Citations

Fatty acids (FAs) not only are a key component of cellular membrane structure, but also have diverse functions in biological processes. Recent years have seen great advances in understanding of how FA metabolism contributes to adaptive immune response. Here, we review three key processes, FA biosynthesis, FA oxidation and FA uptake, and how they direct T and B cell functions during immune challenges. Then, we will focus on the relationship between microbiota derived FAs, short‐chain FAs, and adaptive immunity. Along the way, we will also discuss the outstanding controversies and challenges in the field.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA) targeting single-domain antibodies, demonstrated early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who had been heavily pretreated (Berdeja, Lancet, 2021). After a median follow-up of 12.4 months, the overall response rate (ORR; as assessed by independent review committee) was 97%, with 67% of pts achieving stringent complete response (sCR). The 12-month progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively. Here, we report updated results from CARTITUDE-1 with longer duration of follow-up (median 18 months). Methods: Eligible pts had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and had received a PI, IMiD, and an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days (d) after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate cilta-cel efficacy (phase 2). Response was assessed per IMWG criteria by an independent review committee and minimal residual disease (MRD) negativity at 10 -5 by next-generation sequencing. In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS; per Lee et al Blood 2014 grading criteria) and neurotoxicity (by CTCAE v5.0) were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively. Results: As of Feb 11, 2021, 97 pts (58.8% male; median age 61.0 years [range 43-78]) received cilta-cel. Pts had received a median of 6 (range 3-18) prior lines of therapy; 83.5% were penta-drug exposed, 87.6% were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to last line of therapy. ORR was 97.9% (95% CI: 92.7-99.7); 80.4% of pts achieved sCR, and 94.8% achieved very good partial response or better (Figure). The median time to first response was 1 month (range 0.9-10.7), median time to best response was 2.6 months (range 0.9-15.2), and median time to complete response or better was 2.6 months (range 0.9-15.2). The median duration of response was 21.8 months (95% CI: 21.8-not estimable). Of 61 pts evaluable for MRD, 91.8% were MRD negative at the 10 -5 threshold; MRD 10 -5 negativity was sustained for ≥6 months in 44.3% (27/61) of pts and ≥12 months in 18% (11/61) of pts. The 18-month PFS and OS rates were 66.0% (95% CI: 54.9-75.0) and 80.9% (95% CI: 71.4-87.6), respectively. 18-month PFS rates in pts who achieved sustained MRD for ≥6 months and ≥12 months were 96.3% (95% CI: 76.5-99.5) and 100%, respectively. The most common grade 3/4 hematologic AEs in ≥25% of pts were neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), thrombocytopenia (59.8%), and lymphopenia (49.5%). There were no fatalities related to cytopenias, and no new safety signals with longer follow-up. CRS occurred in 94.8% of pts (mostly grade 1/2); median time to onset was 7 d (range 1-12), and CRS resolved within 14 d in 98.9% of pts. There was no new CAR T-cell neurotoxicity since the previous report. Post cilta-cel infusion, 21 deaths occurred during the study: 0 within first 30 d, 2 within 100 d, and 19 more than 100 d post infusion. Ten deaths were due to disease progression, 6 were treatment-related (as assessed by the investigator), and 5 were due to AEs unrelated to treatment. One patient was retreated with cilta-cel (for progressive disease) and had stable disease (per computerized algorithm) post-retreatment with no incidence of CAR T-cell neurotoxicity. Conclusions: At a longer median follow-up of 18 months, a single cilta-cel infusion led to early, deep, and durable responses in heavily pre-treated pts with MM. Follow-up is ongoing and updated data will be presented. Cilta-cel demonstrated a manageable safety profile with no new safety signals observed with longer follow-up. Further investigations of cilta-cel are ongoing in earlier lines of therapy (CARTITUDE-2 [NCT04133636], CARTITUDE-4 [NCT04181827], and CARTITUDE-5 [NCT04923893]) and in outpatient settings. Figure 1 Figure 1. Disclosures Martin: GlaxoSmithKline: Consultancy; Janssen: Research Funding; Sanofi: Research Funding; Amgen: Research Funding. Usmani: Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; EdoPharma: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. Berdeja: Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding. Jakubowiak: Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cohen: Novartis: Research Funding; BMS/Celgene: Consultancy; Takeda: Consultancy; Genentech/Roche: Consultancy; Oncopeptides: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Hari: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Deol: Kite, a Gilead Company: Consultancy. Lesokhin: bristol myers squibb: Research Funding; Iteos: Consultancy; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Janssen: Honoraria, Research Funding. Munshi: Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Legend: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. O'Donnell: Onocopeptide: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Yeh: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Allred: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zudaire: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Olyslager: Janssen: Current Employment. Pacaud: Legend Biotech: Current Employment. Lin: Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Jagannath: Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Abstract Background: Ciltacabtagene autoleucel (cilta-cel) is a novel chimeric antigen receptor T-cell therapy that is being evaluated in the CARTITUDE-1 trial (NCT03548207) in patients with relapsed or refractory multiple myeloma (RRMM) who are triple-class exposed (to immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody). As there is no clear standard of care for this patient population, and due to an absence of direct head-to-head trials evaluating cilta-cel and other relevant treatments, indirect treatment comparisons (ITCs) between cilta-cel and treatments used in current clinical practice, ie, physician's choice of treatment (PCT), have been previously conducted. Meta-analyses were performed to derive single summary effect estimates for overall survival (OS) and progression-free survival (PFS) by pooling ITCs evaluating cilta-cel versus PCT in patients with triple-class exposed RRMM. Methods: ITCs examining the comparative effectiveness of cilta-cel versus PCT on OS and PFS were included. Data on cilta-cel corresponded to the February 2021 data-cut for CARTITUDE-1. Data on PCT was leveraged from the following sources: (i) the Flatiron database, a primarily US community-based multiple myeloma registry, (ii) the long-term follow-up results of three global RRMM daratumumab randomized clinical trials (POLLUX [NCT02076009], CASTOR [NCT02136134], and EQUULEUS [NCT01998971]), (iii) the US-based retrospective MAMMOTH study, and (iv) a representative German patient registry maintained by OncologyInformationService (OIs). In each ITC, the PCT group was comprised of patients who satisfied key eligibility criteria for CARTITUDE-1 and was made comparable to CARTITUDE-1 using inverse probability of treatment weighting. Hence, the ITCs were deemed appropriate to meta-analyze. The meta-analyses used a robust variance estimator to account for the use of CARTITUDE-1 in each pairwise ITC. The main meta-analyses considered all participants treated with cilta-cel in CARTITUDE-1 compared with PCT. Sensitivity analyses considered ITC effect estimates based on all enrolled participants in CARTITUDE-1. Pooled summary effect estimates were presented as hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs). Results: Based on availability of data, the main meta-analyses included four ITCs for OS and three ITCs for PFS. Cilta-cel was associated with a statistically significant improvement in OS (HR: 0.21, 95% CI: 0.13 to 0.34; Figure 1) and PFS (HR: 0.20, 95% CI: 0.07 to 0.63; Figure 2) compared to PCT. Sensitivity analyses including all enrolled participants confirmed the results of the main meta-analyses. Conclusions: In the meta-analyses, cilta-cel demonstrated a significant advantage over PCT in terms of OS and PFS, highlighting its potential as an effective therapy in patients with triple-class exposed RRMM. Figure 1 Figure 1. Disclosures Hari: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Berdeja: EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Gay: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Takeda: 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; Celgene: 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; Sanofi: Consultancy, Honoraria. Hooper: Eversana: Current Employment; Janssen: Consultancy. Haltner: Eversana: Current Employment; Janssen: Consultancy. Kumar: Carsgen: Research Funding; Novartis: Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding. Martin: Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding; Oncopeptides: Consultancy. Mateos: AbbVie: Honoraria; Oncopeptides: 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; Amgen: 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; Celgene - Bristol Myers Squibb: 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; Bluebird bio: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Adaptive Biotechnologies: 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; GSK: Honoraria; Sanofi: 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. Moreau: Sanofi: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Rosta: EVERSANA: Current Employment; Janssen Inc.: Consultancy. Samjoo: EVERSANA: Current Employment; Janssen Inc.: Consultancy. Usmani: GSK: Consultancy, Research Funding; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, 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, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Olyslager: Janssen: Current Employment. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Garrett: Legend Biotech USA: Current Employment. Lee: Legend Biotech: Current Employment, Current equity holder in publicly-traded company. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Valluri: Janssen: Current Employment, Current equity holder in publicly-traded company. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Lin: Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Takeda: Research Funding; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding.

