The risk of malignancy is higher in patients with Primary Immunodeficiency (PID) than in age-matched controls. Lymphoproliferative disorders are responsible for at least 50% of the cases. Patients that undergo haematopoietic stem cell transplantation (HSCT) as a curative therapy for PID are expected to have a reduced risk of malignancy, but it is unknown whether HSCT itself might increase the incidence of malignancy compared to the normal population even in the absence of radiotherapy as part of conditioning. Post transplant lymphoproliferative disorders (PTLDs), usually in association with Epstein Barr virus, may occur after HSCT, usually within 2 years, most often associated with T-lymphocyte depletion and intense immunosuppression, for example in the context of graft versus host disease (GvHD). Data are sparse on occurrence of non-PTLD malignancy post-HSCT in patients with PID. Underlying genetic disease, tissue distribution of genetic defect, GvHD, viral infections and extent of donor chimerism may be important factors that play a role in PID patients developing malignancies post-HSCT.
X-linked lymphoproliferative disease (XLP) is a severe primary immunodeficiency characterised by the loss of function of SLAM-associated protein (SAP) arising from mutations in the SH2D1A gene. SAP is an SH2 domain containing intracellular adaptor protein that relays T cell activatory signals from the T cell receptor (TCR) via ITSM motifs on SLAM family receptors. In the absence of SAP, alternative SH2 domain containing proteins such as SHP1, SHP2 and SHIP bind and induce T cell inhibitory signals leading to abnormal T cell responses. This results in debilitating clinical manifestations such as malignancy, haemophagocytic lymphohistiocytosis (HLH) and dysgammaglobulinaemia through impaired T and NK cell function. Current treatment involves HLH management, replacement immunoglobulin and haematopoietic stem cell transplantation (HSCT); however, HSCT can be associated with significant morbidity and mortality.
In this study we investigate the role of SHP2 in XLP patient T cell function in vitro using a small molecule allosteric inhibitor which stabilises an auto-inhibited conformation of SHP2.
We show restoration of immunoglobulin and cytokine secretion through TFH: B cell co-culture assays, alongside rescue of cytotoxicity and re-stimulation induced cell death (RICD). Deep immunophenotyping and measurement of intracellular phosphorylation of signalling molecules (pSHP2, pERK, pAKT) are consistent with ablation of SHP2 mediated inhibitory signals and restoration of the key signalling events downstream of TCR/SLAM receptors that are required for adequate T cell function.
Collectively, these results support the further evaluation of SHP2 inhibitors as a potential alternative therapy for XLP patients.
Leukocyte Adhesion Deficiency Type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene encoding for CD18, the common subunit of β2 integrins, required for normal leukocyte extravasation to infection sites. LAD-I patients suffer from life-threatening bacterial and fungal infections that cannot be properly resolved. Although allogenic hematopoietic transplantation is the preferred therapy, gene therapy is considered a good option for LAD-I patients.
Aiming the lentiviral-mediated gene therapy of LAD-I patients, we developed a lentiviral vector (LV) in which expression of hCD18 is driven by the CatG/cFES chimeric promoter, preferentially active in myeloid cells. The efficacy of this LV to correct the disease in CD18HYP mice was previously demonstrated.
Here we show that the infusion of gene-modified HSCs in knock-out LAD-I mice corrected the phenotype of these animals. The efficacy of the LV-mediated gene therapy occurred in the absence of any hematotoxic or genotoxic effect. Further studies with a GMP-produced Chim.hCD18-LV allowed us to optimize the transduction of human CD34+ cells using a combination of transduction enhancers. Finally, validation runs of the GMP-transduction procedure were performed, demonstrating robust and reproducible transduction efficiencies of CD34+ cells that retained their repopulation ability in NSG transplanted mice.
Our preclinical studies showed the efficacy of the proposed LV-mediated gene therapy in LAD-I mouse models and demonstrated the efficient transduction of human CD34+ cells under GMP conditions. A Phase I Clinical Trial has been approved for the treatment of patients with severe LAD-I.
LRBA deficiency presents with susceptibility to infections,autoimmunity and lymphoproliferation.Long-term efficacy of CTLA4-Ig as targeted therapy for its immune dysregulatory features remains to be established.We sought to determine the clinical and immunological features of LRBA-deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations.
22 LRBA-deficient patients were recruited from different immunology centers and followed prospectively.Patients on abatacept were evaluated every 3 months for clinical and immunological responses.LRBA expression,lymphocyte subpopulations and circulating T follicular helper cells were determined.
The mean age of the patients was 13.4±7.9years and the follow up period was 3.4±2.3years.Recurrent infections(n:19,86.4%),immune dysregulation(ID,n:18,81.8%) and lymphoproliferation(LP,n:16,72.7%) were common clinical features.The long-term benefits of abatacept in 16 patients were demonstrated by complete control of LP and chronic diarrhea followed by ID,most notably autoimmune cytopenias.Weekly or every other week administration of abatacept gave better disease control compared to every 4-weeks.There were no serious side effects related to the abatacept therapy.cTFH cell frequencies were found to be a reliable biomarker of disease activity,which decreased on abatacept therapy in the majority of subjects.However,high cTFH cell frequencies persisted in two patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy.
The targeted therapy was able to effectively control the different immune dysregulatory disease manifestations in most patients,and more favorable responses were achieved in patients who received abatacept at weekly intervals without serious side effects.Monitoring cTFH cells during abatacept therapy provides a useful measure of disease activity,and may uncover cases of relative therapy resistance that require alternative treatment approaches.
*This work was supported by grant from the Scientific and Technological Research Council of Turkey (217S847)