ALBERT

Description: Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in Fanconi anemia (FA) patients. However, recent advances in lentiviral-mediated gene therapy have shown that corrected FA HSCs develop an in vivo proliferation advantage, facilitating the engraftment of corrected HSCs in non-conditioned FA patients. Based on these observations, we proposed that gene editing might constitute a promising alternative to correct patients' hematopoietic stem and progenitor cells (HSPCs) in this disorder. Since non-homologous end joining (NHEJ) is the most frequent repair pathway in HSCs, particularly in FA-HSCs, we aimed at exploiting this DNA repair mechanism to remove/compensate specific mutations in different FANC genes by the use of CRISPR/Cas9 system, thus mimicking spontaneous genetic reversions observed in FA mosaic patients. Our results in lymphoblastic cell lines from five different complementation groups (FANCA, FANCB, FANCC, FANCD2 and FANCD1/BRCA2) demonstrated the efficiency of this approach to generate potentially corrective events in all the different complementation groups studied. Importantly, corrected cells showed a marked proliferative advantage after in vitro culture and the analysis by next generation sequencing confirmed the expansion of cells harboring therapeutic events. Functional studies showing the reversion of mitomycin C sensitivity, FANCD2 foci formation and chromosomal instability supported the phenotypic correction of different mutations by NHEJ-mediated gene editing. Moving towards the clinical application of NHEJ-mediated repair we focused on improving the gene editing efficiency in HSCs. To this aim, chemically modified small guide RNAs (MS-sgRNAs) enabled us to increase the editing efficacy 8-fold compared to efficacies obtained with in vitro transcribed sgRNAs, reaching up to 89% indels in healthy donor hematopoietic stem/progenitor cells. Moreover, the CRISPR/Cas9 system demonstrated high editing capacity in the primitive HSCs capable of engrafting immunodeficient NSG mice, confirming the efficacy of NHEJ-editing to correct the phenotype of long-term repopulating HSCs. Finally, studies conducted in mobilized peripheral blood and bone marrow CD34+ cells from FA patients demonstrated the feasibility to correct FA HSCs by NHEJ-mediated gene editing and confirmed the proliferative advantage of NHEJ-mediated corrected cells both in vitro and in vivo. Our results suggest that NHEJ-mediated gene editing should constitute a versatile and simple therapeutic approach to efficiently correct specific mutations in FA and other monogenic disorders of the hematopoietic system. Disclosures Sevilla: Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Rio:Rocket Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding.

Description: Abstract 1931 Mobilization of peripheral blood stem cells (PBSC) for autologous transplant in children can be challenging especially in those with prior intensive chemotherapy and radiotherapy, and with increasing use of sequential high-dose therapy that requires high PBSC collection doses. Plerixafor is currently not licensed for use in children, but is approved for PBSC mobilization in adults. We present a series of 40 children from 19 centers worldwide who had PBSC mobilised with plerixafor off-licence, mostly on the North American or European Compassionate Use Programs. Thirteen of these cases were included in a series presented in abstract form at ASH 2010, and a further 6 were presented at EBMT 2011, and these cases are now presented with updated clinical data; the remaining 21 cases have not been presented elsewhere at the time of submission. Median age was 10 years (range 3 months–17 years); median weight was 31 kg (range 6–78 kg). Diagnoses were neuroblastoma (n=13), Ewing's sarcoma (n=10), medulloblastoma (n=5), lymphoma (n=5), PNET (n=4), multicentric Castleman's disease (n=1), Osteosarcoma (n=1) and Desmoblastic Small Round Cell Tumor (n=1). Most patients had received extensive multi-agent chemotherapy prior to plerixafor mobilization, and 13 had also received radiotherapy. For 7 patients, plerixafor had been introduced on a “rescue” basis in the course of the patient's first PBSC mobilization attempt, because of poor peripheral CD34+ counts predicting a high likelihood of mobilization failure without plerixafor use. The remaining 33 patients had undergone 45 prior failed conventional PBSC mobilization attempts: no apheresis in 31 cases; 8 were