Establishment of Humanized Mice from Peripheral Blood Mononuclear Cells or Cord Blood CD34+ Hematopoietic Stem Cells for Immune‐Oncology Studies Evaluating New Therapeutic Agents

Verma, Bhavna; Wesa, Amy

doi:10.1002/cpph.77

Cited by 44 publications

(38 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…43 Other researchers also reported that durability of CD34+ humanized mouse model ranged from 4 weeks to 20 weeks (online supplemental table 2). [44][45][46][47][48] In contrast, our humanized mouse model showed long-term survival and long-lasting humanization status (hCD45+ cells ≥ 25% to mice PBMCs) that was maintained up to 11 months. When the human cancer cell line or PDTX tissues were implanted in our humanized mice, persistent tumorigenicity was confirmed from the early period of 12 weeks up to 11 months from the injection of human HSCs.…”

Section: Discussionmentioning

confidence: 66%

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Park

Pandey

Chang

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

show abstract

Section: Discussionmentioning

confidence: 66%

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Park

Pandey

Chang

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…The immune system of a humanised mouse model constructed using PBMCs is mainly composed of human T cells. Other key immune subpopulations, such as B cells and dendritic cells, are lacking [30].…”

Section: Discussionmentioning

confidence: 99%

A Novel Combination of Bevacizumab and Pembrolizumab Stimulates Tumour Immunity Through Vascular Normalisation in Humanised Mouse Model

Qiao

Guo

Meng

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Immunotherapy has dramatically changed the treatment landscape of cancer. Immunotherapies targeting the programmed death 1/programmed death ligand 1 pathway have been shown to lead to durable responses in patients with a variety of cancers. However, combination approaches are required to extend this benefit beyond a subset of patients. Studies have suggested that anti-angiogenic therapy can elicit or enhance tumor immunity response.Therefore, we hypothesised that combining immunotherapy with anti-angiogenic treatment may have a synergistic effect and may enhance the efficacy of both treatments.Methods: We evaluated the combination of bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) and pembrolizumab (anti-programmed death 1 monoclonal antibody) in two mouse models of human non-small cell lung cancer cell lines (H1299 and A549). We monitored tumour growth and examined changes in the tumour vasculature, along with the frequency and phenotype of tumour-infiltrating lymphocytes.Results: The combination of bevacizumab and pembrolizumab synergistically inhibited tumour growth in vivo without overt toxicity in both cell lines. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T cell infiltration, thereby turning tumours with different phenotypes into inflamed (‘hot’) tumours. This is potentially mediated by vascular normalisation and endothelial cell activation, as demonstrated by a reduction in the number of microvessels and an increase in adhesion molecules.Conclusions: Taken together, our preclinical studies demonstrate that the combination of bevacizumab and pembrolizumab had a synergistic anti-tumour effect and provides a theoretical basis for translating basic research into clinical applications.

show abstract

“…The humanized mouse field is in constant progress, with new mouse models being able to resemble more accurately the human immune system. As an example, NSG or NOD/Shi-scid/IL-2Rγ null (NOG) mice that express human cytokines such as G-CSF, GM-CSF, or IL-3, lead to better engraftment, generation and development of the human immune system after injection of human CD34 + stem cells (257,258). Another consideration in designing relevant GBM models is the inoculation site of tumor cells.…”

Section: The Need To Have Immunocompetent Pre-clinical Models That Rementioning

confidence: 99%

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

2021

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range of solid tumors have made CAR T cells one of the most promising fields for cancer therapies. CAR T cell therapy is currently being investigated in solid tumors including glioblastoma (GBM), a tumor for which survival has only modestly improved over the past decades. CAR T cells targeting EGFRvIII, Her2, or IL-13Rα2 have been tested in GBM, but the first clinical trials have shown modest results, potentially due to GBM heterogeneity and to the presence of an immunosuppressive microenvironment. Until now, the use of autologous T cells to manufacture CAR products has been the norm, but this approach has several disadvantages regarding production time, cost, manufacturing delay and dependence on functional fitness of patient T cells, often reduced by the disease or previous therapies. Universal “off-the-shelf,” or allogeneic, CAR T cells is an alternative that can potentially overcome these issues, and allow for multiple modifications and CAR combinations to target multiple tumor antigens and avoid tumor escape. Advances in genome editing tools, especially via CRISPR/Cas9, might allow overcoming the two main limitations of allogeneic CAR T cells product, i.e., graft-vs.-host disease and host allorejection. Here, we will discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM.

show abstract

Establishment of Humanized Mice from Peripheral Blood Mononuclear Cells or Cord Blood CD34+ Hematopoietic Stem Cells for Immune‐Oncology Studies Evaluating New Therapeutic Agents

Cited by 44 publications

References 19 publications

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

A Novel Combination of Bevacizumab and Pembrolizumab Stimulates Tumour Immunity Through Vascular Normalisation in Humanised Mouse Model

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

Contact Info

Product

Resources

About