Summary by:
Juha Grönholm (MD, fellow in pediatric hematology and oncology)
Pasi Huttunen (MD, consultant in pediatric hematology and oncology)
Heljä Lång (MD, consultant in pediatric hematology and oncology)
HUS Helsinki University Hospital, New Children’s Hospital, Division of Hematology-Oncology and Stem Cell Transplantation.
Session I: Stem cell therapy in metabolic diseases chaired by Maria Ester Bernardo & Robert Wynn
Valeria Galbi discussed Arca-cel treatment for MLD (demyelinating lysosomal storage disease) with follow up data on 39 patients. Treated patients showed improvement in MSF as compared to NHx, and preservation of motor, and cognitive abilities.
Maria Ester Bernardo introduced the OTL-203 Ph 1/2 trial with 8 patients presenting with a severe phenotype. Preliminary results from 4 years FU indicate that OTL-203 is generally well tolerated with evidence of extensive metabolic correction and beneficial effects on multisystem burden of MPS-IH.
Robert Wynn presented a phase I/II clinical trial using autologous CD34+ HSCs transduced ex vivo with CD11g lentiviral vector encoding for human SGHS. 5 patients with rapidly progressive MPSIIIA had been recruited aiming to compare findings with historical cohorts. The treatment yielded supra physiological concentration of SGSH enzyme in leukocytes and rapid reduction in heparan sulphate storage in multiple compartments.
Claire Horgan presented a phase I/II clinical trial of cryopreserved autologous CD34+ hematopoietic stem cells transduced ex vivo with CD11B lentiviral vector encoding for IDS.APOEII in patients with neuropathic MPSII. The goal is to recruit 5 eligible subjects and study objectives will be primary safety and tolerability and IMP -related toxicity.
The first patient was recruited in July 2024 with IMP infusion planned to be conducted later this year.
Alessandro Aiuti described a lenti-viral vector design for DLS gene therapy. The transgene expression has been studied in healthy donor cells and in vivo in humanized mice. The aim is to continue with a clinical trial.
Case presentation by Nathaniel Lucas described a 3-year-old patient with Farber's lipogranulomatosis who underwent HSCT. Disease related nodules were clearly reduced d58 post-transplant and the patient showed almost full recovery on d176 post-transplant.
Robert Chiesa talked about the IEWP osteopetrosis study, a retrospective study looking at outcomes of children undergoing HSCT for osteopetrosis between 1990-2022. The aim is to evaluate the impact of age, conditioning and stem cell source on overall survival, event free survival and graft failure. In addition, incidence of specific complications and disease -specific outcomes are evaluated. As preliminary findings high mortality and graft failure rates have been noted. Thus far 195 questionaries have been returned and the centers were kindly asked to include their data.
Francesca Tucci introduced a study on using ST-TIGET TCIRG1 gene therapy to treat autosomal recessive osteopetrosis combining ex vivo UM171-based autologous HSPC expansion and lentiviral gene therapy. Functional osteoclasts with expanded CD34+ cells have been successfully created in their in vitro studies and humanized mice showed high engraftment in all immunological organs. The planned Phase I/II clinical study is estimated to last 5 years, aiming to enroll 7 patients within 3 years, with a 2-year follow-up period.
Session II: Pathophysiology of IEI and its role in cellular therapy chaired by Mikko Seppänen & Kate Orf
Sophie Hambleton described two novel causes of severe combined immune deficiency (SCID) and the benefits of obtaining correct molecular diagnosis. The first case presented with features of Omenn syndrome had a homozygous NUDCD3 variant leading to T-B-SCID. This rare variant was further found from four distinct families. The second case was a T cell immunodeficiency picked up by newborn screening from an infant with eczematous skin. Whole exome sequencing revealed aheterozygous de novo missense variant in PSMB10. After the initial patient, six patients have been reported.
Carsten Speckmann discussed the treatment choices for STAT1 and STAT3 gain-of-function (GOF) variants. Currently there are no commercially licenced JAKi available for treatment of IEI, but JAKi has been found to be effective in a study for IEI with activated JAK/STAT-pathway. The outcome of small series on patients undergoing HSCT with previous JAKi treatment showed promising results. JAKis should be evaluated in a RCT to validate which JAKi and with which dosing would be the most suitable for different age groups.