suboptimal (CD34+ dose 〈 2×10^6/kg); 5 procedures had yielded insufficient cells for planned sequential high-dose therapy. Plerixafor was used in 44 mobilization episodes (4 patients had undergone two mobilizations using plerixafor). In 29 cases, the drug was given after G-CSF 10 mcg/kg/day for 4 days, without prior mobilizing chemotherapy. In the remaining 15 cases, plerixafor was introduced to chemomobilization protocols at the time of initial neutrophil recovery, with exact protocols varying between centers. Three plerixafor mobilisation episodes were entirely unsuccessful (no apheresis); 10 episodes were suboptimal (CD34+ dose of 2×10^6/kg). For the 41 episodes where apheresis was undertaken, a median of 3.5×10^6/kg CD34+ cells (range 0.26–11.8) was collected in a median of 2 aphereses (range 1–5) after a median of 2 plerixafor doses (range 1–5). A total of 16 possible plerixafor toxicities were reported, all graded mild or moderate: these were injection site reactions (3), nausea (3), bone pain (3), vomiting (2), diarrhoea (2), insomnia (2) & headache(1). Seven patients were lost to follow-up after plerixafor due to transfer to other centers; of the remainder, 22 patients (67%) remain alive and 16 (48%) remain progression-free at a median of 9 months' follow-up post-plerixafor (range 3–63 months). Autologous PBSC transplant was performed in 27 patients & allograft in 1 patient. All transplanted patients achieved neutrophil engraftment (median of 11 days to neutrophils〉1.0×10^9/litre; range 10–23 days). There was one case of secondary AML at 〉3 years post-autograft. Plerixafor is safe and highly effective in this difficult-to-mobilize patient group. Disclosures: Douglas: Genzyme Europe: Honoraria. Duarte:Genzyme Europe: Honoraria.

Description: Fanconi anemia (FA) is a DNA repair syndrome characterized by bone marrow failure, congenital abnormalities and cancer predisposition. Based on previous experimental results showing the in vivo proliferative advantage of gene corrected FA patients' hematopoietic stem cells (HSCs; Rio, Navarro et al. Blood 2017) a gene therapy trial in non-conditioned FA-A patients was initiated in 2016. Six patients have been treated to-date using fresh and cryopreserved CD34+ cells mobilized to peripheral blood with G-CSF and plerixafor, and transduced with the PGK-FANCA.Wpre* lentiviral vector. Cell doses infused in four patients with a follow-up of at least 12 months varied from 0.6 to 1.4 million CD34+ cells/kg. Transduction efficacies of these samples, determined as vector copies per cell, ranged from 0.17 to 0.53 copies/cell. Despite the absence of patients' conditioning, a marked in vivo expansion of gene-corrected cells was observed in all hematopoietic cell lineages analyzed in BM and PB. Significantly, up to 44% of corrected cells were determined in total PB cells at the most recent follow-up visit (24 month) in the first treated patient. Insertion site analyses in PB cells showed an oligoclonal pattern of hematopoietic reconstitution, and revealed engraftment of multipotent corrected HSCs and no evidence of insertion-site mediated clonal expansion. Functional studies showed significant increases in the resistance of BM progenitors to mitomycin C in all treated patients. Additionally, patients with higher levels of corrected cells also showed significant increases in the chromosomal stability of T cells exposed to diepoxybutane. Finally, analyses discriminating the presence of corrected and uncorrected PB cells in these patients showed marked increases in the total number of corrected leukocytes, contrasting to progressive decreases of uncorrected cells. Our studies demonstrate for the first time that lentiviral-mediated gene therapy results in progressive engraftment and phenotypic correction of HSCs in non-conditioned FA patients, suggesting that this gene therapy approach may constitute a low-toxicity option for the treatment and prevention of BMF in patients with FA. Disclosures Bueren: Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Segovia:Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Casado:Rocket Pharmaceuticals Inc: Patents & Royalties. Schwartz:Rocket Pharmaceuticals: Employment, Equity Ownership. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Rio:Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties.

Description: Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational “hot-spot” but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.

