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We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 x 10(6) ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade >= 3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CAR High T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CAR High T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.

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 .

Metabolism; Resistance; Vaccines Metabolisme; Resistència; Vacunes Metabolismo; Resistencia; Vacunas Background Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. Methods This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. Results A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. Conclusions The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities. The study was funded by grants from the FIS PI17/00732 from Instituto de Salud Carlos III, Premi Fi de Residència Emili Letang from Hospital Clínic Barcelona, Plan Nacional de I + D (PID-107139RB-C21 to DB-R and PID2020-115051RB-I00 to MC) and Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD). The study was funded with Grants from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474, 2017-SGR-1174 and 2017-SGR-1033), Fundació la Marató de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A. 2019/2020) to JM. IMMETCOLS signature is under patent protection (EP21382772.8.) This research was financially supported by GEMCAD and (OR Avelumab was provided) by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945) and Pfizer.

Cancer vaccines are a type of immune therapy that seeks to modulate the host’s immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes.

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.

B ackground: ARI0002h is an academic autologous CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA, which is being tested in the CARTBCMA-HCB-01 clinical trial for patients (pts) with RRMM (NCT04309981). A fractionated infusion of 3x10 6 CAR+ cells (ARI0002h)/kg (10/30/60%) was administered after lymphodepletion regimen (LR). A second dose of 3x10 6 CAR+ cells/kg was planned starting at 4 months after the first dose, with or without LR according to persistence of CAR-T in peripheral blood (PB). Clinical results have been submitted in a separate abstract (#147188); here we present the correlative biological studies performed and related to disease response. Methods: ARI0002h production data were obtained and analyzed, including % CAR transduction in the final product (FP) by flow cytometry (FC). PB samples were obtained at inclusion and sequentially after infusion. Bone marrow (BM) samples were obtained at inclusion, at d28, d100 and at 6 months (m), to evaluate BCMA expression on plasma cells (PCs) and minimal residual disease (MRD) by next generation flow (NGF) with 10 -6 sensitivity. Apheresis, FP, and PB/BM samples on d28 were analyzed for T-cell subpopulations and surface markers. Persistence of ARI0002h was evaluated in PB after infusion by PCR. If a second infusion was administered, CART detection after 3 and 7d was also checked. Plasmatic soluble BCMA (sBCMA) was determined by ELISA prior to infusion, at d28 and if a relapse was observed. Human anti-human antibodies (HAHAs) were evaluated at d100 (using FC on transduced HEK cells). Clinical and response data were collected for analysis. Results: Mean BCMA molecules/cell on malignant BM PC at inclusion were 1306 (SD ±889) with non-significant (NS) correlation with response at d100. Thirty-three apheresis were obtained and transduced, with a median manufacturing time of 11d (range 9-14). All FP were successfully obtained at first attempt but one, which could be produced with a second apheresis. The mean % transduction of ARI0002h on autologous T cells was 56% (SD ±25). A higher CD4/CD8 ratio in the apheresis was correlated with achievement of stringent complete response (sCR) (p=0.003); this association was not observed in the FP. Moreover, T-cell subpopulations in the FP did not correlate with response (Figure 1A). A significant increase of PD-1 (p=0.0001), TIGIT (p=0.037) and LAG3 (p=0.003) expression was observed in CD4 CAR-T cells, as well as PD-1 in CD8 (p=0.0001), between the FP and d28 PB paired samples; similar results were observed in BM CAR-T cells at d28, except for LAG3 (Figure 1B). ARI0002h CAR-T cells showed maximum PB expansion at 14d (range 7d - 5m). Among pts with 3 and 6 m follow-up, 54% and 24% had evidence of CAR+ T cells in PB, with a median persistence of 4m (range 2-not reached). Expansion levels by PCR and PB persistence did not correlate with MM response. 22 out of 27 eligible pts (81%) received a 2 nd dose, with a subsequent CART expansion in 10 of 20 (50%) evaluable pts; LR was readministered in only 30% of these 10 pts. B-cell aplasia was observed in all pts concurring with CART expansion (Figure 1C). Also, a decline in B-cell counts was observed in some pts after reinfusion, with no association with response. Patients with detectable sBCMA at inclusion became sBCMA negative in all the subsequent tested samples at d28 and d100. None of these pts have relapsed. 27 pts had MRD assessed at day +100. In 3, the BM was severely hemodiluted and inadequate for MRD testing. Of 24 MRD-evaluable pts, 22 (92%) were MRD-negative (59% were negative at a sensitivity of 1x10 -6, 36% at 1x10 -5 and 5% at 1x10 -4), and 2 were MRD positive (one BCMA positive and another with BCMA undetermined result). Only 1 of 27 (4%) evaluable pts had positive HAHAs at day 100. CAR-T cells were undetectable at day 70 in this patient, but after receiving a 2 nd dose at m4 a short-lasted expansion was observed. Despite that, the patient deepened the response from partial response (PR) (d100) to very good PR (m6). Conclusion: ARI0002h production is fast and feasible. The peak of CART expansion occurs after 14d of infusion and also in some pts after reinfusion, regardless of LR, which suggests that LR may not be mandatory to allow further expansion after booster dose. Responses obtained are deep and construct immunogenicity seems to be low. Figure 1 Figure 1. Disclosures Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Cabañas: Sanofi: Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero: Regeneron: Honoraria; Celgene-BMS, Janssen, Amgen, Sanofi, GSK, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosinol: Janssen, Celgene, Amgen and Takeda: 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. Prósper: Oryzon: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria, Research Funding. Mateos: Roche: 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; Celgene - Bristol Myers Squibb: 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; 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; Oncopeptides: Honoraria; GSK: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: 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; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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. Fernandez de Larrea: GSK: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Research Funding.