Abstract Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-501A is a genetically modified anti-CD19 AlloCAR T™ cell product that uses TALEN ® gene editing to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD). Here we present an update on the preliminary safety, efficacy, and correlative data. ALLO-501A uses Cellectis technologies. Methods ALPHA2 (NCT04416984) is a single-arm, open-label, Phase 1/2 trial of ALLO-501A in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL including [R/R] diffuse LBCL [DLBCL], transformed follicular lymphoma [tFL], marginal zone lymphoma [tMZL], primary mediastinal B-cell lymphoma [PMBCL], follicular lymphoma grade 3B [FL3B]) who received ≥2 prior lines of therapy (including an anthracycline and anti-CD20 mAb), have an ECOG performance status of 0 or 1. Subjects with donor specific antibodies are excluded. Following LD with ALLO-647, fludarabine 30 mg/m 2/d x 3d (F), and cyclophosphamide 300 or 500 mg/m 2/d x 3d (C), either a single (40 [DL1] or 120 [DL2] x 10 6 viable CAR T cells) or consolidation dose of ALLO-501A (DL2) are given. For consolidation dose, pts with ≥stable disease (SD) at day 28 receive consolidation with second ALLO-647 (no chemo) for LD and ALLO-501A (DL2) cell infusion. Results As of July 9, 2021, 20 pts were enrolled; 15 pts were treated with ALLO-501A (12 evaluable and 3 pending D28 assessment); 3 pts pending treatment; 2 pts withdrew due to adverse event (AE)/progressing disease (PD) prior to dosing. Patients were heavily pretreated with advanced-stage disease (Stage III: 4 [22.2%], Stage IV: 8 [44.4%]), median number of prior treatments was 3 with a high of 7. Three pts (16.7%) had primary refractory disease. Safety profile was manageable in both single dose and consolidation cohorts. Events of interest in the single dose cohort have been previously reported (ASCO 2021). In the consolidation cohort (13 enrolled, 9 pts dosed thus far), no cytokine release syndrome (CRS), no GvHD, no immune effector cell-associated neurotoxicity syndrome (ICANS), no dose-limiting toxicities (DLTs), no dose reductions, no Grade (Gr) 3+ infections and no related serious adverse events (SAEs) occurred, and infusion-related reactions were Gr 1. Among all treated, cytopenias were the most common AE and occurred in 72% of pts. Of the 12 evaluable pts (6 each treated in the single dose and consolidation dose cohort), both the overall response rate (ORR) and complete response (CR) were 50% (95% CI: 21.1, 78.9). In the consolidation cohort, both ORR and CR rate were 66.7% (95% CI: 22.3, 95.7) with 3/3 partial responses (PRs) converting to CR after consolidation; 1 pt had CR at days 28 and 56 post consolidation and 2 pts had PD at month 1 and did not receive consolidation. In single dose cohort, 2 pts have ongoing CR at 9 and 12+ months. CAR T expansion was greater in pts who achieved a CR with a geometric mean area under the curve (AUC) at D1-28 of 206,990 copies/ug*days (n=6; GSD 4.94) compared to pts who did not achieve a CR with AUC at D1-28 of 3,571 copies/ug*days (n=3; GSD 2.41). Pts who received the consolidation dose continued to have CAR T expansion after the 2 nd CAR T infusion with geometric mean AUC from D30-56 of 92,893 copies/ug*days (n=4; GSD 5.42). Conclusions ALLO-501A with consolidation dosing demonstrated comparable safety and an improved efficacy profile compared to single dosing with all 4 pts who received consolidation remaining in CR. Persistence of CAR T at D28 and expansion after consolidation dose was observed in addition to the observed deepening of responses in pts whose initial response was PR. Additional follow up is needed to determine whether consolidation also improves the durability of response. Consolidation was well tolerated and given the generally favorable overall safety profile, ALLO-501A may have the potential to be given in the outpatient setting. Enrollment is ongoing. Updated efficacy and follow-up will be presented at the meeting. Currently, an ALLO-501A Phase 2 trial is planned. Disclosures Locke: Cowen: Consultancy; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Legend Biotech: Consultancy, Other; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Popplewell: Novartis: Other: Travel; Pfizer: Other: Travel; Hoffman La Roche: Other: Food. Abramson: Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genentech: Consultancy. Munoz: Pharmacyclics/Abbvie: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Debiopharm: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding, Speakers Bureau; Millennium: Research Funding; Targeted Oncology: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Roche: Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau. Shin: Allogene Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Loomis-Navale: Allogene: Current Employment, Current equity holder in publicly-traded company. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Patents & Royalties. OffLabel Disclosure: Discussion of fludarabine and cyclophosphamide in combination with ALLO-647 as conditioning regimen prior to administration of ALLO-501A in patients with R/R LBCL.