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The ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR; 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care; overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86); 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461

The anti-CD19 chimeric antigen receptor (CAR)–T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Background: In the ELARA (E2202) trial (NCT03568461), tisagenlecleucel (tisa-cel) demonstrated high response rates in patients with relapsed/refractory follicular lymphoma (r/r FL), including those with high-risk disease, with an overall response rate (ORR) of 86% and complete response rate (CRR) of 66%. As ELARA did not include a comparator arm, an adjusted indirect treatment comparison (ITC) using patient-level data from a global retrospective cohort study was conducted. This study aimed to provide comparative, contextual evidence to the efficacy outcomes of tisa-cel from ELARA relative to standard of care (SOC) in routine practice. Methods: ELARA is an ongoing, single-arm, global, multicenter, phase II trial which evaluates the efficacy and safety of tisa-cel in adult patients with r/r FL. As of March 29, 2021, 98 patients were enrolled with a median follow-up of 15 months. SOC data were obtained from ReCORD-FL, a global retrospective cohort study of clinical outcomes in patients with r/r FL meeting the ELARA eligibility criteria who were treated per routine practice at 10 academic centers across North America and Europe; 7 ReCORD-FL sites are also participating in ELARA, but no patients are enrolled in both studies. In ReCORD-FL, with a data cutoff date of December 31, 2020, a total of 187 patients with ≥2 lines of previous treatment were identified for inclusion, with a median follow-up from third-line of 57 months. A complete-case comparison analysis was performed for 97 ELARA apheresed patients and 143 ReCORD-FL patients with complete data on all baseline variables and prognostic factors used for adjustment. For the comparative analysis, one line of therapy (LoT) per patient was selected using a propensity score model to identify the LoT which had the highest chance of being enrolled in ELARA conditional on baseline characteristics and prognostic factors available at the start of the LoT (i.e., the selected LoT was the one with the highest propensity score to be in ELARA). After selection of LoT, an adjusted ITC was performed to assess the effect of tisa-cel versus SOC by measuring CRR, ORR, progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT). A subgroup analysis of SOC patients with ≥1 eligible LoT initiated from 2014 on (coinciding with the introduction of the Lugano response criteria as well as regulatory approval of idelalisib) was performed for all endpoints. Results: Baseline characteristics for the tisa-cel and SOC cohorts are described in Table 1; after weighting, baseline variables, including number of previous lines of systemic therapy (median: 4 lines) were well balanced between the tisa-cel and SOC cohorts. Treatment regimens observed for ReCORD-FL patients at LoT selection were: anti-CD20 antibody plus alkylator (31.5% of patients), anti-CD20 antibody without alkylator (25.9%), alkylator without anti-CD20 antibody (17.5%), and regimens other than anti-CD20 antibody and alkylator (25.2%). After LoT selection and adjusting for differences in baseline variables, tisa-cel was associated with improvement over SOC in CRR (69.1% vs. 37.3%), ORR (85.6% vs. 63.6%), as well as PFS, TTNT and OS (Table 2, Figures 1-2), with a numerically higher 6-month PFS rate vs. SOC (85.3% vs. 66.5%), as well as higher 24-month OS rate (87.8% vs. 64.8%). Further, there was an estimated 80% reduction in death risk in favor of tisa-cel over SOC, a 40% reduction in risk of progression in favor of tisa-cel over SOC and a 69% reduction in risk of death or requiring a new anticancer therapy (Table 1). In the sub-analysis of SOC patients with lines of therapy initiated in or after 2014, the superiority of tisa-cel over SOC was confirmed in all the efficacy outcomes (CRR: 69.1% vs. 30.5%; ORR: 85.6% vs. 58.8%; hazard ratios substantially < 1 for OS, PFS, TTNT). Conclusion: The ITC results suggest that tisa-cel has superior efficacy over SOC in r/r FL for all evaluated endpoints. A key limitation of this study is that response assessment criteria and schedule was more heterogeneous in ReCORD-FL than in ELARA. However, the sub-analysis on SOC patients assessed with a LoT selected in 2014 or later (when more patients could have been assessed using the Lugano response criteria) showed similar favorability for tisa-cel over SOC in all the efficacy outcomes. Moreover, outcome parameters independent of response criteria, namely OS and TTNT, were also significantly better for tisa-cel vs. SOC. Figure 1 Figure 1. Disclosures Salles: Abbvie, Epizyme, Morphosys, Regeneron: Consultancy, Honoraria; Bayer: Honoraria; Beigene, BMS/Celgene, Debiopharm, Genentech/Roche, Genmab, Incyte, Ipsen, anssen, Novartis. Kite/Gilead, Loxo, Miltneiy, Rapt, TAKEDA, Velosbio, Allogene: Consultancy. Schuster: Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Dreyling: BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Kuruvilla: AbbVie: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria, Research Funding; Antengene: Honoraria; Roche: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria; Merck: Honoraria; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Novartis: Honoraria; Medison Ventures: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; TG Therapeutics: Honoraria. Patten: ROCHE: Research Funding; GILEAD SCIENCES: Honoraria, Research Funding; ABBVIE: Honoraria; NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; JANSSEN: Honoraria. Von Tresckow: AbbVie: Other: Congress and travel support; Amgen: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: Congress and travel support; BMS-Celgene: Consultancy, Honoraria, Other: Congress and travel support; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Smith: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Celgene, Genetech, AbbVie: Consultancy. Davis: Novartis, Vertex Pharmaceuticals, Pfizer, Eisai, Eli Lilly, AstraZeneca: Research Funding. Anjos: Novartis: Current Employment. Chu: Novartis: Current Employment, Current equity holder in publicly-traded company. Zhang: Novartis: Current Employment, Current equity holder in publicly-traded company. Lobetti Bodoni: Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: NHS: Ended employment in the past 24 months; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dickinson: Janssen: Consultancy, Honoraria; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Link: Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy; Novartis, Jannsen: Research Funding.

Left truncation and right censoring (LTRC) presents a unique challenge for nonparametric estimation of the hazard rate of a continuous lifetime because consistent estimation over the support of the lifetime is impossible. To understand the problem and make practical recommendations, the paper explores how the LTRC affects a minimal (called sharp) constant of a minimax MISE convergence over a fixed interval. The corresponding theory of sharp minimax estimation of the hazard rate is presented, and it shows how right censoring, left truncation and interval of estimation affect the MISE. Obtained results are also new for classical cases of censoring or truncation and some even for the case of direct observations of the lifetime of interest. The theory allows us to propose a relatively simple data-driven estimator for small samples as well as the methodology of choosing an interval of estimation. The estimation methodology is tested numerically and on real data.

Background Tisagenlecleucel, a chimeric antigen receptor T-cell therapy, has demonstrated efficacy and manageable safety in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the global, multicenter, pivotal, phase 2, JULIET trial (NCT02445248). The primary endpoint, overall response rate (ORR), was met at the interim analysis (ORR: 59% [CR, 43%; PR, 16%]). Here, we report an updated analysis with a median 19 mo follow-up. Methods Adult pts ≥18 y with r/r DLBCL that had progressed after ≥2 lines of therapy including rituximab and an anthracycline and who were ineligible for or failed autologous stem cell transplant (ASCT) were enrolled. Tisagenlecleucel was manufactured from autologous T cells at 2 facilities (Morris Plains, NJ, USA [main cohort]. and Leipzig, Germany [cohort A]) and provided to pts at 27 treatment centers in 10 countries across the globe. Efficacy analyses include all pts with ≥3 mo of follow-up or earlier discontinuation. Safety analyses include all infused pts. Results In the JULIET study, 115 pts (99 in main cohort; 16 in cohort A) received a single dose of tisagenlecleucel infusion as of 21 May 2018. Prior to infusion, 90% of infused pts received bridging chemotherapy and 93% received lymphodepletion chemotherapy. Pts were a median 56 y (range, 22-76 y); 77% of pts had stage III/IV and 17% had double/triple-hit disease at the time of entry. Approximately half (51%) of pts had received ≥3 prior lines of chemotherapy (range, 1-6); 49% received prior ASCT. ORR was 54% (40% CR, 13% PR; 95% CI, 43%-64%) with a median follow-up of 19.3 mo post-infusion. Median duration of response (DOR) was not reached. The relapse-free probability was 66% (95% CI, 51%-78%) at 6 mo and 64% (95% CI, 48%-76%) at 12 or 18 mo. Consistent ORR was reported across prognostic subgroups (eg, prior ASCT; double/triple-hit lymphoma) and DOR was similar among age groups and disease status (Figure). Median OS was not reached for pts in CR and was 11.1 mo (95% CI, 6.6 mo-NE) for all infused pts. The probability of OS was 48% (95% CI, 38%-57%) at 12 mo and 43% (95% CI, 33%-53%) at 18 mo (max follow-up, 29 mo). No pts proceeded to allogeneic SCT or ASCT while in remission. During the first 8 wks post-infusion, grade 3/4 adverse events of special interest were cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurologic events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). Tocilizumab was administered to 16% of pts with CRS, and no treatment-related death was reported. Conclusions This updated analysis with longer follow-up confirms earlier findings. Tisagenlecleucel produced a durable high ORR, consistent efficacy across all predefined subgroups, and had a manageable safety profile in pts with r/r DLBCL.

Background: In the phase 2 JULIET trial, tisagenlecleucel, an anti-CD19 CAR-T cell therapy, demonstrated durable responses and manageable safety in adult patients (pts) with r/r DLBCL. Here, we examine the impact of key product cellular attributes of tisagenlecleucel on clinical outcomes. Methods: JULIET is a single-arm, global, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. Samples from 115 tisagenlecleucel individual products were examined at the end of manufacturing at the batch release testing for various product attributes (Table). Additional detailed immunophenotyping for 66 attributes was conducted on previously frozen product samples via flow cytometry (FC). For each cell population of CAR+ T cells, the percentage and absolute number of the subpopulation were analyzed. Univariate and multivariate analyses were performed to evaluate effects of product attributes and CAR+ T-cell phenotypes on efficacy (Month 3 response [M3R], duration of response [DOR], progression-free survival [PFS], overall survival [OS]) and safety (cytokine release syndrome [CRS] and neurological events [NE], grade 0-2 [low] vs 3-4 [severe]). Several exploratory approaches, including machine learning methods (eg, elastic net and random forest), were pursued in conjunction with logistic regression to identify a set of variables associated with clinical outcomes. We included clinically relevant characteristics evaluated at baseline per protocol (LDH, CRP, and tumor volume) with the product attributes in multivariate modeling. Logistic regression was used to model M3R, CRS, and NE. Cox regression was used to model DOR, PFS, and OS. Results: As of December 11, 2018, 115 pts were infused and evaluable. The median T-cell transduction efficiency by FC was 28% (range, 5.3-63.2%); no relationship of these attributes with efficacy (M3R, DOR, PFS, or OS) or safety (severe CRS or NE) was observed. The percentage of viable cells had no impact on efficacy or safety outcomes; this was anticipated since tisagenlecleucel dose is formulated based on the number of viable CAR+ T cells. Tisagenlecleucel demonstrated in vitro functional activity upon CD19-specific stimulation, as evidenced by IFNγ release, with a wide range among different batches (range, 23.7-938 fg/CAR+ cell). Durable responses were observed across the entire range of IFNγ release; high IFNγ release was not associated with severe CRS or NE. The median ratio of CAR+ CD4+ to CD8+ cells was 3.70 (range, 0.26-65.3); no relationship with clinical outcomes was observed (Figure). CAR+ T cells showed variability in T-cell phenotypes, with central memory (CM) cells as the predominant subpopulation of both CD4+ and CD8+ CAR+ T cells (Figure). The majority of CAR+ T cells were highly activated (co-expressing HLA-DR and CD38), as measured by FC. Relative and absolute number of less mature T cells (naive and CM T cells) in the product did not correlate with efficacy. There was no significant correlation between cell populations and efficacy on multivariate analyses. For CRS, the total number of certain CD4+ T cells expressing activation markers (HLA-DR+, CD25+, or HLA-DR+CD38+) and CM cells showed trends of correlation with more severe CRS, but none of these were significant after p-value adjustment; in a multivariate regression model adjusted for LDH and other clinically relevant factors, HLA-DR+ CD38+CD4+ T cells showed a correlation with severe CRS. Correlation analyses did not reveal product attributes significantly related to severe NE. Conclusions: In JULIET, tisagenlecleucel CAR-T cell product attributes had no significant impact on efficacy or NE; the total number of activated CD4+ cells infused positively correlated with higher-grade CRS. There is great variability in the product attributes, especially with respect to T-cell phenotypes, though this variability appears to play a minor role on efficacy. Additional analyses with larger data sets are required to confirm these findings. ClinicalTrials.gov Identifier: NCT02445248. Disclosures Bachanova: Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Incyte: Research Funding. Tam:BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; AbbVie: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property . Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis:Celgene: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Roche: Equity Ownership; Pharmacyclics: Research Funding; Merck: Research Funding; Gilead: Consultancy; Kite: Consultancy; Genentech: Consultancy, Employment; Juno: Research Funding. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Curis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke:Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; EBMT/EHA: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; IACH: Other: Travel support. Teshima:Novartis: Honoraria, Research Funding. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Schuster:Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Maziarz:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten:Celgene: Consultancy, Research Funding; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards. Wagner-Johnston:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Corradini:Celgene: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria. Chu:Novartis: Employment. Gershgorin:Novartis: Employment. Choquette:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Jeschke:Novartis: Employment.

Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after ≥ 2 prior lines of therapy. T-cell exhaustion due to an immunosuppressive environment has been a hypothesized mechanism for CAR-T cell therapy failure. Subgroup analyses of the JULIET trial suggested an association between programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) interaction in baseline biopsies and lack of response (Agoulnik et al. EHA. 2018). Moreover, the anti-PD-1 monoclonal antibody pembrolizumab has shown clinical activity in r/r DLBCL after failing tisagenlecleucel therapy (Chong et al. Blood. 2017). PORTIA is a phase 1b, multicenter, open-label trial investigating the safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL. We report data from a completed cohort of the ongoing study. Methods: Eligible patients must be ≥ 18 years old with a confirmed diagnosis of DLBCL that has relapsed after or is refractory to ≥ 2 prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients treated with prior allogeneic stem cell transplantation, anti-CD19 therapies, or checkpoint inhibitors are excluded. Lymphodepleting chemotherapy consists of fludarabine-cyclophosphamide. Patients receive a single tisagenlecleucel intravenous infusion (target dose: 0.6-6.0x108 cells) on Day 1. Pembrolizumab is given at 200 mg every 21 days, for up to 6 doses. Pembrolizumab was started on Day 15 post-tisagenlecleucel in Cohort 1, with the option of moving to Day 8 or 22 in subsequent cohorts, based on observed data and guided by a Bayesian Logistic Regression Model with Escalation with Overdose Control principle, evaluating the distribution of dose-limiting toxicities (DLTs) occurring in the 21 days following the first pembrolizumab dose. As per study protocol, a total of 20 patients will be treated at the optimal dose timing. Primary endpoints are the proportion of patients receiving pembrolizumab per protocol schedule, the incidence of DLTs in the dose-timing selection phase, and the overall response rate in the dose-expansion phase. Secondary outcomes include duration of response, progression-free survival, overall survival, safety, cellular kinetics, and immunogenicity. Results: As of 5 March 2019, 5 patients were screened for Cohort 1. Four patients were enrolled and received tisagenlecleucel and pembrolizumab. Median age was 54 (range, 35-79). Median follow-up from time from tisagenlecleucel infusion to data cut-off was 46 days (range, 36-85). Patients received 1.7-3.0x108 CAR-positive T cells, and 1, 2, 2 and 4 pembrolizumab doses, respectively, with no delays. All 4 patients experienced at least 1 adverse event (AE), with no exacerbation or recurrence of tisagenlecleucel-related AEs following pembrolizumab infusion. No pembrolizumab-related AEs were observed. No DLTs or grade 3-4 treatment-related adverse events (TRAEs) were observed. TRAEs and AEs are summarized in Table 1. Two patients discontinued pembrolizumab treatment (after 1 and 2 doses, respectively) due to disease progression. All 4 patients experienced initial expansion between Days 6 and 15 post-tisagenlecleucel infusion, with peak transgene levels ranging from 1,980 to 77,200 copies/µg DNA (Figure 1). No secondary expansion was observed after pembrolizumab administration. The overall exposure is consistent with the observed exposure in r/r DLBCL patients in the JULIET trial. With very limited follow-up, 1 partial response has been observed. Cohort 2 (pembrolizumab starting Day 8) was ongoing at the time of submission. Conclusions: Overall, PD-1 blockade with pembrolizumab on Day 15 after tisagenlecleucel infusion was feasible and showed a manageable safety profile in the first 4 patients. No DLTs and no clinically significant exacerbation of AEs were observed, supporting the initiation of Cohort 2. Efficacy and safety data with an updated cutoff for Cohort 1 and new data from Cohort 2 will be presented at the congress. Clinical trial information: NCT03630159. Disclosures Jaeger: Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau. Fleury:AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chu:Novartis: Employment. Abdelhady:Novartis: Employment. Forcina:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy.

BACKGROUND JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy targeting CD19, that has shown a high rate of durable complete responses (CR) and a manageable safety profile in adult patients with clinically active relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with an overall response rate (ORR) of 59% (CR, 43%; partial response [PR], 16%). Here, we present an updated analysis of the JULIET trial, with a median of 19 months of follow-up, an additional 5 months since the previous report (Schuster et al. EHA 2018), demonstrating sustained activity in this patient population. METHODS Eligible patients were ≥18 years with r/r DLBCL, had received ≥2 lines of therapy, including rituximab and an anthracycline, and were ineligible for or had failed autologous stem cell transplant (ASCT). Tisagenlecleucel was centrally manufactured at 2 facilities (Morris Plains, NJ, USA [main cohort] and Leipzig, Germany [cohort A]) using cryopreserved apheresis material and provided to patients at 27 treatment sites across 10 countries on 4 continents using a global supply chain. The primary endpoint was ORR (CR + PR) per independent review committee. Efficacy results are reported for patients in the main cohort with ≥3 months of follow-up or earlier discontinuation; safety is reported for all infused patients. RESULTS At data cutoff (May 21, 2018), 167 patients were enrolled and 115 were infused (99 in the main cohort and 16 in cohort A) with a single dose of tisagenlecleucel (median, 3.0×108 [range, 0.1-6.0×108] CAR-positive viable T cells). 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease and 17% had double/triple hit disease. 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. 51% of patients had received ≥3 prior lines of antineoplastic therapy (range, 1-6); 49% had undergone a prior ASCT. All 99 patients in the main cohort had ≥3 months of follow-up or discontinued earlier and were evaluable for efficacy. ORR was 54% (95% CI, 43%-64%), with 40% CR and 13% PR. ORR was consistent across prognostic subgroups (including prior ASCT and double/triple-hit lymphoma). Median duration of response (DOR) was not reached; the probability of being relapse free was 66% (95% CI, 51%-78%) at 6 months and 64% (95% CI, 48%-76%) at 12 and 18 months. DOR was similar by age group (≥ vs < 65 years) and by relapsed or refractory status (Figure). No relapses were observed beyond 11 months after infusion. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). No patients proceeded to allogeneic SCT or ASCT while in remission. Grade 3 or 4 adverse events (AEs) of special interest within 8 weeks of infusion included cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurological events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). 16% of patients received tocilizumab for CRS management. 3 patients died within 30 days of infusion (all due to disease progression). No treatment-related mortality was reported. Since the previous report, no new deaths occurred due to causes other than disease progression. CONCLUSION Results from this longer-term follow-up show that tisagenlecleucel produced high response rates and durable responses in a cohort of heavily pretreated adult patients with r/r DLBCL. Efficacy was consistent in all predefined subgroups, including elderly patients, patients with r/r disease, and other clinical or biological subgroups expected to have a worse prognosis with available treatments, as demonstrated by similar and sustained DOR and OS following tisagenlecleucel treatment. Figure. Figure. Disclosures Schuster: Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Celldex: Research Funding; Kalytera: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Jaglowski:Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy. Tobinai:Abbvie: Research Funding; SERVIER: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Incyte Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Genentech Inc.: Honoraria, Research Funding; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Astellas: Honoraria. Fleury:F. Hoffmann-La Roche Ltd: Consultancy; Lundbeck: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Merck: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene: Consultancy. Mielke:Celgene: Speakers Bureau; KIADIS Pharma: Speakers Bureau; Miltenyi Biotec: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Bachanova:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding. Foley:Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel expenses ; Amgen: Honoraria; Janssen: Speakers Bureau; Jazz Pharma: Other: Travel expenses . Ho:Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting; Celgene: Other: travel to meeting. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chu:Novartis Pharmaceuticals Corporation: Employment. Jary:Novartis Pharma AG: Employment. Anak:Novartis Pharma AG: Employment. Salles:Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Acerta: Honoraria; Morphosys: Honoraria; Servier: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Abbvie: Honoraria. Maziarz:Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties.