ◽  
Wei Guo ◽  
Yangzhi Zhao ◽  
Jia Li ◽  
Xin Wan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Combination Therapy ◽  
Immune Cells ◽  
Burkitt Lymphoma ◽  
Theoretical Basis ◽  
Tumor Model ◽  
M2 Macrophages ◽  
Promising Target ◽  
Therapeutic Choice ◽  
Targeted Immunotherapy

Abstract Background: M2 macrophages, as the most prominent immune cells in Burkitt lymphoma (BL), are promising targets and anti-CD47 antibody could enhance the phagocytosis but be unable to eradicate tumor cells. JQ1, a C-MYC inhibitor, may enhance the function of macrophages and be a choice for combination therapy. Methods: The effect JQ1, on the expression of CD47 was measured. Then the synergy of JQ1 and anti-CD47 antibody was measured using phagocytosis assays. The effect of JQ1 on the polarization of macrophages was also detected. Finally, the efficiency and safety of JQ1 and anti-CD47 antibody combination therapy was explored in a groin orthotopically implanted Raji tumor model. Results: JQ1 could suppress the expression of CD47 on the surface of BL cells, thus synergize with anti-CD47 antibody to enhance the phagocytosis of macrophages. JQ1 could polarize macrophages from M2 to M1 while inhibiting the proliferation, inducing the apoptosis and blocking the cell cycle of BL cells. Finally, JQ1 and anti-CD47 antibody combination therapy could repress the progression of BL in NOD/SCID mice. Conclusions: Macrophages may be a promising target in BL and JQ1 combined with anti-CD47 antibody may be a potential therapeutic choice, providing theoretical basis for the use of this new targeted immunotherapy in clinical practice.

scholarly journals Temporal Changes in Immune Responses within the Tumor Microenvironment in the 4T1.2-HER2 Mammary Tumor Model

2021 ◽  
Author(s):  
Yitong Xu ◽  
Connie Rogers
Keyword(s):  
Immune Responses ◽  
Tumor Growth ◽  
Immune Cells ◽  
Tumor Regression ◽  
Tumor Model ◽  
Second Phase ◽  
Tumor Inoculation ◽  
Cancer Model ◽  
Breast Cancer Model ◽  
Initial Tumor

Abstract Background: The murine 4T1.2 triple-negative breast cancer model is widely used, but is poorly immunogenic with no defined tumor-associated antigens. A modified 4T1.2 model has been developed that stably expresses a surrogate tumor antigen, human epidermal growth factor receptor-2 (HER2). The goal of the current study was to characterize host immune responses in the 4T1.2-HER2 tumor model, focusing on the tumor microenvironment (TME) during the early stage of tumor development. Methods: Female BALB/c mice were orthotopically inoculated with 4T1.2-HER2 tumor cells and sacrificed at day (D) 6, 9, 12, 15 and 18 post tumor inoculation. The phenotype and function of tumor-infiltrating immune cells were assessed. Results: 4T1.2 and 4T1.2-HER2 tumor cells had similar proliferation rates in vitro. In contrast to the rapid progression of the parental 4T1.2 model, the 4T1.2-HER2 model demonstrated initial tumor growth followed by spontaneous tumor regression by D18 post tumor inoculation, which was not observed in scid mice. Following tumor regression, mice demonstrated either a second phase of tumor outgrowth or complete tumor rejection. Within the TME, the percentage of T cells was reduced at D9 and increased during tumor regression through D18 (p<0.05), whereas the percentage of myeloid-derived suppressor cells (MDSCs) increased during the initial tumor growth and was reduced by D18 (p<0.01). There was a stepwise increase in the percentage of IFNg+, IL-2+ and perforin+ T cells and NK cells peaking at D12-15. Furthermore, tumor regression occurred concurrently with HER2-specific IFNg production from tumor-infiltrating immune cells at D12 and D15 (p<0.05). During the second phase of 4T1.2-HER2 tumor growth, tumor volume was negatively correlated with immune infiltration (r=0.662, p=0.052). Conclusions: These results suggest that the integration of a surrogate tumor antigen, human HER2, into the clinically relevant, yet poorly immunogenic 4T1.2 breast cancer model enhanced its immunogenicity and induced HER2-specific immune responses.

scholarly journals Theoretical Basis for the Measurement of Small Differences in the Length of the Cell Cycle between Two Cell Populations

2009 ◽  
Vol 2 (1) ◽  
pp. 95-100
Author(s):  
Juan Sebastian Yakisich
Keyword(s):  
Experimental Data ◽  
Cell Cycle ◽  
Theoretical Basis ◽  
Cycle Length ◽  
Cell Populations ◽  
Experimental Variability ◽  
Cell Strains ◽  
Novel Strategy ◽  
Cell Cycle Length

The length of the cell cycle (TC) is a tight regulated process and is important for proper development and homeostasis. Although several methods are available for estimating the duration of the cell cycle, it is difficult to determinate small differences of TC between two different cell populations due to biological and/or experimental variability. A novel strategy based in co-cultivation of two cell strains followed by a series of dilution and propagation of the culture will allow the quantification of very small differences in the length of two cell populations at resolution levels not possible at present with current methods. This is achieved by a separation of the endpoint variable measured to compare between two cell populations. The theoretical basis of this approach is discussed in the context of published experimental data and simulation of idealized experiments using virtual strains of different cell cycle length.

Anlotinib enhanced penpulimab efficacy through remodeling of tumor vascular architecture and immune microenvironment in hPD-L1/hPD-1 humanized mouse model.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2581-2581
Author(s):  
Yunlong Shan ◽  
Chongjin Zhong ◽  
Qi Ni ◽  
Mengying Zhang ◽  
Guangji Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Mouse Model ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumor Volume ◽  
Combined Therapy ◽  
Control Group ◽  
Tyrosine Kinase Receptor ◽  
Humanized Mouse ◽  
Humanized Mouse Model

2581 Background: Even though immune checkpoint inhibitor (ICI) such as anti-PD-1 mAb has emerged as effective treatment for tumor regression, the response rate of ICI monotherapy in solid tumor is low. Many studies have demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. Penpulimab (AK105), a humanized IgG1 mAb that blocks PD-1 binding to PD-L1, engineered to eliminate FcγR binding and ADCC/ADCP completely. Here, we explore a new combined therapy of penpulimab and anlotinib, an oral multi-targeted tyrosine kinase receptor inhibitor. Methods: MC38-hPD-L1 tumor-bearing B-hPD-1 humanized mouse model were conducted to investigate the effects of anlotinib (1 mg/kg, every day, p.o) or penpulimab (5 mg/kg, twice a week, i.p) alone or in combination. Immunofluorescence was applied to elucidate tumor vessel normalization. In vivo imaging was conducted to detect the distribution of AF647-labelled penpulimab after anlotinib treatment. Flow cytometry and other techniques were performed to investigate intratumoral immune cells. Results: After 3-week treatment, immunotherapeutic administration of anlotinib or penpulimab showed moderate inhibition of tumor growth (tumor volume: 66.5% and 58.4% of control group, respectively), while combined treatment of anlotinib with penpulimab significantly decreased tumor volume to 36.5% of control group. Tissue pathological and blood biochemical results showed no significant toxic and side effects. Immunohistochemistry revealed that anlotinib induced tumor vascular normalization, indicated by decreased CD31+ area, increased α-SMA around tumor vessels and reduced GLUT1+ area. Furthermore, anlotinib markedly enhanced the delivery of AF647-penpulimab into tumors. Combining anlotinib with penpulimab also promoted infiltration and activity of anti-tumoral immune cells by reducing the level of immune checkpoint TIM3 and increasing the IFNγ secretion from T cells. Conclusions: Our work provides a strong scientific rationale for the combination therapy of anlotinib and penpulimab to improve tumor microenvironment and immunotherapy, which highlights the clinical potential for this new combined therapy.

scholarly journals Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-24 ◽  
Author(s):  
Rodolfo Soria-Castro ◽  
Alejandro Schcolnik-Cabrera ◽  
Gloria Rodríguez-López ◽  
Marcia Campillo-Navarro ◽  
Nahum Puebla-Osorio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Valproic Acid ◽  
Immune Cells ◽  
Histone Deacetylases ◽  
Drug Repurposing ◽  
Promising Alternative ◽  
Expression Of Genes ◽  
Adaptive Immune Cells ◽  
Activation Of Transcription ◽  
Activation Mechanisms