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell (CAR-T) therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies, is being evaluated in patients (pts) with relapsed/refractory multiple myeloma (RRMM). In the phase 1b/2 CARTITUDE-1 (NCT03548207) study, a single dose of cilta-cel led to early, deep, and durable responses in heavily pretreated pts with MM, with a manageable safety profile (Berdeja, Lancet, 2021). At median 18 months of follow-up, the overall response rate (ORR) was 98%, with 80% of pts achieving stringent complete response. Median duration of response (DOR) was 21.8 months (95% CI, 21.8-not estimable); 18-month progression-free survival (PFS) and overall survival (OS) rates were 66% and 81%, respectively. Here, we report the efficacy and safety of cilta-cel in various subgroups of pts in CARTITUDE-1. Methods: Eligible pts had MM and received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose: 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS) graded by Lee et al (Blood 2014) criteria and neurotoxicity by CTCAE v5.0 were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively. Efficacy and safety were evaluated in the following subgroups: ≥65 years of age, Black/African American, 3 prior LOT, ≥4 prior LOT, triple-class refractory, penta-drug refractory, standard- and high-risk cytogenetics, International Staging System stage III, bone marrow plasma cells at baseline (≤30%, >30 to <60%, and ≥60%), BCMA tumor expression at baseline (<80%, ≥80%), and presence of soft tissue plasmacytomas (bone-based and extramedullary). Results: As of February 11, 2021, 97 pts in the overall population received cilta-cel; 58.8% were male, median age was 61 years (range 43-78), and median time from diagnosis to enrollment was 5.9 years (range 1.6-18.2). ORR across all evaluated subgroups was comparable to the overall population, and was consistently high (range 95.1-100%) including in those with high-risk cytogenetics, ISS stage III MM, baseline bone marrow cells ≥60%, and baseline plasmacytomas (Table). Median DOR for most subgroups, including high-risk cytogenetics, was consistent with the overall population or not reached but was shorter in pts with ISS Stage III MM and baseline plasmacytomas (Table). Across all subgroups, 80%-100% of MRD-evaluable pts achieved MRD negativity (10 -5 threshold). 18-month PFS and OS rates were consistent with the overall population in most subgroups, including high-risk cytogenetics, and lower in ISS stage III and baseline plasmacytomas (Table). Incidence of CRS, ICANS, and other CAR T-cell neurotoxicities (events not reported as ICANS [ie, onset after a period of recovery from CRS and ICANS]) in various subgroups was consistent with the overall population, with no new safety signals. Conclusions: At median follow-up of 18 months, a single infusion of cilta-cel yielded deep, durable responses in all evaluated subgroups in CARTITUDE-1. An ORR of 95%-100% was observed in pts across all subgroups, including those with high-risk cytogenetics, ISS stage III MM, baseline bone marrow cells ≥60%, and baseline plasmacytomas. In patients with ISS stage III and with baseline plasmacytomas, median DOR appeared shorter and 18-mo PFS and OS rates lower. Cilta-cel safety profile across the subgroups was consistent with the overall population, with no new safety signals. Ongoing evaluation of cilta-cel in the multicohort CARTITUDE-2 (NCT04133636) study in pts with unmet need in varying stages of treatment for MM will further explore the treatment benefit of cilta-cel, including in those with high-risk disease. Figure 1 Figure 1. Disclosures Jakubowiak: GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Usmani: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; GSK, Ichnos Sciences, Incyte: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Lilly, Novartis: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Poseida, Sanofi, Teva: Research Funding. Cohen: Oncopeptides: Consultancy; Genentech/Roche: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Takeda: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; AstraZeneca: Consultancy; Novartis: Research Funding. Hari: Karyopharm: Consultancy; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Yeh: Janssen: Current Employment. Olyslager: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Allred: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zudaire: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Geng: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Lin: Janssen: Consultancy, Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Juno: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Takeda: Research Funding; Sorrento: Consultancy; Merck: Research Funding; Gamida Cell: Consultancy. Martin: Janssen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Papilledema is optic nerve swelling caused by increased intracranial hypertension, which has the potential to cause significant vision loss. Papilledema from idiopathic intracranial hypertension (IIH) is typically bilateral and symmetric, but can sometimes be asymmetric and even unilateral. The cause for this asymmetry is unknown. The purpose of this study was to develop ultrasound vibro-elastography (UVE) for assessing patients with papilledema to evaluate for biomechanical differences in these eyes. Nine patients with papilledema from IIH and 9 age-matched healthy control subjects were enrolled. A local harmonic vibration was used to generate wave propagation through the eyelid. Three excitation frequencies of 100, 150, and 200 Hz were used. A 6.4 MHz ultrasound probe was used to measure wave propagation in the eye structures. Wave speeds were measured in the posterior sclera of the maculae. The magnitudes of the wave speed of the IIH patients’ posterior sclera were significantly higher than those of healthy subjects. In patients with unilateral papilledema, the wave speed of the posterior sclera were higher in the eyes with papilledema than in the contralateral eyes without papilledema. UVE provides a noninvasive technique to measure the wave speed of posterior sclera, which is stiffer in eyes with papilledema.

