Abstract: Bone marrow transplant (BMT) can be a curative therapy for patients with primary immunodeficiency (PID) syndromes, however those with end-stage lung disease are ineligible for either BMT or bilateral orthotopic lung transplantation (BOLT). Thus, definitive treatment for patients with PID/end-stage lung disease represents an unmet clinical need. This U01 project proposes a single center clinical trial to evaluate the safety and efficacy of performing BOLT followed by CD3+/CD19+-depleted BMT from the same cadaveric, partially HLA-matched donor, in patients with PID/end-stage lung disease. We hypothesize that tandem BOLT/BMT in patients with PID/end-stage lung disease will result in correction of the underlying PID, normalization of lung function, restoration/preservation of pathogen-specific immunity and the establishment of immune tolerance that will allow withdrawal of immunosuppression therapy (IST). To test our hypothesis, we propose 3 aims. In Aim 1, we will conduct a phase I/II tandem BOLT/BMT clinical trial in 8 patients with PID/end-stage lung disease. This trial will be conducted under the direction of two Co-PIs with complementary expertise: Dr. Paul Szabolcs (contact PI; BMT) and Dr. John McDyer (Co-PI; lung transplant). Key oversight bodies will include the NIAID DSMB, a NIAID-appointed monitor, and the University of Pittsburgh Education and Compliance Office for Human Research. This trial incorporates intensive safety monitoring, a milestone-driven protocol, and rigorous data collection and management for safety reporting and endpoint analyses. Scheduled collection of blood, bronchoalveolar lavage (BAL) and bronchial brush samples for basic studies in each study patient will coincide with routine clinical monitoring. In Aim 2, we will test the hypothesis that tandem BOLT/BMT restores and/or preserves pathogen-specific T cell mucosal/systemic host immunity in study patients. We will perform flow cytometry-based assays to interrogate pathogen-specific systemic/lung mucosal T cell responses to key opportunistic pathogens such as CMV, EBV, Aspergillus, Pseudomonas, Staph, RSV, flu and use RNA sequence analysis to assess the airway transcriptome. In Aim 3, we will test the hypothesis that tandem BOLT/BMT will result in a level of chimerism sufficient to establish long-term lung allograft/BMT tolerance, thereby facilitating withdrawal of IST. We will assess chimerism using an ultra-sensitive technique and perform comprehensive mixed lymphocyte reaction studies to test alloreactivity and evaluate differential mechanisms of anticipated immune tolerance throughout the study toward the goal of complete withdrawal of IST. The PIs have assembled an outstanding, multidisciplinary team with broad expertise, and will use the multiple PI format for this U01 project. Drs. Szabolcs, McDyer and their teams are highly dedicated to advancing the currently limited treatment options for patients with PID/end-stage lung disease. Success in this novel U01 project will be represent a paradigm shift in the fields of lung transplantation and BMT, and proof-of-concept for tandem BOLT/BMT could potentially be extended to other solid organ candidates in an effort to achieve tolerance.

For patients with primary immunodeficiencies (PID) who develop the complication of end-stage lung disease, neither bone marrow transplantation (BMT) nor lung transplantation are therapeutic options. This is the first clinical trial to evaluate the safety and efficacy of a combined-tandem strategy of lung transplant followed by BMT from the same organ donor to correct the defective immune system after they receive new lungs. As part of this clinical trial, we will also perform laboratory tests to determine if BMT restores the ability to fight infection in these patients, and whether ‘resetting’ the immune system allows acceptance of the lungs, permitting eventual withdrawal of all immunosuppression medications in these unique, combined transplant recipients.