Feasibility Assessment of Autologous Human Immune System (HIS) ImmunoGraft Platform Development Using Autologous Mobilized Peripheral Blood (MPB) CD34 Cells Derived from Adult HNSCC Patient

TL;DR

This study shows that it is possible to create mice with human immune systems and tumors from adult head and neck cancer patients, which could improve cancer research and treatment testing.

Contribution

The study introduces a novel method to generate autologous human immune system and tumor models in mice using patient-derived cells.

Findings

HSC engraftment in mice was observed in 100% of cases at 8 weeks post-transplant.

Human T-cell and myeloid development was observed in mice over time.

The method is technically and clinically feasible for HNSCC patients.

Abstract

Humanized mice generated by hematopoietic stem cell (HSC) transplantation are limited by the immune system developed being allogeneic to the tumor. We have innovated a platform to reconstitute an autologous human immune system (HIS) in immunodeficient NOG-EXL mice from mobilized peripheral blood (MPB)-CD34 cells, along with PDX generated from the same patient’s tumor tissue. Patients consented under an IRB-approved protocol for tumor biopsy and HSC apheresis at Emory University. HSC collection included mobilization with G-CSF and plerixafor, immunomagnetic bead isolation with CliniMACS, and cryopreservation of CD34+ cells. PDX were established from biopsies or surgical specimens by passaging into immunodeficient mice. Irradiated NOG-EXL mice were engrafted with HSCs by intravenous transplantation of CD34+ HSC. Engraftment of human T cells, B cells, and myeloid cells in peripheral blood was assessed by serial flow cytometry of blood samples, with final assessment of immune components in spleen and bone marrow at 30 weeks. Twenty-eight PDX models were generated from 43 patients with HNSCC; 1 patient underwent apheresis. HSC engraftment in blood was observed in 100% of NOG-EXL mice at 8 weeks post-transplant, with 5–20% hCD45+ cells present in the periphery. B-cell development was predominant at early time points and declined over time. Human T-cell and subset development of CD4+ and CD8+ T cells were observed in blood from 15 weeks post-transplant. Strong development of the myeloid lineage (CD33+) was observed starting at 8 weeks and persisted throughout the study. These data demonstrate that mobilization and apheresis of HNSCC patients is technically and clinically feasible and may allow the establishment of autologous HIS-PDX mice.

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