The Primary Immune Deficiency Treatment Consortium: how can it improve definitive therapy for PID?

KEYWORDS:

• Primary immune deficiency
• SCID
• Wiskott Aldrich syndrome
• chronic granulomatous disease
• hematopoietic cell transplantation
• gene therapy
• enzyme replacement therapy

1. What is the PIDTC?

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a National Institutes of Health (NIH)-sponsored rare disease consortium of 44 centers in North America and 3 in Europe, focused on the diagnosis, management, and definitive treatment of heritable disorders affecting the immune system [1,2]. Supported since 2009 by the National Institute of Allergy and Infectious Diseases (NIAID) and the Office of Rare Diseases Research, National Center for Advancing Translational Research, NIH, the PIDTC is conducting multicenter prospective and retrospective observational and cross-sectional studies of severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Wiskott Aldrich syndrome (WAS) [2]. Primary immunodeficiency diseases (PID) are sufficiently rare that the number of patients cared for at an individual center is limited, and historically this led to center-specific, generic approaches to definitive treatments such as hematopoietic cell transplantation (HCT). The rationale for creating the PIDTC was to enable sharing of data by participating centers, to allow for analysis of the many variables that affect outcomes, to determine optimal therapy [3,4]. Further, we anticipate this collaboration will provide a foundation for prospective intervention trials to determine best practices to guide the care that these patients receive.

To further its goals, the PIDTC works with Patient Advocacy Groups (PAGs) including the Immune Deficiency Foundation, Jeffrey Modell Foundation, SCID Angels for Life, Wiskott Aldrich Foundation, and Chronic Granulomatous Disease Association. These groups provide critical input in the development of PIDTC protocols and help to disseminate information to patients and parents regarding PIDTC findings. They also collaborate with the PIDTC by encouraging enrollment and generating patient/parent surveys to study, for example, quality of life and nonmedical supportive care. Monthly conference calls with all participating centers as well as frequent conference calls of the PIDTC Steering Committee, the PAGs, and protocol working teams help to maintain the momentum of the programs and determine new directions of study.

Another function of the PIDTC is to promote training and research in PID. To that end, the PIDTC Research Fellowship program supports two fellows or junior faculty per year with $25,000 grants and also funds a pilot project every year that is focused on PID ($50,000/year). Finally, the annual PIDTC Scientific Workshop brings together representatives from all participating centers in addition to outside speakers for updates on progress and findings from PIDTC studies, presentations, and discussions on important areas of research in PID, and strategies and priorities for future studies. An Education Day preceding the Workshop is directed to trainees and junior faculty interested in immunology and cell therapy.

The ultimate goal of the PIDTC is to provide definitive treatments to cure PID; achieving this will require the PIDTC to develop and conduct multicenter clinical trials of therapeutic interventions.

2. PIDTC protocols

A detailed summary of the PIDTC protocols can be found in the references [1,2]. PIDTC Protocol 6901 is a prospective observational study of SCID in which newly diagnosed patients are enrolled prior to treatment. The treatment is determined by the center, but uniform data are collected in electronic case report forms. The results of this study will help to determine the effects of patient, donor, and transplant-related factors on early survival, time to and extent of immune reconstitution and early clinical outcome after HCT, gene therapy (GT), and enzyme replacement therapy. As the cohort increases and is followed over time, it will be possible to evaluate the late effects of various therapeutic approaches.

PIDTC Protocol 6902 is a retrospective and cross-sectional study of patients treated for SCID since 1968. It will characterize the impact of various factors on long-term outcomes and late effects. The cross-sectional component focuses on quality of life, immune reconstitution, and mechanistic studies of the basis for continuing defects of T- and B-cell immunity in long-term survivors.

PIDTC Protocol 6903 is an analysis of patients treated for CGD since 1995 and will identify which patients should be candidates to receive HCT in addition to determining critical factors that predict survival and disease correction post HCT. This study also is evaluating the microbiome pre and post HCT.

PIDTC Protocol 6904, an analysis of patients treated for WAS since 1990, will characterize the factors that determine survival, immune reconstitution, and long-term outcomes as well as biomarkers that may predict the development of autoimmunity post HCT. This protocol is augmented by a pilot study investigating the molecular and cellular mechanisms of autoimmunity in patients with WAS undergoing HCT.

3. How can the PIDTC improve definitive therapy for PID?

The biggest issue for rare PID disorders is that most centers see so few SCID, CGD, or WAS patients per year that they have used in-house, generic HCT protocols for nonmalignant or malignant diseases, in the absence of tailored protocols that might be more appropriate for a particular disease or even genetic subtype of SCID. The small number of North American centers that ‘specialize’ in PID and see more patients per year are committed to their own protocols. Published reports have mostly been from single or possibly a few centers, retrospective, and focused on relatively short-term survival and immune reconstitution. The number of patients included in these reports is generally small and inadequate for meaningful statistical analysis. To date, there has never been a prospective multicenter treatment trial for SCID, WAS, or CGD or most other PID.

The PIDTC has been able to bring together a large number of centers in North America to contribute a detailed, uniform data set for each patient. Standardized disease definitions have been established [5], and a review panel determines the eligibility of each patient proposed for each protocol. Finally, the PIDTC is beginning to develop and implement prospective treatment studies and the consortium will eventually become a platform for multicenter intervention trials.

4. What has the PIDTC done to date?

The PIDTC has analyzed interim results for both the prospective and retrospective observational studies of SCID. The PIDTC studies of CGD and WAS are still enrolling patients so those analyses are not yet available.

