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We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19+ malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 106 ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583 .

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We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19(+) malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 10(6) ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583.

Background: ARI0002h is an academic lentiviral autologous second-generation CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA. In pre-clinical studies, ARI0002h has demonstrated potent in vitro and in vivo activity. Here, we report the first safety and efficacy results of the CARTBCMA-HCB-01 multicenter clinical trial for patients with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) who received ARI0002h in 5 Spanish centers. Methods: Patients (pts) aged 18-75 years old with RRMM were eligible for this study if they had measurable disease, as assessed by M-protein or serum free light chain levels, received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug (lenalidomide or pomalidomide) and an anti-CD38 antibody, and were refractory to the last line of treatment. Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m 2) and fludarabine (30 mg/m 2) on days -6 to -3 were used as lymphodepletion regimen. The targeted dose was 3x10 6/kg CAR+cells (range 1.2-3x10 6) and was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A second dose of 3x10 6 CAR+ cells/kg was planned at least 4 months after the first dose in pts who had any response and had not presented MM progression or serious complications after the first administration, with or without repeated lymphodepletion depending on the persistence of CAR-T cells. Primary objectives were overall response rate (ORR; at less partial response -PR-) within 3 months of the first infusion and rate of cytokine release syndrome (CRS) and/or neurological toxicity in the first 30 days. Response was assessed as per IMWG criteria and bone marrow minimal residual disease (MRD) was analyzed by next-generation flow. Adverse events (AEs) were graded using CTCAE v5.0. CRS and neurotoxicity were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Results: As of July 19 th, 35 pts (median age 61 years) with RRMM were included in the trial. Four pts could not receive ARI-0002h due to MM progression before apheresis (2 pts) or treatment (2 pts) and one pt died of a fungal infection. Therefore, 30 pts received ARI0002h cells (modified intention-to-treat population), of which 47% received bridging therapy. The main characteristics of these pts and previous treatments are described in Table 1. Median CAR-T cell production time was 11 days (range 9-14) with a 100% manufacture success. Median follow-up after ARI0002h administration for surviving pts was 8 months (range 2-12). The ORR of 27 evaluable pts at 3 months was 96%, with a stringent complete remission (sCR) rate of 44.4% (Table 1) and very good partial response (VGPR) observed in 18.6% of pts. Median time to first response was one month. All pts achieved at least a PR and only one patient progressed after 4 months exclusively with extramedullary disease. Of 25 MRD-evaluable pts at day +100, 92% were MRD-negative. Median progression-free survival (PFS) and overall survival (OS) were not reached and the 6-month PFS and OS rates were 92.1% (Figure 1) and 95.8%, respectively. AEs reported in >70% of pts were CRS (87%; grade [gr] 3/4 0%; gr 1 73%), neutropenia (97%; gr 3/4 100%), anemia (85%; gr 3/4 43%), and thrombocytopenia (79%; gr 3/4 70%). Median duration of CRS was 4 days (range 1-12). No CAR-T cell-related neurotoxicity cases were reported. Tocilizumab and corticosteroids were administered in 76% (mainly for persistent grade 1 CRS) and 12% of pts, respectively. One death occurred due to unrelated causes (cranial traumatism). ARI0002h cells demonstrated peak expansion on day 14 (range 7-100 days). Among the pts with 3 and 6 months follow-up, 54% and 24% had measurable CAR+ T cells in peripheral blood, respectively. 22 out of 27 eligible pts (81%) have already received the second dose (range 1.2-3x10 6 CAR+ cells/kg). Median time after first infusion was 4 months; 36% received a second lymphodepletion. No relevant toxicities after second infusions were reported. Responses deepened over time and at 6 months, 5 pts who had reached PR achieved VGPR and one improved from VGPR to sCR. Conclusion: ARI0002h is the first European academic CAR T-cell for RRMM that has demonstrated excellent feasibility in a clinical trial, with deep and durable responses and a favorable safety profile, including the absence of neurotoxicity. Figure 1 Figure 1. Disclosures Fernandez de Larrea: Takeda: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Cabañas: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Reguera: BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen, Kite/Gilead, Novartis: Speakers Bureau. Corral: Novartis: Consultancy; Gileqd: Honoraria; Gilead: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences. Prósper: BMS-Celgene: Honoraria, Research Funding; Janssen: Honoraria; Oryzon: Honoraria. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Mateos: Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Autologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients. Patients and methods Patients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, were randomised to EA versus CA. Stratification criteria: ECOG PS (0–1 versus 2) and lactate dehydrogenase ( ULN). EA was administered subcutaneously till progressive disease. Primary end-point was progression-free survival (PFS) at 4 months. Results Fifty-two patients were included (28 EA/24 CA). An interim analysis recommended early termination for futility. No objective radiological response was observed in EA. Median PFS in EA was 2.7 months (95% confidence interval [CI], 2.3–3.2 months) versus 2.3 months (95% CI, 2.1–2.5 months) in CA (p = 0.628). Median overall survival (OS) was 6.2 months (95% CI, 4.4–7.9 months) in EA versus 4.7 months (95% CI, 2.3–7 months) in CA (p = 0.41). No ADC-related adverse events were reported. Immunization induces tumour-specific T-cell response in 21 of 25 (84%) patients. Responder patients have an OS of 7.3 months (95% CI, 5.2–9.4 months) versus 3.8 months (95% CI, 0.6–6.9 months) in non-responders; p = 0.026). Conclusion Our randomised clinical trial comparing ADC + BSC versus BSC in mCRC demonstrates that ADC generates a tumour-specific immune response but not benefit on PFS and OS. Our results do not support the use of ADC alone, in a phase III trial.

Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has beenrecently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.

3048 Background: No treatments are available for patients (pts) with metastatic colorectal cancer (mCRC) that progresses after all approved therapies. Autologous tumor lysate dendritic cell vaccine...