Background: Chimeric Antigen Receptor-modified T cell (CAR-T) therapies have revolutionized cancer immunotherapy, especially in hematological malignancies. Although great results have been achieved during the last years, long-term efficacy is still compromised in some cases and factors behind CAR-T cell disfunction are not fully understood. Recent studies have shown that the control of CAR expression influences CAR-T fitness and antitumoral efficacy 1. Therefore, we hypothesized that CAR density on the membrane of CAR-T cells could directly affect CAR-T cell function. In this study we perform a functional and genomic analysis of FACS-isolated subpopulations of CAR-T cells with different CAR densities (CAR High and CAR Low). Methodology: Second generation CAR-T cells with 4-1BB costimulatory domain targeting BCMA were generated by lentiviral transduction of αCD3/αCD28 activated T cells that were expanded for 12-14 days in the presence of IL-7/IL-15. Phenotypic analyses were performed by flow cytometry before and after coculture with MM cells. Cytotoxic activity and cytokine production were measured by standard procedures. In vivo antitumoral efficacy was evaluated in xenogeneic tumor models in NSG mice. Transcriptomic (RNA-seq) and epigenetic (ATAC-seq) analysis were performed following stablished protocols 2. Single cell analysis was performed using the Chromium Single Cell Immune Profiling solution from 10x Genomic that allows simultaneous analysis of gene expression and paired T-cell receptors from a single cell. Gene Regulatory Network (GRN) analysis was performed using SimiC, a novel computational method that infers regulatory dissimilarities 3. Results: RNA-seq and ATAC-seq analysis revealed completely different profiles between CAR High- and CAR Low-T cells in both CD4 +and CD8 + cell subsets, with >3500 differentially expressed genes (2086 for CD4 + and 1553 for CD8 +) that were related with increased tonic signaling, T cell activation and proliferation in CAR High-T cells. Functional studies at resting state (before antigen encounter) corroborated that CAR High-T cells presented increased tonic signaling, that lead to a higher basal activation and a more differentiated phenotype with skewed presence of CCR7 +/CD45RA +/CXCR3 + T SCM cells. After antigen-driven activation, increased cytotoxicity and cytokine production was observed in CAR High-T cells, that also presented higher percentage of terminally differentiated effector cells (CCR7 -/CD45RA +), along with increased exhaustion (PD1 +/LAG3 +/TIGIT +). This effect was also observed in the infusion products of CARTBCMA-HCB-01 clinical trial for patients with R/R MM (NCT04309981), where products enriched in CAR High-T cells presented increased cytotoxic activity. Although no significant differences were observed in the antitumoral efficacy in vivo, CAR Low-T cells presented increased persistence, suggesting that higher CAR levels could reduce long-term efficacy. Further characterization of CAR-T cells at single cell level (scRNA-seq) showed enrichment of CAR High-T cells in activated CD4 + and exhausted CD8 + cell clusters. The analysis of regulatory dissimilarities driven by different CAR densities with SimiC revealed an increased activity of the regulon associated to NR4A1 transcription factor (a well-known TF driving T cell exhaustion 4) in CAR High-T cells, providing mechanistic insights of the regulatory networks behind differential functionality of CAR High-T cells. Finally, to evaluate the impact of CAR density in the clinical outcome of CAR-T therapies, we developed a gene signature associated to increased CAR density, that was applied to transcriptomic data available from public studies 5. We score the infusion products of several clinical trials testing CTL019 (NCT01029366, NCT01747486 and NCT02640209) and we observed an enrichment on CAR High signature in the products from non-responder patients. Conclusions: Our data demonstrate that CAR density on the membrane of engineered T cells plays important roles in CAR-T activity with a significant impact on clinical outcome. Moreover, the comprehension of regulatory mechanisms driven by CAR densities at the single cell level offer an important tool for the identification of key regulatory factors that could be modulated for the development of improved therapies. Figure 1 Figure 1. Disclosures Rodríguez-Otero: Oncopeptides: 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, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, 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; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. 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. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Prósper: Oryzon: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria, Research Funding.