Description: Abstract 3194 Poster Board III-131 Background Immunosuppressive therapy (IST) is considered to be the first-line treatment in patients with severe aplastic anemia (AA) who are not eligible for hematopoietic stem cell transplantation (HSCT). Most IST schemes are based on the combination of anti-thymocyte globulin (ATG) plus cyclosporine A (CsA). Differently from other countries, two ATGs have been approved in Spain for AA from 2003 to 2007: Lymphoglobuline (LG) (raised in the sera of horses) and Thymoglobuline (TG) (produced in rabbits). So, during this period of time, the standard therapeutic protocol of the Spanish study group for AA included both options, and the physicians chose LG or TG based on their own wishes. Most published studies in AA are with LG, which is no longer manufactured. Recent limited data have confirmed therapeutic efficacy of TG, but no randomized studies have been performed comparing both products' activity. The aim of this report is to communicate the outcomes of a group of patients with AA who received either a LG- or TG-based scheme as first-line treatment. Patients and methods we retrospectively investigated the outcome of 110 patients with AA treated with IST at front line between 2003 and 2008. Thirty-five patients (32%) got LG (15 mg/kg/day/x5 days), and 75 patients (68%) got TG (2.5 mg/kg/day/x5 days). All patients also received methylprednisolone and CsA. Response rate (RR) was assessed at post-IST day +90, day +180, and day +365. If complete response (CR) was not reached, patients received a second course of IST, a second-line therapy (HSCT or androgens), or no treatment. When a second course of IST was employed, it included LG at the same dose as in the first course (15 mg/kg/day/x5 days), or TG at a higher dose (3.5 mg/kg/day/x5 days). CR was defined as a neutrophil count 〉1.5×109/L, a platelet count 〉100 ×109/L, and a hemoglobin level 〉120 g/L. Partial response (PR) was defined as a neutrophil count 〉0.5×109/L, a platelet count 〉20 ×109/L, and a hemoglobin level 〉80 g/L. Subgroup analyses were conducted and differences in response were tested using the chi-square statistic test. Results After the first course of IST, CR was achieved in 31 patients (28%) (group A), and PR in 20 patients (18%). Overall response (OR) was similar for both globulins (LG: 49%, TG: 45%). Thirty-five of the patients who did not reach CR after the first IST course, received a second course of IST (6 with LG and 29 with TG) (group B), and 44 patients underwent a different approach (second-line therapy or no treatment) (group C). After the second course of IST, 14 patients achieved CR (40%) and 11 patients PR (31%). OR was similar for LG (67%) and TG (72%). If we exclude patients in group C, the RR among the remaining 66 patients (who underwent 1 or 2 courses of IST) was 85% (68% CR, and 17% PR). No major drug-related toxicities were reported in the whole group of patients. Conclusions ATG-based schemes with both LG and TG were well tolerated as treatment of patients with AA. OR after first course of IST was similar in the LG and in the TG group (49% versus 45%). RR after second course of IST was also similar when LG and TG were employed (67% versus 72%). After excluding those patients who, not having reached CR after the first course, underwent an approach different from a second course of IST, RR to IST was 85%, with 68% of CR. No statistical differences were found based on the type of ATG administered. The results of this study show that TG is, at least, as effective as LG for the treatment of AA patients. Based on these and other recently published data, the current standard therapeutic protocol of the Spanish study group for AA includes TG at the dose of 3.75 mg/kg/day/x5 days for both the first and, if necessary, second course of IST. To our knowledge, no reports are available in the medical literature comparing the outcome of patients with AA who received LG or TG as the first-line therapy for AA. So, in spite of the fact that our study is retrospective and not randomized, we think our data are unique and very useful for helping physicians in switching from LG to TG. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, genetic life-threatening syndrome characterized by hyper-inflammation that is mainly driven by high production of interferon (IFN)-?, leading to the development of fever, splenomegaly, cytopenias and coagulopathy. There are currently no approved treatments for HLH, and recent attempts to improve the dexamethasone/etoposide-based regimen (HLH-94) did not show a significant improvement in overall probability of survival. Emapalumab (NI-0501) is a fully human, anti-IFN-? monoclonal antibody that binds to and neutralizes IFN-? and is in development for treatment of HLH. Methods: This open-label pivotal study (NCT01818492) includes patients ≤18 years with a diagnosis of pHLH based on genetic confirmation, family history, or the presence of ≥5 of the 8 HLH-2004 diagnostic criteria. Patients were either treatment-naïve or had failed previous conventional HLH therapy prior to study entry. The emapalumab initial dose was 1 mg/kg given intravenously every 3-4 days. Subsequent doses could be increased up to 10 mg/kg based on the evolution of clinical and laboratory response parameters. Emapalumab was administered concomitantly with 5 to10 mg/m2/day of dexamethasone which could be tapered during the study. Treatment duration was 8 weeks (with possible shortening to a minimum of 4 weeks). Treatment could be extended up to allogeneic hematopoietic stem cell transplantation (HSCT) whenever needed. The primary efficacy endpoint of the study was overall response at end of treatment assessed by pre-defined objective parameters. Overall Response Rate (ORR) was assessed as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen and/or D-Dimer levels, central nervous system (CNS) abnormalities, with no sustained worsening of sCD25 serum levels. The primary analysis used an exact binomial test to evaluate the null hypothesis that ORR be at most 40% at a one-sided 0.025 significance level. Data presented are from 34 patients of whom 27 entered the study after failing conventional HLH therapy. Following completion of the main study patients entered into an extension phase (NCT02069899). The data cut-off applied is July 20 2017. Results: Patient characteristics are summarized in Table 1. Disease presentation at study entry was consistent with the broad spectrum of pHLH abnormalities, both in terms of HLH-2004 diagnostic criteria and other known HLH features; over 30% of patients had signs and/or symptoms of CNS disease. Efficacy results are summarized in Table 2. ORR was significantly higher than the pre-specified null hypothesis of 40%; thus the primary endpoint was met. The response rate based on investigator's clinical judgement was 70.6% and 70.4% in the two groups. Emapalumab infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. The observed safety events pre-HSCT conditioning mostly included HLH manifestations, infections or toxicities due to other administered drugs. Infections caused by pathogens potentially favored by IFN-? neutralization occurred in 1 patient during emapalumab treatment (Disseminated histoplasmosis), and resolved with appropriate treatment. No off-target effects were observed. Conclusions: This is the first prospective HLH study that reports response rates based on pre-defined objective criteria. Our results indicate that emapalumab should be considered as a new therapeutic option in pHLH thanks to its targeted mode of action. Treatment with emapalumab was able to control HLH activity with a favorable safety and tolerability profile in a very fragile population. The majority of patients proceeded to HSCT with favorable outcome. Disclosures Jordan: Novimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allen:Novimmune: Membership on an entity's Board of Directors or advisory committees. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties; Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years . Grom:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AB2Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; NovImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Benedetti:Novartis: Consultancy, Research Funding; SOBI: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; UCB: Consultancy; Eli-Lylli: Consultancy; Abbvie: Research Funding; Novimmune: Research Funding; Pfizer: Research Funding. Ferlin:Novimmune: Employment, Equity Ownership, Patents & Royalties. Ballabio:Novimmune: Employment, Equity Ownership. De Min:Novimmune: Employment, Equity Ownership.