To date, PIDTC Protocol 6901 has enrolled 203 of a goal of 259 patients. The initial study of the first 50 prospectively enrolled patients reported on baseline demographics and types of therapy without any outcome information [6]. An analysis of the first 100 patients who received HCT for either typical SCID (n = 68) or leaky SCID/Omenn syndrome (n = 32) and have at least 1 year of follow-up is nearly complete. One interesting finding has been that in 2010 (when newborn screening (NBS) for SCID was uncommon in the US), ~55% of new patients were identified because of an infection history and only ~15% by NBS. As of 2016, those numbers have reversed, with 90% identified by NBS and only 10% presenting with infections. A second interesting observation was that significantly higher B-cell chimerism at 100 days post HCT was found to be associated with use of reduced intensity or myeloablative conditioning (RIC/MAC), as compared to immunosuppression (IS) alone or no conditioning (100% vs. 3%, p < 0.001). However, there was uniformly good recovery of T-cell immunity independent of the type of conditioning. Further, 51% of those treated with RIC/MAC were off immunoglobulin replacement therapy at 1 year posttransplant as compared to 14% in the IS or none group (p = 0.007). Finally, this study is identifying risk factors for survival or need for a second transplant. Preliminary findings indicate that a CD3 count < 300/uL, CD8 < 50/uL or CD45RA < 10% at 100 days were all associated with an increased risk of death or second HCT by 2 years post HCT. Finally, an unrelated adult donor or umbilical cord blood transplant or administration of RIC or MAC was more associated with those who died or needed a second HCT.

In 2014, the PIDTC completed a retrospective analysis of 240 patients with typical SCID who received an HCT from 2000 to 2009 and were enrolled on PIDTC Protocol 6902 in order to document the status of HCT for patients in the most recent decade [7]. As expected, an HLA-matched sibling donor (MSD) provided the best outcome regardless of the age or infectious status of the patient. Moreover, regardless of donor type, 94% of patients were alive at 5 years if they were <3.5 months old at HCT while 90% were alive at 5 years if >3.5 months old at HCT and without prior infectious history. For patients with active infection at the time of HCT, survival was best for recipients of a MSD transplant (90%). However, if an alternative donor was used, survival was better with a haplocompatible donor without conditioning (61% survival) compared to all other alternative donors with conditioning (~33% survival). Overall, conditioning with RIC or MAC did not adversely affect 5-year survival if the patient was <3.5 months of age at the time of HCT. Finally, the use of RIC or MAC was strongly associated with freedom from immunoglobulin replacement therapy. Importantly, however, late effects were not addressed in this study.

Other initiatives that the PIDTC has participated in include the first national study of the incidence of SCID in the U.S., based on outcomes of NBS for SCID in 11 screening programs involving over 3 million infants [8]. There were 52 SCID cases (42 typical, 9 leaky, and 1 Omenn syndrome) for an overall incidence of 1:58000 births and a survival of 92% in those who underwent HCT. The PIDTC has established collaborations with the Inborn Errors Working Party of the European Society for Blood and Marrow Transplant. This has resulted in manuscripts defining changes in the pharmacokinetics of busulfan in infants and children [9], assessing outcomes in patients with SCID who received an unrelated donor transplant without any preconditioning therapy [10], and characterizing the quality of life in patients with WAS (in preparation).

The future goals of the PIDTC include studies of other rare PIDs such as the immune dysregulatory disorders, IPEX and IPEX-like diseases. Intervention trials will include a multicenter clinical trial to identify the lowest effective dose of busulfan for HCT in newly diagnosed SCID patients. This trial will be the first of its kind for SCID and has the potential to be practice-changing. A prospective study is also planned to test the efficacy of ‘off the shelf’ third-party virus-specific cytotoxic T cells in PID patients pre and post HCT.

5. Summary

The PIDTC is the only clinical consortium in North America to focus on the diagnosis, management, and definitive therapy for PID. Studies from the ongoing retrospective and prospective observational and cross-sectional protocols of SCID, has already improved our understanding of the effects of therapy for this disorder and form the basis for developing future clinical trials. The PIDTC has brought together a large group of clinicians and scientists as well as patient advocates interested in PID and willing to work together to optimize therapy, something never before possible. We are developing prospective multicenter trials with the ultimate goal of setting the standard for the definitive treatment of PID.

Declaration of interest

MJ Cowan is on the Scientific Advisory Boards for Exogen Bio, Inc and Homology Medicine, Inc and the Data Safety Review Board for Bluebird Bio, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

There are many people who are responsible for the establishment and functioning of the PIDTC including the members of the Steering Committee (Luigi Notarangelo (co-PI), Jennifer Puck, Don Kohn and Linda Griffith (NIAID Medical Officer)), the members of the Scientific Planning Committee that includes the center PI’s, the Patient Advocacy Groups (Marcia Boyle and Barb Ballard, IDF; Heather Smith, SCID Angels for Life; Sumathi Iyengar, Wiskott Aldrich Foundation; Mary Hurley, CGD Association; Fred and Vicki Modell, Jeffrey Modell Foundation) and the project managers (Elizabeth Dunn, Tara Bani, and Megan Murnane). Special thanks to Jennifer Puck (UCSF) and Linda Griffith (NIAID, NIH) for their careful editing and thoughtful comments.

The Primary Immune Deficiency Treatment Consortium (U54-AI082973) is part of Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). The PIDTC is funded by the National Institute of Allergy and Infectious Diseases (NIAID), NCATS-ORDR, and, NIH. The PIDTC Annual Scientific Workshop is funded in part by a grant from the NIAID (R13 AI094943) with supplemental funding from the ORDR, NCATS.

Additional information

Funding

MJ Cowan receives partial salary support from grants from National Institute of Allergy and Infectious Diseases (U54-AI082973) and the California Institute of Regenerative Medicine (CLIN1-08363 and DR2-05365).