Valproic acid (VPA) is widely recognized for its use in the control of epilepsy and other neurological disorders in the past 50 years. Recent evidence has shown the potential of VPA in the control of certain cancers, owed in part to its role in modulating epigenetic changes through the inhibition of histone deacetylases, affecting the expression of genes involved in the cell cycle, differentiation, and apoptosis. The direct impact of VPA in cells of the immune system has only been explored recently. In this review, we discuss the effects of VPA in the suppression of some activation mechanisms in several immune cells that lead to an anti-inflammatory response. As expected, immune cells are not exempt from the effect of VPA, as it also affects the expression of genes of the cell cycle and apoptosis through epigenetic modifications. In addition to inhibiting histone deacetylases, VPA promotes RNA interference, activates histone methyltransferases, or represses the activation of transcription factors. However, during the infectious process, the effectiveness of VPA is subject to the biological nature of the pathogen and the associated immune response; this is because VPA can promote the control or the progression of the infection. Due to its various effects, VPA is a promising alternative for the control of autoimmune diseases and hypersensitivity and needs to be further explored.

Cell Cycle–Dependent Antagonistic Interactions between Paclitaxel and γ-Radiation in Combination Therapy

2004 ◽  
Vol 10 (14) ◽  
pp. 4848-4857 ◽  
Author(s):  
Meihua Sui ◽  
Jennifer M. Dziadyk ◽  
Xueming Zhu ◽  
Weimin Fan
Keyword(s):  
Cell Cycle ◽  
Combination Therapy ◽  
Γ Radiation ◽  
Cycle Dependent ◽  
Antagonistic Interactions

An engineered immunotherapy (NKTR-214) with altered selectivity toward the IL2 receptor: Efficacy and tolerability in a murine tumor model.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3060-3060
Author(s):  
Deborah H. Charych ◽  
Murali Addepalli ◽  
Steve Lee ◽  
Thomas Chang ◽  
Xiaofeng Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Immune Cells ◽  
Tumor Model ◽  
Optimal Dose ◽  
Growth Delay ◽  
Blue Dye ◽  
Tumor Localization ◽  
Tumor Growth Delay ◽  
Polymer Conjugation

3060 Background: Cytokine-based immunotherapy has been successful for the treatment of cancer, with potential for durable responses in multiple indications. One approach towards stimulating the immune system is to target the heterotrimeric interleukin2 receptor, IL2R. NKTR-214 uses polymer technology to alter receptor subunit selectivity to favor expansion of CD8+ memory effector T cells (CD8T) in the tumor over CD4+ regulatory T cells (Treg). In addition, polymer conjugation is designed to improve exposure and enhance tumor localization, significantly improving efficacy, modulating vascular leak syndrome (VLS) and allowing flexible dosing regimens. Methods: C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with NKTR-214 at a variety of doses (0.25-4.0 mg/kg) and schedules (q5dx3 to q14dx2). Mice treated with clinically validated IL2 were administered 3mg/kg, bidx5 for 2 cycles. Efficacy was measured by monitoring tumor volumes. Tolerability was evaluated by survival. VLS was measured by injection of Evans Blue dye followed by colorimetry in lungs. Tumor immunotyping, by flow cytometry. Results: Tumors from mice receiving NKTR-214 had a CD8/Treg ratio of over 1,000 versus 14 for IL2. NKTR-214 administered at 2 mg/kg, q9dx3 was identified as the optimal regimen and showed tumor growth delay of 26 days compared to 9 days for optimally dosed IL2. 90% of NKTR-214 treated mice tolerated treatment compared to 67% for IL2. VLS was completely resolved prior to administration of the next dose of NKTR-214, unlike IL2. NKTR-214 was well tolerated in rats at two schedules, at MTD. Conclusions: NKTR-214 is a highly differentiated cytokine with a new mechanism of action that may provide options for cancer immunotherapy. Polymer conjugation of a clinically validated cytokine alters the IL2R selectivity to favor expansion of tumor killing immune cells (CD8T) over regulatory immune cells (Treg) in the tumor. The conjugate is also designed to improve exposure and enhance tumor localization, offering more options of dose and schedule. The optimal dose and schedule is cytokine-sparing, provides substantial tumor growth delay, and reduces toxicity.

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