scholarly journals Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Tianyun Qiao ◽  
Yanlu Xiong ◽  
Yangbo Feng ◽  
Wenwen Guo ◽  
Yongsheng Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Preclinical Model ◽  
Small Subset ◽  
Therapeutic Effects ◽  
Humanized Mouse ◽  
Humanized Mouse Model

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

scholarly journals Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment

2019 ◽  
Vol 105 (1) ◽  
pp. 26-42 ◽  
Author(s):  
Julie Lang ◽  
Anna Capasso ◽  
Kimberly R Jordan ◽  
Jena D French ◽  
Adwitiya Kar ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Human Tumor ◽  
Tumor Growth Inhibition ◽  
Preclinical Model ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Patient Derived Xenograft

Abstract Context Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. Objective To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. Design, Setting, and Intervention To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. Results Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. Conclusions Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.

Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14544-e14544 ◽  
Author(s):  
Michal Abraham ◽  
Inbal Mishalian ◽  
Yaniv Harel ◽  
Shiri Klein ◽  
Yaron Pereg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Growth ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cxcr4 Antagonist ◽  
Immunomodulatory Agents

e14544 Background: Cancer cells affect their micro-environment by recruiting immune cells that support tumor growth, metastasis and inhibition of anti-tumor effector T and NK cell recruitment. In this study, we investigated the role of BL-8040, a CXCR4 antagonist in cancer immunotherapy and its ability to modulate the immunosuppressive tumor micro-environment. Methods: The effect of BL8040 on tumor micro-environment was tested in 3 different cancer mouse models: lung cancer, pancreatic cancer and melanoma. The mobilization of immune cells to the periphery in response to BL8040 was tested, as well as the accumulation of immune cells both within and surrounding the tumor in the pancreatic cancer mouse model. Results: BL8040 was found to be a potent and robust mobilizer of immune cells. Immunophenotyping of the mobilized cells revealed that the mobilization of CD4 and CD8 T lymphocytes, as well as of dendritic cells (DC), was significantly increased in the cancer-bearing mice compared to their naïve counterparts. Importantly, a significant mobilization of effector CD8 T cells and activated CD8 T cells in the cancer-bearing mice was also detected following BL8040 treatment. Concomitantly, in the pancreatic cancer mouse model, treatment with BL8040 increased CD8 T cell accumulation within the tumor and inhibited tumor growth. Conclusions: The immune cell population that is mobilized in response to BL8040 treatment is different in cancer mouse models and naïve mice. The ability of BL8040 to induce mobilization of leukocytes, cytotoxic and activated CD8 T cells and DCs is affected by the presence of a tumor. In our models of pancreatic cancer, mobilization of immune cells from the bone marrow into the circulation and their accumulation within the tumor and tumor microenvironment resulted in inhibition of tumor growth. These results indicate that BL8040 may affect the tumor microenvironment and therefore can potentially synergize with immunomodulatory agents. In vivo pre-clinical studies as well as clinical studies are currently ongoing for testing the combination of BL8040 with immunomodulatory agents in different cancer models.

scholarly journals 15 A novel CD28 humanized mouse model for efficacy assessment of CD28-targeting therapies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A15-A15
Author(s):  
Fabiane Sônego ◽  
Gaelle Martin ◽  
Chloé Beuraud ◽  
Audrey Beringer ◽  
Yacine Cherifi ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
Mouse Model ◽  
Cytokine Production ◽  
List Type ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Efficacy Assessment ◽  
Human And Mouse ◽  
Stimulation Of

BackgroundImmuno-intervention through targeting of activating and inhibitory immune checkpoints (ICP), has shown promising results in the clinic over the last years. To facilitate these researches, mouse models expressing humanized ICP instead of their mouse counterparts were developed. Herein, we describe a novel CD28 humanized mouse model (hCD28 model), designed to test compounds targeting human CD28 (hCD28).MethodsHuman and mouse CD28 (mCD28) have different signalling responses, with hCD28 being known for inducing higher levels of pro-inflammatory cytokines upon stimulation with ligands/superagonists. This can be explained by the expression of CD28i, a hCD28 amplifier isoform which is not found in mouse. Additionally, evidences suggested that the different signalling between human and mCD28 relies on one amino acid change in the intracellular domain (ICD).1 Because the hCD28 model was developed to assess hCD28-targeting therapeutics, we decided to keep the expression of both canonical and CD28i isoforms to avoid undermining the biological effects of the testing antibodies. Although keeping the human ICD could favour the evaluation of cytokine production and therefore the safety of the test therapeutics, we decided to keep the mouse ICD to enable a proper interaction of CD28 with its signalling partners, allowing a physiological stimulation of CD28 in efficacy studies.Results hCD28 mice express hCD28 on T cells and the frequency of CD3 T cells is comparable in both WT and hCD28 mice. Stimulation of hCD28 mice-isolated T cells with hCD28 ligands and agonist antibodies resulted in T cell proliferation and cytokine production, suggesting that hCD28 is functional in mouse cells. MC38 uptake rate and kinetic of growth were comparable in WT and hCD28 mice, suggesting no major defect in the immune response in the hCD28 mice. Importantly, splenocytes and tumor draining lymph nodes cells isolated from tumor-bearing hCD28 mice showed higher production of IL-2 and IFN-gamma upon in vitro re-challenged with MC38 when compared to WT cells. Since the frequency of CD3 cells (Treg, CD4+ and CD8+) is comparable to WT mice, this could be explained by the expression of the amplifier CD28i isoform, which is absent in WT mice.ConclusionsThe hCD28 model described here supports the efficacy assessment of hCD28-targeting biologics, enabling PK/PD studies as hCD28 expression levels and pattern are physiological. However, after careful consideration of the CD28 biology, we decided to keep the mouse ICD, although it triggers lower pro-inflammatory cytokine production than CD28 human ICD. As such, this model is not suitable for toxicology/safety studies.ReferencePorciello N, Grazioli P, Campese AF, et al. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun 2018; 9:1–16.

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 A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maria M. Klicznik ◽  
Ariane Benedetti ◽  
Laura M. Gail ◽  
Suraj R. Varkhande ◽  
Raimund Holly ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Human Skin ◽  
Memory T Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model
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