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 Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop a light-chain (AL) amyloidosis due to the deposition of amyloidogenic light chains causing organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become the most promising approach in treating cancer patients, especially hematologic malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA) CART which is currently being tested in a clinical trial for relapsed/refractory MM. Methods A 61-year-old woman diagnosed with an IgA-lambda symptomatic MM in 2014, with several prior lines of treatment presented with edema and significant non-selective albuminuria (24-hour proteinuria of 2626 mg with urinary M-protein of 307 mg, serum albumin 28 g/L) with preserved renal function (creatinine 0.6 mg/dL) and an increase in serum M protein, with a bone marrow (BM) infiltration by 23% plasma cells. There was no evidence of extramedullary disease by PET-CT and no CRAB signs were found. A subcutaneous fat aspiration and a renal biopsy established the diagnosis of systemic AL amyloidosis without cardiac involvement. At this point AL amyloidosis was the main reason to treat the patient, who received a fractioned dose of 3×106/kg BCMA-CAR T cells after lymphodepletion, developing a grade I cytokine release syndrome and treatment-related cytopenias (grade 4 neutropenia and grade 2 thrombocytopenia), with no neurotoxicity. Results On day +28, the patient had already obtained a deep hematologic response with negative measurable residual disease by flow cytometry in the BM. After 3 months, the patient maintained the hematologic complete response and achieved renal response. After 1 year follow-up, the patient remains in hematologic complete remission and renal response with a decrease in proteinuria of 70%. Conclusions Here, we present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of a MM, successfully treated with CART therapy targeting BCMA. This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.

The success of genetically engineered T-cells modified with a chimeric antigen receptor as an adoptive cell immunotherapy and the subsequent last regulatory approvals of products based on this therapy are leading to a crescent number of both academic and pharmaceutical industry clinical trials testing new approaches of this "living drugs". The aim of this review is to outline the latest developments and regulatory considerations in this field, with a particular emphasis to differences and similarities between academic and industry approaches and the role they should play to coexist and move forward together. To do that, the main considerations for the manufacturing process are firstly discussed, from the chimeric antigen receptor design to final production steps, passing through ex vivo T-cell handling, gene delivery methods, patient´s final product infusion observations or possible associated side effects of this treatment.

Aparició en l'adult; Malalties autoinflamatòries; Variants de baixa penetrància Aparición en el adulto; Enfermedades autoinflamatorias; Variantes de baja penetrancia Adult onset; Autoinflammatory diseases; Low-penetrance variants Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date. Objective: To analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset. Methods: A retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series. Results: Our series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups. Conclusion: This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset. This study has been supported by Ministerio de Economía y Competitividad (SAF 14/57708-R) and co-funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, and Una manera de hacer Europa (JH-R).

Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)–CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA–CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.