New Clinical Trials in Crohn’s Disease, Systemic Sclerosis, Sickle Cell Disease, and Tandem Lung/BMT Transplant

The Division of Blood and Marrow Transplantation and Cellular Therapies (BMT-CT), led by Paul Szabolcs, MD, Division chief and professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine, places special emphasis on the development and use of reduced-intensity/toxicity transplant regimens for a range of non-malignant conditions.

Historically, these have been applied to inborn errors of immunity and inherited metabolic disorders such as muco  polysaccharidosis syndromes (MPS) and leukodys tro phies. In fact, the Division is submitting data for publication reporting on their prospective trial outcome that shows ~ 95% survival at the critical one-year valuation point — even with unrelated donor cord blood or bone marrow grafts (ClinicalTrials.gov NCT01962415) — which is unsurpassed anywhere.

Clinical research within the Division has led to new trial designs that recently have been approved by the U.S. Food and Drug Administration (FDA) and Institutional Review Board (IRB) of the University of Pittsburgh to bring a cure or alleviate advanced cases of certain autoimmune disorders such as Crohn’s disease (CD) and systemic sclerosis (SSc). Another exciting new protocol also received FDA and IRB approval, whereby all sickle cell disease (SCD) patients who may benefit from allogeneic transplant would be able to find partially matched healthy unrelated stem cell donors.

Toward these objectives, the BMT-CT Division is collaborating with pediatric and adult gastroenterology, rheumatology, cardiology, and pulmonary specialists from UPMC and the University of Pittsburgh, to form CD, SSc, and SCD disease-specific task forces led by Dr. Szabolcs. Pediatric and adult candidates who have traveled from distant locations in the United States are already being screened and treated. UPMC Children’s Hospital of Pittsburgh is the only entity in the world currently performing tandem cadaveric lung and bone marrow transplantation for both pediatric and adult patients diagnosed with a primary immunodeficiency with progression to end-stage lung disease. Early favorable experience has now led to new indications that are focusing first on combined bone marrow and lung failure related to a diagnosis of idiopathic pulmonary fibrosis.

Collaborating With the New UPMC Immune Transplant and Therapy Center

In February 2018, UPMC and the University of Pittsburgh announced the establishment of the UPMC Immune Transplant and Therapy Center (ITTC), a bold and ambitious effort to revolutionize the way the world thinks about — and treats — a variety of diseases and conditions. ITTC brings together immunotherapy and transplant researchers in the areas of cancer, organ transplantation, and aging to collaborate, share ideas, and drive further development in this promising new frontier of medicine.

Dr. Szabolcs has joined ITTC as part of its transplant program, and will be working to continue his research and clinical trials into various aspects of immunotherapy and blood and marrow transplantation. The first trials Dr. Szabolcs will conduct through ITTC are a modification to his existing autologous stem cell transplant protocol for Crohn’s disease, and new trials focused on tandem lung/BMT transplant, systemic sclerosis, and sickle cell disease.

“We hope to make a significant impact in terms of outcomes, both for proving immune transplantation as a safer than previously believed technology and for making it more effective, either as a complete cure or at least by providing a significant improvement in quality of life or number of diseases. For some conditions, like sickle cell disease, immune transplantation can be curative 
by replacing the faulty hematopoietic system with a healthy one. For other conditions, for example, autoimmune diseases, we could achieve a new steady-state of disease where the patient’s immune system is no longer eroding and attacking their tissues, be it the lungs, intestines, or skin,” says Dr. Szabolcs.

New Tandem Lung and BMT Transplant Trial

Building off of an in-progress, NIH-funded clinical trial to perform cadaveric bilateral orthotopic lung transplantation followed by sequential bone marrow transplantation for patients with primary immunodeficiency and end-stage lung disease with study collaborator John McDyer, MD, associate professor in the Division of Pulmonary, Allergy, and Critical Care Medicine, and director of the Lung Transplantation Translational Research Program, Dr. Szabolcs and team recently received IRB and FDA approval for a second, similar trial that will study the effects of tandem lung and bone marrow transplant in patients with combined lung and bone marrow failure. The goal of this study is to correct the patient’s bone marrow failure and potentially help to build tolerance to the transplanted lungs, thus eliminating the need for lifelong immuno-suppression while improving quality of life. In the new trial through ITTC, Dr. Szabolcs hopes to perform lung transplantation for patients with idiopathic pulmonary fibrosis or COPD/emphysema, followed by a bone marrow transplantation protocol designed by Dr. Szabolcs.

“The BMT and conditioning therapy for this trial is tailored for the specific pathology and also comorbidities of this patient population.

The radiation is a bit more intense than in our other trial, but we will be using more shielding to other organs and the chemotherapy aspect is scaled down,” says Dr. Szabolcs.

This study protocol focuses on performing combined transplantation for candidates who are unable to undergo a standard lung trans - plant. Lung transplantation followed by BMT would allow for restoration of pulmonary and hematologic function post-BMT transplantation.

The secondary objectives of the trial are to evaluate the feasibility and long-term complications associated with combined solid organ transplant and BMT, including the ability to initiate and successfully withdraw participants from immunosuppression following BMT and attain independence from growth factors and red blood cell or platelet transfusions. This first-in-human pilot study hopes to enroll eight participants between the ages of 18 and 60 and is expected to be completed in 2026.

Autologous Stem Cell Transplant Trial for Crohn’s Disease

Dr. Szabolcs and collaborators have modified an existing autologous stem cell transplant protocol for Crohn’s disease (started in 2012 at UPMC Children’s) to provide a safer and anticipated more effective conditioning regimen for these patients. The protocol for the trial includes a high-dose chemotherapy conditioning regimen followed by a stem cell transplant consisting of a CD34-selected graft, https://clinicaltrials.gov/ct2/show/NCT00692939.

This trial is based out of UPMC Children’s, with assistance from UPMC Presbyterian for adult patients, and is targeted at individuals between the ages of 10 and 60.

“We performed the first proof-of-principle transplant with the new protocol in December 2017. At present, we are at the end of our 12-month evaluation process and the patient is doing dramatically better. We are now enrolling the next subjects, most of whom are middle-aged adults,” says Dr. Szabolcs.

Systemic Sclerosis — New Clinical Trial

The trial, “Autologous Stem Cell Transplantation with CD34-Selected Peripheral Blood Stem Cells (PBSC) in Patients with Treatment-Resistant Systemic Sclerosis (SSc),” utilizes low doses of radiation paired with more intense immunoablative serotherapy in preparation for an autologous CD34-selected stem cell transplant for patients diagnosed with systemic sclerosis.

“We hypothesize that this conditioning regimen, followed by an autologous stem cell transplant, is a safer method compared to other centers with more aggressive conditioning regimens that will possibly delay disease recurrence or progression,” says Dr. Szabolcs.

This study is open to children and adults between the ages of 16 and 70. For additional requirements and criteria, please visit https://clinicaltrials.gov/ct2/show/NCT03630211.

Sickle Cell Disease Study

This trial, led by principal investigator Beth Carella, DO, also from the BMT-CT Division, is named “T-Cell Depleted, Alternative Donor Transplant in Pediatric and Adult Patients with Severe Sickle Cell Disease (SCD) and Other Transfusion-Dependent Anemias.” Drs. Szabolcs and Carella collaborated with SCD specialists from both adult and pediatric hematology in the development of this trial. This reduced intensity, immunoablative conditioning regimen is expected to prevent severe graft-versus-host disease by T-cell depletion, while at the same time minimizing the possibility of immune rejection in patients with sickle cell disease and other transfusion-dependent anemias such as beta-thalassemia or Diamond-Blackfan anemia. If successful, participants in this trial should achieve sufficient engraftment to allow for their disease-related symptoms and quality of life to improve.

This study is open to children and adults between the ages of 5 and 40. For additional requirements and criteria, please visit https://clinicaltrials.gov/ct2/show/NCT03653338.