Prevention of Primary Manifestations
Restoring a functional immune system is essential and can be achieved in several ways. The choice of therapy is complex and depends on a number of factors, including the affected person’s age and clinical status, the expectations and desires of the parents, and the specific experience and expertise of physicians in treating ADA-deficient SCID. A workshop held in 2008 developed consensus guidelines for therapy [Gaspar et al 2009] (full text).
Bone marrow/stem cell transplantation (BMT/SCT) from an HLA-identical healthy sib is the method of choice for treating all forms of SCID.
This can be performed without cytoreductive conditioning of the affected individual, and without depletion of donor T-cells.
Results vary among transplant centers, but the procedure is curative in approximately 70% or more of affected individuals.
The main risks are graft-versus-host disease and delayed or incomplete recovery of humoral immune function, requiring continued immunoglobulin replacement.
For the majority of individuals with ADA-deficient SCID who lack an HLA-identical related donor, the following two forms of treatment can be considered [Gaspar et al 2009, Gaspar 2010, Candotti et al 2012, Baffelli et al 2015].
BMT/SCT from a "non-ideal" donor
Donor-derived T-cells are depleted to minimize the risk of graft-versus-host disease.
Pre-transplant cytoreductive "conditioning" of the recipient (individual with SCID) is often performed to prevent graft loss, which occurs with relative frequency in those with ADA-deficient SCID who are not conditioned.
Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [
Buckley et al 1999]. However, this latter approach has frequently been associated with a failure to achieve stable engraftment [
Gaspar et al 2009,
Gaspar 2010,
Hassan et al 2012].
Following a T-cell-depleted transplant, return of functional T-cells requires three to four months. B-cell reconstitution is delayed longer, or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy.
Note: Universal agreement regarding the best methods for performing partially mismatched BMT/SCT does not exist [Cancrini et al 2010, Gaspar 2010, Hassan et al 2012]. When considering therapeutic options, it is therefore important for parents to obtain specific information about prior experience and long-term results of transplants for ADA-deficient SCID at the center where their child will be treated.
Enzyme replacement therapy (ERT) has been used as a primary therapy in individuals who lack an HLA-identical marrow/stem cell donor when the risks associated with a partially mismatched transplant are deemed too great or when the risk of graft failure is high, as in older individuals with a delayed- or late-onset phenotype.
Polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA) is composed of purified bovine ADA covalently linked to multiple strands of PEG (average mass: 5 kd) in order to prolong circulating life and reduce immunogenicity. It is administered by intramuscular injection once or twice a week (~15-60 U/kg per week).
ERT is not curative; PEG-ADA must be given regularly and at a sufficient dose to maintain a nontoxic metabolic environment.
PEG-ADA has also been used as a secondary therapy in affected individuals who have failed to engraft following an unconditioned BMT/SCT, or in whom an acceptable recovery of immune function has not been achieved following experimental
gene therapy.
Most individuals treated with PEG-ADA recover partial immune function that is sufficient to prevent opportunistic infections and other clinical manifestations of SCID. A lag of approximately two to four months occurs before T-cell function appears, but B-cells often increase earlier than after BMT/SCT. Lymphocyte counts and in vitro lymphocyte function usually increase during the first year of ERT, but beyond the first year or two most PEG-ADA-treated individuals remain lymphopenic and in vitro lymphocyte function fluctuates widely. Most individuals remain clinically well, but over time both T and B lymphocytes gradually decline in number and display various functional abnormalities [Chan et al 2005, Malacarne et al 2005, Serana et al 2010, Brigida et al 2014]. Approximately half of those maintained on ERT were continuing to receive immunoglobulin replacement.
More than 300 affected individuals have received PEG-ADA. Survival of PEG-ADA-treated individuals beyond five years and through approximately ten years is approximately 75%-80%, comparable or superior to that achieved with BMT/SCT (i.e. in individuals who lack an HLA-identical donor). Most deaths occurred during the first six months of treatment, with the majority in the first month due to life-threatening infections present at diagnosis.
Lymphoproliferative disorders have developed in eight individuals who received PEG-ADA for eight to 22 years [Hershfield 2004; Chan et al 2005; Kaufman et al 2005; Husain et al 2007; Author, unpublished data]. Hepatocellular carcinoma developed in one affected individual after 13 years of ERT, and was present in another at the time ERT was initiated following an unsuccessful stem cell transplant. A third affected individual died of hepatoblastoma after 2.5 years of ERT; the tumor was thought to have been present but undetected prior to ERT. Several other affected individuals have developed persistent hemolytic anemia, which in some cases began in association with a viral infection or with central catheter sepsis [Hershfield 2004, Lainka et al 2005].
The limitations of PEG-ADA therapy include primary failure to recover protective immune function, the development of neutralizing antibodies that reduce or eliminate efficacy, immune dysregulation (particularly in the first few months of therapy), and a risk that immune function will eventually (i.e., beyond 10-15 years) decline to an inadequate level. Approximately 20% of affected individuals have discontinued ERT in order to undergo BMT/SCT. In most of these cases, the transplant had been intended at the time of diagnosis but not performed because a suitable donor was not available or the affected individual had been too ill to undergo the procedure. In a minority of individuals, the transplant was performed because of declining immune function while receiving PEG-ADA. Overall, approximately half of these secondary transplants have been successful [Hershfield 2004, Gaspar et al 2009].
Most individuals treated with PEG-ADA for longer than a year develop antibodies that bind specifically to bovine ADA and are detectable by an enzyme-linked immunosorbent assay (ELISA); these are of no clinical significance. Neutralizing antibodies that inhibit catalytic activity and enhance clearance of PEG-ADA (and which do compromise efficacy) have developed in fewer than 10% of treated individuals [Chaffee et al 1992, Hershfield 1997]. No allergic or hypersensitivity reactions to PEG-ADA have occurred, and the treatment has generally been well tolerated.
Gene therapy, while still technically experimental, is still another treatment option for those who have failed all other options (see Therapies Under Investigation).
Therapies Under Investigation
Experimental gene therapy for ADA-deficient SCID employing gamma retroviral vectors has been under clinical investigation for more than 20 years [Engel et al 2003, Cavazzana-Calvo et al 2005]. Clinical trials since about 2000 have employed an approach that was first reported for two affected individuals treated in Milan, Italy and later updated for ten others [Aiuti et al 2002, Aiuti et al 2009]. This strategy involved discontinuing PEG-ADA (in those receiving ERT) and administering non-myeloablative conditioning prior to the infusion of vector carrying human ADA cDNA in order to transduce autologous CD34+ stem cells. Variations on this protocol have also been under investigation in the UK, US, and Japan. More than 40 affected individuals (most of whom had been receiving PEG-ADA) have been treated at these centers [Aiuti et al 2002, Gaspar et al 2006, Engel et al 2007, Aiuti et al 2009, Cappelli & Aiuti 2010, Selleri et al 2011, Candotti et al 2012, Sauer et al 2012, Gaspar et al 2013]. In most treated individuals, stable ADA expression in lymphoid cells has been achieved, along with correction of metabolic abnormalities in erythrocytes, which has been accompanied by reconstitution of both T and B cell immune function, although this reconstitution may take a year or more. Good health has been maintained without the need for ERT.
In contrast to the experience with gene therapy for X-linked SCID, no individuals with ADA deficiency have developed leukemia as a result of vector-associated insertional mutagenesis, and at this time no deaths have been reported [Cicalese et al 2016]. In May of 2016, GlaxoSmithKline announced that the European Commission had approved the gamma retroviral vector developed in Milan for use in treatment of SCID due to ADA deficiency. However, because of remaining concerns about potential insertional mutagenesis, and in order to achieve more effective ADA expression, clinical investigation of gene therapy using lentiviral vectors has now begun [Farinelli et al 2014, Candotti 2016].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
