We generated a novel CD19CAR (CAT) with a lower affinity than FMC63, the binder utilised in many clinical studies. CAT CAR T cells showed increased proliferation/cytotoxicity in vitro and enhanced proliferative capacity and anti-tumor activity than FMC63 CAR T cells in a xenograft model. In a clinical study (CARPALL, NCT02443831), 12/14 patients with relapsed/refractory pediatric BALL obtained molecular remission after CAT CAR T cell therapy. CAR T cell expansion compared favourably with published data on other CD19CARs and persistence was demonstrated in 11 of 14 patients at last follow-up. Toxicity was low with no severe cytokine release syndrome. At a median follow up of 14 months, 5/14 patients (37%) remain in molecular CR with circulating CAR T cells.

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BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE:To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS:We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS:We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor Tcell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS:HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.Aydin et al.

Treosulfan is given off‐label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients ( n = 87) receiving treosulfan‐fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two‐compartment model. During follow‐up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC (0‐∞) ) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC (0‐∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC (0‐∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.

Background UCART19 is an allogeneic, genetically modified CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells, in which TRAC and CD52 genes have been knocked out to allow its administration in non-HLA matched patients (pts). Aims Preliminary safety/anti leukemic and cellular kinetics data of UCART19 administered to pediatric and adult patients with R/R B-ALL are reported. Methods Data of patients included in the ongoing CALM study (adult) and PALL study (pediatric) have been pooled. CALM is a dose-escalation study (approximate dose level [DL] 1: 1x105 cells/kg,DL2: 1x106 cells/kg, DL3: 3x106 cells/kg) and PALL is testing a unique dose of 1.1 to 2.3x106 cells/kg. Eligible patients presented with a morphological disease (>5%) or MRD load ≥1x10-3. A lymphodepleting regimen (LD) combining cyclophosphamide (1500 mg/m² in CALM, 120 mg/kg in PALL) and fludarabine (90 mg/m2 in CALM, 150 mg/m2 in PALL) without (FC) or with alemtuzumab (FCA) (1 mg/kg) was administered one week before UCART19 infusion on Day 0 (D0). Cellular kinetics of UCART19 was assessed by flow cytometry (flow) in CALM and by vector copy number in PALL. Results As of 15 July 2018, 20 pts had received at least one UCART19 infusion, including 13 pts in CALM (6 at DL1; 6 at DL2 and 1 at DL3) and 7 pts in PALL. Seventeen pts had completed D28 evaluation (1 pt died at D15, 2 pts have not reached D28 yet). Prior to LD, blasts % in the bone marrow (median [range]) was 6% [0-68%] in PALL and 25% [0-96%] in CALM. Seventeen pts received LD with FCA and 3 pts received LD with FC. Safety was evaluable in 18/20 pts. Cytokine release syndrome (CRS) was reported in 17/18 pts and was mild and reversible in the majority of cases (2 G1, 12 G2, 2 G3, 1 G4). One pt died in context of CRS G4 and neutropenic sepsis. According to data available to date, the severity of CRS does not seem to follow the levels of serum cytokines (IL-6, IL-10 and IFNγ). Mild self-limited neurotoxicity events were reported in 6 pts (5 G1 and 1 G2). Two pts (1 infant and 1 adult) developed G1 acute skin GvHD (non-biopsy proven for 1 pt) that was reversible with steroids. Grade 1-4 viral infections were reported in 8/18 pts. The majority of events recovered, except in 2 pts who died after allo-SCT in context of prolonged cytopenia (defined as persistent G4 beyond D42 post UCART19 infusion): 1 child with BK virus infection and 1 adult with adenovirus infection. A further 4 pts developed prolonged cytopenia and all recovered after allo-SCT. Cellular kinetic data was available for 18/20 pts. UCART19 was detectable in blood from D7. Peak expansion was observed in 72% (13/18) pts between D10 and D17, mostly at D14, with a median persistence duration of 28 days. Expansion occurred at each dose tested; without consistent relationship between administered dose and magnitude of expansion. One patient treated at DL2 presented a high expansion and a long persistence (very low detection by flow at D120). UCART19 persistence could not be assessed beyond D42-D56 in 3 pts because the remaining CARs were ablated by the transplant conditioning regimen. No expansion was observed in 5/18 pts in whom early lymphocyte recovery was detected from D14. Of these 5 pts, 3 did not receive alemtuzumab. The role of clinical status, tumor burden and lymphodepleting regimen on UCART19 expansion is under investigation. Anti-leukemic activity was evaluable in 16/20 pts (1 pt died at D15, 1 pt was not assessed at D28, 2 pts have not yet reached D28). After UCART19 infusion, 88% of evaluable pts (14/16) achieved CR or CRi by D28 or D42 and 86% (12/14) of these pts were MRD negative (MRD- stands for < 1x10-4 copies) by flow or qPCR. Two out of 16 pts had no expansion and showed refractory disease. Among 12 pts achieving MRD-, 5 pts remain in molecular remission 4.5 to 16.4 months post UCART19. In total, 11 pts underwent allo-SCT (5 in PALL and 6 in CALM). Preliminary data suggests that in the majority of pts, anti-leukemic activity is linked with CAR expansion. Conclusion Pooled data of 20 pts show an acceptable and manageable safety profile of UCART19. Severe CRS was reported in 15%. Only 2 G1 cutaneous acute GvHD were observed and no severe neurotoxicity was reported. In this heavily pre-treated population, 88% pts of evaluable pts (14/16) achieved CR or CRi of which 86% (12/14) achieved MRD-. All pts who achieved MRD- had evidence of UCART19 expansion. Updated data, including data for the highest dose level in CALM study, will be presented (NCT 02746952, NCT02808442). Disclosures Benjamin: Servier: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Pfizer: Research Funding. Graham:Servier: Research Funding. Yallop:Pfizer: Consultancy; Servier: Other: Travel funding. Jozwik:Servier: Honoraria, Research Funding. Ciocarlie:Servier: Research Funding. Jain:Cellectis: Research Funding; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Servier: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Verastem: Research Funding; BMS: Research Funding; Servier: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maus:adaptimmune: Consultancy; novartis: Consultancy; windmil therapeutics: Consultancy; agentus: Consultancy, Research Funding; crispr therapeutics: Consultancy, Research Funding; kite therapeutics: Consultancy, Research Funding. Boissel:Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larghero:Gilead: Consultancy. Baruchel:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Amgen: Consultancy; Servier: Consultancy; Celgene: Consultancy. Mohty:Takeda: Honoraria, Speakers Bureau; Molmed: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Frey:Novartis: Consultancy; Servier Consultancy: Consultancy. Konto:Pfizer: Equity Ownership. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Qasim:Bellicum: Research Funding; Autolus: Equity Ownership; Orchard: Equity Ownership; Servier: Research Funding.