Description: Background: Kinase domain (KD) mutations is a common resistance mechanism, secondary to the tyrosine-kinase inhibitors (ITKs) treatment in the case of chronic myeloid leukemia (CML) and Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) patients. Sanger sequencing is the gold standard technique and already the currently recommended method for BCR-ABL1 KD mutation detection. However, Sanger sequencing has limited sensitivity and cannot firmly identify populations with variant allele frequencies (VAF) 〈 15-20%. Next-generation sequencing (NGS) allow us the screening of mutations in the whole KD with variants with a VAF greater than 1%. The aim of this study is to evaluate the clinical and prognostic implications of CML and Ph-positive ALL patients who have been studied for mutations in BCR-ABL1 by NGS. Methods: Seventy CML and Ph-pos ALL patients have been studied for BCR-ABL1 mutations between years 2015-2017. The study reason was warning or failure according to European Leukemia Net recommendations in the case of CML patients, and diagnostic or relapse in the case of ALL patients. Clinical characteristics of the patients are depicted on Table 1. Categorical variables are described as frequency, and quantitative variables as medians. Contingency tables were used to analyze associations between categorical variables (χ2). Median test was used to compare medians of continuous variables between groups. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between patients using the log-rank test. Results: We have found 37 patients with mutations (51%), the most frequent being p.T315I, p.L248V and p.L387M. 28 out of 59 were found in CML (47%) vs 9 out of 13 (69%) in ALL. Of the 37 patients with mutations, double mutations have been found 10 times (27%). In the 72 analyses performed, 62 mutations were found in total, 41 of them were variants of uncertain significance (VUS) and 21 were well-known mutation. The median levels of BCR-ABL1 (IS) at the time of analysis were 3.00 (0.01-196.18) %. Regarding CML patients, we have found 12 and 16 cases with pathogenic mutations and VUS, respectively. The mean survival for CML and ALL were 75.2 months (CI 95%, 65.7-84.6) and 24.7 months (13.3-36.2), respectively. There are significant differences between the overall survival curves for patients with CML who have mutations in BCR-ABL1 compared to those who have VUS or do not (p-value = 0.024, n=59), suggesting a second role of the VUS variants in the resistance of the patients to the TKI. These two groups have no significant differences in ALL patients (p-value= 0.32, n=13). Overall survival at 10 years from the date of diagnosis is 74% for CML patients with mutations and 90% for CML patients without mutations. Data dropped significantly for ALL patients, but the number of cases is too low. Conclusions: - Mutations have been identified in 47% of CML patients studied in the case of failure or warning and 69% of the patients of ALL at diagnosis or relapse moments. - The identification of pathogenic variants has poor prognosis in patients with CML (p = 0.024), however no differences were observed in ALL. - The identification of VUS is not associated to poor prognosis and these variants could not confer resistance to ITK. Disclosures Sevilla: Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Steegmann:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding.

Description: Nine Fanconi anemia patients complementation group A (FA-A), age 2-6 years, have been infused with autologous hematopoietic cells after genetic correction with the therapeutic PGK-FANCA.Wpre* lentiviral vector. In all instances patients underwent CD34+ cell mobilization with G-CSF and plerixafor and were subsequently infused in the absence of any pre-conditioning regimen, in order to avoid genotoxic side effects in a population characterized by DNA repair defects and cancer predisposition. The first four patients were treated between January 2016 and March 2017 and were infused with an estimated number of 170,000 and 410,000 transduced CD34+ cells/Kg. The other five patients were treated more recently with cell numbers that ranged between 50,000 to 1.6x106 corrected CD34+ cells/kg. The analyses of the first four patients showed the presence of corrected cells both in BM and PB after six months post-infusion and progressive increases of gene marking were observed thereafter in all these patients until the most recent follow-up (2 to 〉3 years post-infusion). Gene marking in BM CD34+ cells correlated with the survival of the CFCs to mitomycin-C, with levels up to 70% at 3 years post-infusion. Additionally, progressive decreases in the percentage of PB T cells with diepoxybutane-induced chromosomal breaks were observed in the patients with higher levels of gene marking. Similarly, stabilized PB cell counts have been observed in patients with higher percentages of gene corrected cells. Insertion site analyses revealed the absence of genotoxic events, and demonstrated the engraftment of pluripotent HSCs and a pattern of oligoclonal reconstitution, consistent with the number of infused corrected CD34+ cells and the absence of conditioning. In the five additional patients treated more recently, the presence of gene corrected PB cells has been confirmed; levels of gene marking have been consistent with data observed in the first four treated patients and with the number of infused CD34+ cells. Our results confirm the engraftment of gene corrected HSCs in non-conditioned FA-A patients, in some cases through more than 3 years of follow-up, suggesting the relevance of this therapeutic approach in FA. Disclosures Rio: Rocket Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents. Segovia:Rocket Pharmaceuticals, Inc.: Equity Ownership, Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Wang:GeneWerk: Employment. Casado:Rocket Pharmaceuticals, Inc.: Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents. Galy:Genethon: Employment. Cavazzana:SmartImmune: Other: Founder. Schwartz:Rocket Pharmaceuticals: Employment, Equity Ownership. Schmidt:GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership; German Cancer Research Center, Heidelberg, Germany: Employment. Díaz de Heredia:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sevilla:Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding.