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Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient’s own T cells, disease progression and death prior to return of engineered cells. T cell dysfunction is known to occur in cancer patients, and several groups have recently described differences in CAR-T cells generated from chronic lymphocytic leukaemia (CLL) patients compared with those from a healthy donor. This is thought to contribute to the low response rate in this disease group. Healthy donor, gene-edited CAR-T cells which do not require human leucocyte antigen (HLA) matching have the potential to provide an ‘off the shelf’ product, overcoming the manufacturing difficulties of producing CAR-T cells for each individual patient. They may also provide a more functional, potent product for malignancies such as CLL, where T cell dysfunction is common and frequently cannot be fully reversed during the manufacturing process. Here we review the potential benefits and obstacles for healthy donor, allogeneic CAR-T cells.

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.

No abstract

Cellular therapy is a key tool to treat haematological malignancies. Over 40,000 allogeneic and autologous haematopoietic stem cell transplants (HSCTs) are performed annually across Europe. Since 2017, a new T cell therapy, chimeric antigen receptor-T (CAR-T) cells have been licensed outside clinical trials. CAR-T cells have extremely potent antitumour activity, but also have a profile of toxic side effects not seen before. Cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES) are common, predictable and potentially lethal side effects. Patients frequently require admission to intensive care, and management from a number of medical specialties. This exciting and powerful new therapy requires the formation of new multispecialty medical teams for safe delivery and to successfully manage the resultant complications.

Purpose: UCART19 is an “off-the-shelf” genome-edited anti-CD19 CAR-T cell product, manufactured from unrelated healthy donor cells. Patients and Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Results: Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than non-responders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells didn’t exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected interleukin-7 and UCART19 kinetics, while negatively correlating with host T-lymphocyte AUC0-28. Conclusions: UCART19 expansion is a driver of response in adult R/R B-ALL patients. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on interleukin-7 and host-versus-graft rejection.

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