Home / HSC and PBMC Humanized Models

HSC and PBMC Humanized Models

Evaluate Immunotherapies within a Fully Functional Human Immune Microenvironment

Evaluating novel immunotherapies requires a system where human therapeutic agents can interact directly with human immune cells inside the tumor microenvironment (TME). Because standard immunodeficient mice lack functional T, B, and NK cells, conventional patient-derived xenograft (PDX) platforms cannot effectively assess therapeutics targeting immune-mediated pathways.

Our platform addresses this translational bottleneck through advanced cell-based humanized mouse models. By reconstituting severely immunodeficient host strains (such as NSG or NOG) with either human peripheral blood mononuclear cells (hu-PBMC) or human CD34+ hematopoietic stem cells (hu-HSC), we build a predictive, in vivo translational engine for modern immuno-oncology pipelines.

Technical Comparison of Humanized Platforms

The choice between a hu-PBMC or a hu-HSC platform relies entirely on your therapeutic mechanism of action, study timeline, and safety or efficacy endpoints.

hu-PBMC Model Platform

  • Primary Immune Reconstitution: Mature, functional human T cells (CD3+, CD4+, CD8+)
  • Model Generation Time: Rapid (1 to 2 weeks)
  • Optimal Study Window: 3 to 5 weeks (Restricted by onset of acute GvHD)
  • Preconditioning Needed: No host preconditioning required
  • Ideal Therapeutic Targets: Bispecific or Trispecific antibodies, CAR-T cell therapies, T-cell engagers

hu-HSC (CD34+) Model Platform

  • Primary Immune Reconstitution: Diverse, multi-lineage system (T cells, B cells, NK cells, Myeloid/DC subsets)
  • Model Generation Time: Extended (10 to 12 weeks for full differentiation)
  • Optimal Study Window: Long-term (greater than 20 weeks; minimal to no GvHD risk)
  • Preconditioning Needed: Requires sub-lethal irradiation or chemical ablation
  • Ideal Therapeutic Targets: Checkpoint inhibitors (PD-1/PD-L1, CTLA-4), Combination therapies, Cytokine modulators

Mechanistic Workflows and Study Setup

To maintain exceptional data reproducibility across longitudinal study cohorts, we implement standardized, rigorous protocols for both human immune system (HIS) platforms.

Phase 1: Donor Screening and Sourcing

Human tissue materials are ethically sourced under strict IRB compliance. CD34+ HSCs are extracted from umbilical cord blood pools, while PBMCs are isolated via Ficoll gradient separation from healthy adult donors. Donors are pre-screened in vitro to verify baseline activation parameters and minimize immediate alloreactivity.

Phase 2: Host Preconditioning (hu-HSC Only)

For the CD34+ stem cell model, 3-to-4-week-old immunodeficient host mice undergo sub-lethal irradiation or targeted chemical ablation. This clears endogenous niche space within the bone marrow, allowing the incoming human stem cells to home and engraft successfully. The hu-PBMC model bypasses this step completely.

Phase 3: Immune Reconstitution and Validation

Mice are injected intravenously with the selected human donor cells. Reconstitution kinetics are closely monitored via longitudinal flow cytometry. hu-PBMC cohorts achieve operational T-cell levels within 7 to 14 days. hu-HSC cohorts undergo a 10 to 12 week maturation phase, confirming robust human chimerism (hCD45+ greater than 25 percent) prior to study enrollment.

Phase 4: Tumor Engraftment and Therapeutic Evaluation

Fully characterized cell line-derived (CDX) or patient-derived xenografts (PDX) are implanted orthotopically or subcutaneously into the humanized cohorts. Once tumors establish, therapeutic dosing begins. This enables high-fidelity monitoring of tumor-infiltrating lymphocytes (TILs), cytokine release profiles, and real-time tumor volume kinetics.

Core Applications in Immuno-Oncology

  • Immune Checkpoint Inhibitors (ICIs): Determine the mechanistic efficacy of mono- or combination therapies targeting PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3 pathways.
  • Bispecific T-Cell Engagers (BiTEs): Leverage the rapid, highly active T-cell compartment in hu-PBMC models to evaluate modern multi-specific antibody formats.
  • Adoptive Cell Therapies (ACT): Benchmark the cytotoxic performance and persistence of engineered human CAR-T, CAR-NK, or TCR-T cell populations inside a live tumor environment.
  • Safety and Toxicity Screening: Assess the risk profile of immunomodulators by tracking systemic cytokine release syndrome (CRS) profiles and off-target cross-reactivities.