Alexandra Kreins introduced the ESID guidelines for congenital athymia, illustrating them with four patient cases. About 10% of patients with a T-B+NK+ phenotype lack a molecular diagnosis and for these genetically unidentified cases, a 2D ex vivo T-lymphopoiesis assay can help differentiate between SCID and congenital athymia and guide the choice between HSCT and thymus transplantation.
Session III: Infections (focus on viruses) chaired by Krzysztof Kalwak & Olaf Neth
Krzysztof Kalwak reported first on a phase 2b study, where letermovir was used for 14 weeks post HSCT in three different pediatric age groups, at a median age of 11 years. Primary objective was to evaluate letermovir PK. Efficacy in pediatric patients was as good or better than in adults.
Results from a retrospective EMBT PDWP study were reported. In a multicenter study with 87 patients, all <12 years and the majority being leukemia patients, letermovir was found to be very effective for both primary and secondary CMV prophylaxis.
Austen Worth reported on the GOSH experience on metagenomic samples from CSF, blood and tissue samples. Metagenomics can detect any pathogen (virus or bacteria) in one go and in 2024 the method received full accreditation for GOSH.
Corentin Le Floch told about a study recruiting IL2RG-SCID patients w/o HPV infections post HSCT (no conditioning).
EVAH virus infection in the HSCT setting
Bénédicte Neven talked about EVAH (Enteric-virus associated hepatitis) which is a consequence of defective antibody response against enteric viruses and is T cell (CD8) driven. Possible responsible viruses include Aichi, Noro, Parecho and Sapo viruses.
Keynote Lecture: Gene therapy for IEI by Donald Kohn
Donald Kohn gave a fascinating keynote lecture on the status of gene therapy for inborn errors of immunity.
Contemporary hematopoietic stem cell therapy results in a similar overall survival than gene therapy. ADA SCID gene therapy trial in UCLA/UCL/GOSH is lentiviral based EFS-ADA with busulfan-based conditioning. SIN lentiviral vector - makes high titer of ADA (even from single vector), much better production of ADA compared to retrovirus. Mobilized peripheral blood is better than bone marrow. Gene therapy resulted in 100% OS and 96% EFS with 48/50 patients with engrafment and immune reconstitution.
CD3delta SCID is found in Mennopolite populations and causes a block in T cells development between TCRVb and TCRVa expression stage (ISP4/TCR-DP stage). The condition is fatal without HSCT. Adenine base editing experiments are underway. It was concluded that converting academic “proof of principle” manufacturing approaches to commercial-grade manufacturing is expensive.
Session IV: Gene therapy chaired by Sung-Yun Pai & Claire Booth
David Rawlings talked about a lentiviral vector-based gene therapy project for XLA which is currently in clinical vector production phase in Seattle.
Daniele Canarutto introduced an upcoming phase I/II clinical gene therapy trial of gene edited T cells for CD40L which is opening late 2025 with plans to enroll 6 patients.
Anna Villa talked about gene editing in RAG1-SCID. A phase I/II clinical trial with 3 RAG1-SCID patients (MND.coRAG1 LV) resulted in adequate immunological reconstitution.
Arjan Lankester gave an update on the phase I/II clinical trial for lentiviral based gene therapy trial for RAG1 SCID, which is still recruiting. This is a multicenter study open currently in 7 centers and so far, 4 patients have been infused. Cells travel, not patients.
Claire Booth introduced a phase I non-randomized open label study of Product XLP-T01 to treat XLP which is planned to open spring 2025. The IMP product will be manufactured in GOSH and the plan is to enroll 7 patients.
Marina Cavazzana gave an update on ARTEGENE trial, which is a phase I/II lentiviral-based clinical trial with DCLRE1C gene addition strategy in Artemis SCID/leaky SCID. 3 patients have been enrolled so far. There is still room for improvement, and a new protocol with the addition of transduced pro-T cells will be submitted.
Claire Booth gave an update on the p47-CGD gene therapy trial in GOSH together with NIH which is recruiting patients over 6 months of age and no 10/10 MRD available. Primary endpoint is engrafment of gene modified cells and secondary endpoints include safety, long term engraftment, EFS and overall health.
Keynote lecture: Genetics of Incomplete Penetrance by Dusan Bogunovic
Dusan Bogunovic gave a fantastic talk on the mechanisms of incomplete penetrance, which is likely more common than reported in monogenic diseases. For heterozygous disease-causing variants, differences between monoallelic and biallelic expression patterns can lead to altered clinical phenotypes, explaining some cases of incomplete penetrance. One reason for these differences could be variations in DNA and histone methylation between alleles. In some cases, monoallelic expression of a heterozygous variant can result in a complete loss of protein expression.
Session V: Challenging indications and novel approaches chaired by Despina Moshous & Manfred Höning
Despina Moshous discussed somatic variants that can mimic inborn errors of immunity. These can occur early in development or later in life, leading to mosaicism in a wide range or specific subset of cell lineages. Occasionally, somatic variants may reverse the effects of another pathogenic variant. Due to their low variant allele frequency, these somatic variants are often missed by whole-genome or whole-exome sequencing. Somatic mosaicism can expand the phenotypic spectrum of immunohematological disorders.
Maria Trabazo presented a case of a 13-year-old boy with APLAID syndrome, a rare condition characterized by systemic inflammation and varying degrees of immunodeficiency due to monoallelic mutations in the PLCG2 gene.
Manfred Hönig talked about immunological reconstitution after secondary HSCT. He presented two patient cases with RAG1 SCID.
Mirjam van der Burg presented results of a newborn screening (NBS) program from her institute, which has screened 600,000 children. Out of this population, there were 65 referrals, including 7 cases of severe combined immunodeficiency (SCID). The majority of referrals were for secondary T cell defects. The talk raised discussion on the potential of neonatal genetics as a first tier screening tool for inborn errors of immunity, highlighting its power but also the need for careful consideration in its implementation.
Session VI Characteristic diseases of the Finnish population chaired by Samppa Ryhänen & Heljä Lång
Svetlana Vakkilainen presented a cohort of over 100 patients with Cartilage-Hair Hypoplasia (CHH), a syndromic inborn error of immunity (IEI), which belongs to the Finnish disease heritage. She concluded that the severity of CHH associated immunodeficiency varies markedly.
Heljä Lång summarized the results from previously reported cohorts on CHH patients undergoing HSCT. She then discussed the Finnish HSCT experience with 9 CHH patients transplanted at a median age of 7.4 years at HSCT. A new retrospective IEWP study on HSCT in CHH patients in being initiated.
Saila Laakso discussed using JAK inhibitor ruxolitinib for treating autoimmunity in APS1 (APECED). The disease mechanism is mediated by increased IFNg responses and in a recent study ruxolitinib had a good effect on alleviating the autoimmune manifestations of APS1 patients. A phase II clinical trial at NIH is ongoing with 21 patients, showing remission of 19 autoimmune conditions, including even type 1 diabetes. The recruitment is still open.
Session VII: IEWP Studies and proposals chaired by Bénédicte Neven & Michael ALbert
Reem Elfeky presented a study proposal titled Clinical practice guideline: Long-term follow-up in patients transplanted for IEI. The aim is to standardize long-term follow-up efficiency and improve health outcomes and quality of life through effective screening and early intervention.
Giulia Prunotto proposed a retrospective study on TTC7A deficiency. This condition presents with variable gastrointestinal disease and 75% of patients have variable immune deficiency ranging from CVID to SCID-like phenotype. Hematopoietic stem cell transplantation (HSCT) can correct the immune defect but not the intestinal manifestations.
Etai Adam introduced a retrospective study proposal on hematopoietic stem cell transplantation (HSCT) for Deficiency of Adenosine Deaminase 2 (DADA2). This study would like to receive data on additional patients.
Ina Schim van der Loeff introduced a study proposal on IL2RA and IL2RB deficiencies, which aims to gather data on the natural history and treatment outcomes of these patients.
Emma Morris presented an IEWP retrospective study to evaluate the influence of pre-transplant immune dysregulation on transplant outcomes for non-SCID IEI.
Session VIII: HSCT for IEI in AYAs (focus on CVID) chaired by Emma Morris & Klaus Warnatz
Raffaella Muratori presented a case of 40y old woman diagnosed with GLILD (Granulomatous-lymphocytic interstitial lung disease) and CVID. Later DLBCL was diagnosed. There was discussion on whether to transplant the patient with 9/10 matched URD or with sister or brother with MSH2 mutation (Lynch syndrome).
Klaus Warnatz talked about the role of HSCT in the treatment of CVID. There is considerable clinical heterogeneity in CVID and especially the patients with complex CVID might benefit from HSCT whereas “infection only CVID” probably doesn’t benefit from transplant.
It is the smoldering disease which causes early mortality and in the case of bronchiectasis, lung or liver fibrosis or BM failure it may already be too late for HSCT.
Neil Halliday talked about liver disease in CVID and the role of liver transplantation.
Liver involvement in CVID may be incidental, treatment related or CVID related like porto-sinusoidal vascular disorder. Clinical presentation of liver disease in CVID include abnormal liver enzymes, portal hypertension, cirrhosis, porto-pulmonary hypertension and hepatopulmonary syndrome.
Considering liver transplantation, approx. 30 cases have been reported with 3 years survival of 50%. The timing, indication, strategy and patient selection of liver transplantation remains debated.
Muriel Schmutz presented a cohort of 13 B-cell defect patients treated with cellular therapy. 11 of the patients had chronic liver disease with NRH and all had co-morbidities. Hepatic outcome was good with regression of portal hypertension.
Emma Morris reported on recent CVID Allo HSCT outcomes and proposed COCOA clinical study. IEWP COCOA (Complex CVID Outcomes following HSCT) will include retrospective data collection, and all patients are discussed at the international Adult Immunodeficiency BMT MDT. Primary objective is outcome and secondary include identifying a subgroup of complex CVID patients who benefit allo-HSCT and determine optimal timing for HSCT.
Session IX: Haplo HSCT for IEI chaired by Andrew Gennery & Arjan Lankester
Michael Albert and Su Han Lum gave a joint presentation on takeaways from the IEWP study comparing PTCY and TCR αβ. Both methods have proven efficacy and safety for mismatched HSCT in IEI.
Christopher Dvorak discussed how to best use T-cell directed serotherapy (rATG, Thymoglobuline) in haplo HSCT. rATG exposure seems to impact occurrence of cGVHD and NRM.
Arjan Lankester talked about how to best use T-cell directed serotherapy in haplo HSCT. Individualized ATG dosing based on PK in non-malignant patients results in reduced variability in ATG exposure and favorable clinical outcomes including low mortality, high EFS and very low grade III-IV GVHD.
Madeleine Powys talked about her center’s experience on real-time treosulfan PK, which might help to standardize dosing for treosulfan. In the cohort, 2/6 patients required dose adjustments, and the main priority is avoiding high exposure.
Su Han Lum talked about adoptive cellular therapy with CD45RO+ memory T-cell addback. In a pilot with 27 pts receiving TCRab-HAPLO SCT for non-SCID IEI, early T-cell recovery and anti-viral efficacy was seen in responders and no increased GvHD risk was observed.
Session X: Bridging strategies to HSCT chaired by Reem Elfeky & Carsten Speckmann
Safa Baris talked about the use of CTLA4 fusion proteins as bridge to HSCT in LRBA deficiency. He presented a Turkish cohort including 74 LRBA and 42 CTLA4 haploinsufficient patients where abatacept therapy was able to control immune dysregulatory manifestations in most patients.
Christo Tsilifis gave a presentation on the use of CLTLA4 fusion proteins as bridge to HSCT in CTLA4 deficiency and presented results from the IEWP HSCT study for CTLA-4 deficiency.
Reem Elfeky talked about the use of leniolisib in APDS1/2 patients. Data from a retrospective study with 37 APDS1/APDS 2 receiving leniolisib in Europen centres was presented. A new multicenter retrospective observational study will compare rapamycin and leniolisib in the management of APDS1/2 patients.
Pietro Merli gave a presentation on the use of emapalumab as a bridge to HSCT. In diseases characterized by iFNgamma-driven inflammation, the use of emapalumab may favour engraftment.
Final remarks and Farewell concluded the meeting.
