University of Colorado Cancer Center Support Grant - Lung Cancer Patient-Derived Xenografts with Autologous Human Immune Systems

University Of Colorado Denver, Aurora CO

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Every day, ~350 patients die from lung cancer (LC) in the US, the majority from non-small cell lung cancer (NSCLC). Treatment for NSCLC has advanced with precision medicine (PM)-guided use of oncogenic variants and immune markers (PD-L1) to select targeted, immune checkpoint inhibitor (ICI), and antibody drug conjugate (ADC) therapies. These treatments are validated in patient derived xenograft (PDX) models. Since current PDXs develop in a murine immunodeficient microenvironment, and with more immune-mediated therapies advancing to the clinics, there with is an urgent need to develop PDXs with an autologous human immune system (HIS), where the tumors have a matching tumor immune microenvironment (TIME), for more predictive responses to therapy. The establishment of an autologous HIS-PDX, with HLA-matched tumor, immune, and developmentally mature cells is technically challenging for multiple reasons. For instance, reconstitution of an immunodeficient mice with human blood cells results in T-cell activation and graft-versus-host-disease. Moreover, blood, bone marrow, and hematopoietic stem cells (HSCs) are difficult to acquire from cancer patients and generally have low engraftment rates in immunodeficient mice. In contrast, blood or fibroblast cells from the same cancer patient can be efficiently reprogrammed to induced pluripotent stem cells (iPSCs) and these iPSCs are used to generate an autologous HIS for engraftment in PDXs. Here, we propose to optimize the conditions for generating an iPSC- derived HIS to mimic the natural T-cell differentiation in vitro and in vivo in a panel of autologous NSCLC PDX models. We will utilize high-efficiency RNA-based reprogramming and organoid-based systems to assess the key variables and optimize the conditions for cell induction, differentiation, expansion, and tolerance for the generation of iPSC-derived-T-cells and myeloid cells, and the selection of the optimum timing and recipient strains for the engraftment of autologous HIS in PDX models. We will develop novel NSCLC HIS-PDX models with an autologous HIS, comprising iPSC-derived organoid-matured and thymic-educated polyclonal T-cells and myeloid cells to test responses to ICIs. We will complete these studies with two Specific Aims. In Aim 1, we will generate NSCLC HIS-PDX models that harbor iPSC-derived, organoid-matured, and thymic-educated autologous T-cells. We will assess the T-cell yield, engraftment, functional tolerance, and responses to ICIs. In Aim 2, we will investigate the engraftment and functionality of myeloid cells in the same models and their impact on immune responses to ICIs. We will work with the NCI Patient Derived Model Repository (PDMR) to utilize the optimized conditions for generating HIS-PDX models that can be disseminated to the scientific community for data cross-validation and to enhance model diversity for the evaluation of cancer immunotherapies. This multifaceted translational collaboration is designed to share knowledge, specimens, models, and procedures, in collaboration with PDMR, to develop HIS-PDX models for transforming immunotherapy and oncology research.