Project Grant R01DE036354

The National Institute of Dental and Craniofacial Research awarded The Regents of the University of Colorado (University of Colorado-Denver) $552,009 on August 1, 2026, under the Oral Diseases and Disorders Research program (CFDA 93.121) to develop autologous organoid and humanized mouse models with thymic T cell education capacity for testing head and neck cancer immunotherapy.

The award funds development of stem cell-derived thymic organoids (STOs) and isogenic multicellular models generated from patient-derived induced pluripotent stem cells. These organoids educate developing T cells through positive and negative selection, mimicking human adaptive immunity in ways existing model systems do not. Researchers will reprogram peripheral blood mononuclear cells and cancer-associated fibroblasts from patients into iPSCs, differentiate those into functional thymic organoids combining thymic epithelial cells, mesenchymal cells, and hematopoietic lymphoid progenitors, and implant them into humanized mice for in vivo immunotherapy testing. The T cells educated by these organoids will be exposed to PD-1 inhibitors and other immune checkpoint inhibitors, then co-cultured with autologous cancer cells to generate organoids that test immune-directed therapies in a patient-specific manner. Using non-autologous controls will allow researchers to dissect the contribution of thymic education to immunotherapy response. The work addresses a clinical need: PD-1 inhibitors are approved for head and neck squamous cell cancer, but most patients do not respond, and existing model systems lack key aspects of matched human adaptive immunity.

Performance is scheduled from August 1, 2026, through May 31, 2031, at the University of Colorado-Denver in Aurora, Colorado.