Abstract Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.

AbstractBackgroundWith increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific common data elements (CDEs) to facilitate comparative and pooled analyses.MethodsThe generation of CDEs followed the 4-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution.ResultsThe CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient level and 7 tumor level) as well as 14 supplemental CDEs (7 patient level and 7 tumor level) were defined and described. These CDEs are now made publicly available for dissemination and adoption.ConclusionsCDEs provide a framework for discussion in the neuro-oncology community that will facilitate data-sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.

Abstract Background: Roughly 7–10% of patients with pancreatic ductal adenocarcinoma (PDAC) have a deleterious germline variant. Although identification of germline variants in family members has implications for cancer surveillance and can lead to early cancer detection and interception for PDAC, as well as other cancers, cascade genetic testing rates are low. The GENetic Education, Risk Assessment and TEsting (GENERATE) study evaluates novel methods of providing genetic education and testing for individuals at risk for hereditary PDAC. Methods: Eligible participants had: (1) a first- or second-degree relative with a diagnosis of PDAC and a known familial germline variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 (Known Familial Mutation (KFM)), (2) or were first-degree relatives of PDAC patients (no KFM). Participants were recruited through six academic centers, patient advocacy organizations and online outreach. Enrollment occurred through the study website (www.GENERATEstudy.org). All study participation, including genetic testing via a at home saliva sample kit, was done remotely. Participants were cluster randomized at the family level into one of two arms. Arm 1 (Doxy.me plus Color Genomics) included remote genetic education and testing through a video-based telemedicine platform (Doxy.me) and physician-mediated testing through Color Genomics. Arm 2 included remote genetic education and testing through Color Genomics only. Results: Between 5/8/2019–6/01/2021, 423 families were randomized, comprising 595 participants. Recruitment occurred through patient invitation via healthcare providers (n=128, 21.5%), family members (n=271, 45.5%), friends, advocacy groups, and online outreach (n=223, 37.5%). Participants were referred from the six GENERATE academic centers (n=270, 45.4%) and other institutions (n=325, 54.6%). Study participants were 52.5 years on average, primarily identified as White (n=577, 97%) and from the Northeast (n=184, 30.9%), Midwest (n=154, 25.9%), South (n=158, 26.6%) and West (n=99, 16.6%). Participants were randomized into each arm (n=296 Doxy.me plus Color Genomics; n=299 Color Genomics only). To date, 527 (88.6%) participants have ordered genetic testing. The uptake of genetic testing was 253/296 (85.5%) in the Doxy.me plus Color Genomics arm and 274/299 (91.6%) in the Color Genomics only arm (p=0.049, generalized mixed-effects model). A total of 82 PDAC associated pathogenic variants were identified. The most frequently detected variants were BRCA2 (n=32), ATM (n=25) and PALB2 (n=6). Additionally, 13 non-PDAC associated pathogenic variants and 20 low penetrance variants were detected. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional cascade testing, with genetic testing rates nearly 90%. Participant follow up will assess if satisfaction with decision making, cancer-risk distress, knowledge gained, family communication, and uptake of surveillance were impacted by the mode of delivery of pre-test genetic education. Citation Format: Nicolette J. Rodriguez, Constance S. Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Alison N. Schwartz, Jill Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott Nelson, Sydney Okumura, Sherman Law, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Allyson Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. Comparison of novel healthcare delivery models on the uptake of genetic education and testing in families with a history of pancreatic cancer: The GENetic Education, Risk Assessment and TEsting (GENERATE) study [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-013.