Welcome to the ESID 2022 Meeting Interactive Programme

Background and Aims

Chronic granulomatous disease (CGD) is a well described primary immunodeficiency with a "classic" infectious phenotype. Granulomatous complications present another significant problem in CGD, occur in 70-80% of the patients, and are difficult to diagnose and treat.

Methods

We report results of granulomas treatment in 30 CGD patients. Granulomas were present predominantly in the lungs (26 patients) and liver (8 patients). Antibacterial and antifungal therapy failed to resolve the lesions. For granulomas treatment 12 patients received prednisolone (1 mg/kg/day for 2 weeks, 0.5 mg/kg/day for 2 weeks, then 0.3 mg/kg/day for 1-4 months) and 18 patients - anakinra (8-10 mcg/kg daily for 2 weeks - 6 months). Complete response to treatment was defined as more than 75% reduction of granulomas size.

Results

We demonstrate that complete response to prednisolone was achieved in 37.8% patients with lung granulomas, and in 25.0% with liver granulomas (p<0.01); and 75.0% of the patients receiving prednisolone developed moderate adverse events (AE), 33.3% - severe AE, and 25.0% - life-threatening AE, including pulmonary aspergillosis. 3/12 patients had more than one AE. Complete response to anakinra was achieved in 90.0% of patients with lung granulomas, and in 75.0% with liver granulomas (p<0.01). In this group, 5.6% had mild AE (local reaction at the injection site) and 11.1% had moderate AE (neutropenia), no severe AE was recorded.

Conclusions

We report that IL-1 receptor inhibitor (anakinra) is more effective and safe for the treatment of liver and lung granulomas in CGD patients as compared to the traditionally used steroids.

Background and Aims

Pathogenic variants in genes encoding PI3Kδ (PIK3CD, PIK3R1) causing kinase hyperactivity can result in the primary immunodeficiency and regulatory disorder activated PI3Kδ syndrome. We previously reported use of molecularly targeted inhibition of hyperactive PI3Kδ with investigational drug leniolisib in a phase 3 RCT (NCT02435173). Here we describe interim analysis outcomes from the ongoing open-label, single-arm, long-term extension study (NCT02859727).

Methods

Thirty-seven patients with APDS aged ≥12 years were enrolled globally. Patients were exposed to leniolisib through 5 years, including 20 patients ≥ 96 weeks, and 5 patients approximately 5 years.

Results

Sustained reduction of lymphoproliferation as well as immune reconstitution was notable. The latter included: increased naïve B cells, decreased transitional B cells, reduced PD-1+ and senescent T cells through Extension Day (ED) 252. Immunoglobulin replacement therapy (IRT) infusions were reduced; four patients discontinued IRT; results were maintained. At 2 years, mean improvement in physical component summary and mean change in general health scale of the SF-36 suggest improved HRQoL.

Leniolisib was well tolerated; 32/37 patients experienced AEs Grades 1-3. The majority were Grade 1 (55%), with no Grade 4 AEs. Study drug related AEs occurred in 13.5% of patients. One patient with significant comorbidities (history included disseminated mycoplasma infection and cardiomyopathy) suffered cardiac arrest resulting in death at ED794 determined not related to study drug. This was the only discontinuation. No SAEs were suspected related to leniolisib.

Conclusions

These results demonstrate long-term leniolisib administration with exposure through 5 years was well-tolerated in patients with APDS, with continued improvement in lymphoproliferation and immunophenotype.

Background and Aims

Allogeneic HSCT may cure the haematopoietic components of STAT3-DN hyper-IgE syndrome (STAT3-DN-HIES), though experience on long-term outcomes is limited.

Methods

A survey of international patients undergoing allogeneic HSCT with STAT3-DN-HIES was conducted.

Results

We identified 21 patients receiving 23 grafts. Median age at HSCT was 13.2 years (range: 3.0–25.7) with median follow-up 3.32 years (range: 0.96–25.9).

HSCT indications were recurrent infection (n=18) and lymphoma (peripheral T-cell; high-grade non-Hodgkin’s; n=3). Lung disease typical of STAT3-DN-HIES was present pre-transplant in 19/21 patients and chronic infection at HSCT in 18/21. Patients received peripheral blood stem cells (n=12) or bone marrow (n=11) from matched family donors (n=9), unrelated donors matching ≥9/10 HLA loci (n=13) and one TCRαβ/CD19-depleted haploidentical donor, using busulfan- (n=6), treosulfan- (n=11), and melphalan-based (n=6) conditioning regimens, with serotherapy in 19/21 procedures.

Peri-transplant morbidity included acute graft-versus-host disease (9/21, grade 3-4 in 3 patients), graft rejection/failure (2/21), and intensive care admission (3/21). Two patients died, from graft-versus-host disease and from disseminated adenoviral infection.

At 3 years, overall and event-free survival (defined as survival without graft failure or second procedure) were 89.6% and 85.7% respectively. At data collection, in 19 survivors, median donor chimerism was 100%, median IgE 1720IU/L (range: 10–11813), and Th17 lymphocytes were present in 9/9 patients tested. Survivors reported improvement in lung disease (n=16/19) and reduced infection (n=16/19).

Conclusions

Successful HSCT results in restoration of Th17-IL-17 immunity, improvement in lung and skin disease, and good event-free survival in STAT3-DN-HIES patients with significant pre-transplant morbidity. Further exploration of quality-of-life impact may aid patient selection.

Background and Aims

Bone marrow transplantation (BMT) can cure CGD-related infections, and inflammatory disease. Older patients and those with resistant fungal infections, severe inflammatory bowel disease (IBD), or hypoxemic lung disease are often ineligible for transplant. We have devised a BMT regimen to transplant these patients.

Methods

Conditioning: Campath (1mg/kg over 5d), Busulfan (5mg/kg over 2d) and TBI (300cGy) with post-transplant cyclophosphamide (100mg/kg in 2d) and sirolimus. Patients with C-reactive protein (CRP)>100 were normally excluded as this is an indicator of high mortality; however 5 received exceptions for transplant because of life-threatening recalcitrant infections.

Results

Number: 28 plus 5 with CRP>100 off protocol. Follow up: 6 months to 5 years

Donors: 30 Matched unrelated, 3 Matched related

Ages: Mean 30 (6-58), Gender: 4F, 29M, CGD type: GP91 (25, incl.1 skewed lyonized female), P47 (6), P67 (1), P22 (1)

BMT indications: pulmonary disease (7), IBD (12), active infection (17)

Outcomes: 28 ‘eligible’ (all 33 patients)

Conclusions

Low dose Busulfan with TBI, Campath, post-transplant cyclophosphamide and sirolimus for BMT of CGD patients (CRP<100) results in improved engraftment rates with minimal GvHD. Patients not eligible for transplant at other centers, due to infection, lung inflammation, and/or severe colitis, tolerated the conditioning with resolution of their CGD complications. However, patients with CRP>100 at initiation of conditioning should not be transplanted.

Background and Aims

LAD-I results from mutations in ITGB2 encoding the β2-integrin CD18. Severe LAD-I (<2% CD18+ polymorphonucleocytes [PMNs]) causes severe infections, impaired wound healing, and childhood mortality. Allogeneic hematopoietic stem cell transplant is curative; efficacy is limited by donor availability, graft-versus-host disease, and graft failure. RP-L201-0318 (NCT03812263), employs autologous CD34+ cells transduced with a lentiviral vector carrying ITGB2.

Methods

Patients ≥3 months old with severe LAD-I were enrolled. HSCs were collected via apheresis after mobilization with granulocyte-colony-stimulating-factor and plerixafor and transduced ex-vivo. Myeloablative busulfan conditioning preceded RP-L201. Patients are followed for safety and efficacy including survival to age 2 and ≥1-year post-infusion, peripheral blood [PB] PMN CD18 expression, PB vector copy number [VCN], neutrophilia improvement, decreased infections/hospitalizations, resolution of skin/periodontal abnormalities.

Results

Nine patients (ages 5mos-9yrs) received RP-L201, with 3–24-month available follow-up. RP-L201 cell doses ranged from 2.8x106 to 10x106 CD34+ cells/kg with a drug product VCN from 1.8-3.8. All 9 demonstrated sustained PMN CD18 restoration and VCN >0.1integration. At 1 year, the OS rate is 100% per Kaplan-Meier estimate. The patient with 24 months follow-up showed ~40% PMN CD18 expression with 1.53 PB VCN. Baseline skin lesions resolved with no new infection-related hospitalizations. Subsequent 8 patients were followed for 3-18 months, demonstrating PMN CD18 expression of 25.6-86.6%. Neutrophilia resolved uniformly. Hospitalizations and severe infections were significantly reduced following therapy. The safety profile has been highly favorable with no RP-L201-related SAEs.

Conclusions

RP-L201 confers durable reversal of the severe LAD-I phenotype with improved clinical course in 9 of 9 patients.

Background and Aims

Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops in patients with a genetic predisposition (FHL2-5, CHS, GSII, SAP, XIAP). In previous HLH-94 and HLH-2004 studies, etoposide-based treatment followed by hematopoietic stem cell transplantation (HSCT) led to 50% and 59% overall survival in pHLH patients, respectively. Contemporary data are lacking, but are essential to put novel treatment approaches (emapalumab, alemtuzumab, ruxolitinib) into perspective.

Methods

We evaluated all primary HLH patients registered in the international Histiocyte Society/ESID HLH registry 2016 - 2021 with one-year follow-up.

Results

Among 78 patients, 54 had FHL2-5, 13 had GS2/CHS, 8 had XLP1/2 and 3 had undefined pHLH. 10 patients were diagnosed without symptoms, 8 of them were transplanted and all 10 were alive and well. Among 67 symptomatic patients, 93% fulfilled HLH-2004 criteria, while 3 presented with CNS-HLH and 2 had less than 5 HLH criteria. 8 patients (4 FHL) only received IVIG/steroids/ cyclosporine A, while 59 received major HLH-directed drugs (first-line etoposide in 90%). 32% of patients received at least one additional major drug (mostly alemtuzumab). 65 patients underwent HSCT, 7 died before HSCT. At the 1-year follow-up, overall 63/78 (81%) patients were alive. 74% of patients receiving first-line etoposide were alive after 1 year.

Conclusions

Contemporary prognosis of pHLH patients receiving first-line etoposide-based therapy is better than anticipated, suggesting important advances in early diagnosis, supportive therapies and HSCT procedures. However, salvage therapies were used in 1/3. Importantly, early HSCT of asymptomatic siblings resulted in 100% survival, emphasizing the potential benefit of newborn screening.

Background and Aims

Background: Heterozygous mutations in CTLA4 result in an inborn error of immunity (IEI) (also known as primary immunodeficiency) with a severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic stem cell transplantation.

Aims: We set out to devise a CRISPR/Cas9/AAV6 gene editing strategy to correct CTLA4 insufficiency in T cells.

Methods

We evaluated several universal gene editing strategies that enable correction of most disease-causing mutations with a single edit; the first that inserts the CTLA4 cDNA in exon 1, and a second that inserts the CTLA4 cDNA at the 3’end of the first intron of CTLA4.

Results

Superior editing efficiencies were obtained with the intronic approach compared to the other editing strategies. Functional studies using CTLA4 transendocytosis (TE) assays, demonstrated restoration of CD80 and CD86 internalization in the edited CD4+ T cells. Gene editing of T cells isolated from patients with CTLA4 insufficiency restored CTLA4 expression and rescued transendocytosis of CD80 and CD86 in vitro. Using a similar approach, gene corrected T cells from CTLA4^-/- mice engrafted in immunodeficient mice at clinically relevant frequencies and rescued mice from fatal lymphoproliferation and autoimmunity.

Conclusions

Together these data demonstrated that CTLA4 edited T cells survived in vivo, expressed CTLA4 and were able to control the clinical phenotype of CTLA4 insufficiency, providing a powerful proof-of-principle of our T cell GT approach. Our data provide proof-of-concept that gene editing can restore CTLA4 function in T cells demonstrating the potential of this approach to treat CTLA4 insufficiency.