- Awareness of the gold standard paradox is necessary when using traditional pathologist scores to analytically validate a tIA tool because image analysis is used specifically to overcome known sources of bias in visual assessment of tissue sections.
Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM). bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007 during ex vivo culture to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. To investigate whether DP properties correlate with clinical outcomes including duration of response (DOR), we conducted extensive molecular characterization of patient DPs. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in RRMM patients who received ≥3 prior regimens, including proteasome inhibitor and immunomodulatory agent, or are double-refractory to both classes. In the expansion cohort, patients additionally required prior exposure to an anti-CD38 antibody and were required to be refractory to last line. Planned enrollment is 74 patients, including 50 in the expansion cohort. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive a single infusion of bb21217 at 150, 300 or 450 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. We profiled DP and apheresis starting material (PBMC) by RNAseq and cyTOF and correlated expression of memory/senescence markers from apheresis to DP with clinical outcomes, including DOR. Results: Asof March 1, 2020, 46 patients (median age 62 [33-74]) received bb21217, 24 in escalation (12 at 150, 6 at 300 and 6 at 450) and 22 in expansion (8 at 300 and 14 at 450); median follow up for all patients is 8.5 (<1-29) months. Patients had a median of 6 (3-17) prior lines of therapy with 26/46 (57%) triple refractory. Cytokine release syndrome (CRS) developed in 31/46 (67%) patients and included one death (14 G1, 15 G2, 1 G3 and 1 G5). Median time to first onset was 3 days (1-20); tocilizumab (18 pts) +/- corticosteroids (6 pts) was used to manage CRS. Ten (22%) patients developed neurotoxicity [5 G1, 2 G2, 2 G3, 1 G4] with median time to first onset of 7 (3-24) days. Response was assessed per investigator for 44 patients with ≥ 2 months of follow up or PD/death within 2 months. Twenty-four (55%) patients had confirmed response per IMWG criteria including 8 (18%) with ≥CR and 13 (30%) with VGPR. Median time to CR was 2.5 (1-24) months. The median DOR was 11.9 (95% CI: 8.1-17.0) months across target dose levels of 150-450 x106 CAR+ T cells. The 450 target dose was selected as the RP2D and dose expansion is ongoing. bb21217 DPs from 44 patients were characterized. Paired analysis of T cells from PBMC and DP showed bb21217 DP is significantly enriched for memory-like T cells (LEF1+, CD27+, CCR7+) and depleted of highly differentiated or senescent CD57+ T cells. Patients with DPs most enriched for early memory markers (LEF1+, CCR7+ and CD27+) and with low expression of effector/exhaustion markers (EOMES+, GZMA+, CD57+) were more likely to have higher peak CAR+ T cell expansion. To evaluate the association of these DP markers with DOR, we split the 24 responders (≥PR) on median marker expression (high vs low) and analyzed DOR in these exploratory subgroups. High CD127 expression, associated with long-lasting memory T cell formation, was positively correlated with DOR, while multiple markers associated with differentiated T cells (e.g. EOMES+, TBET+) were negatively correlated with DOR. Conclusions: The adverse events observed are consistent with known toxicities of CAR T cell therapies. Initial efficacy results with bb21217 are encouraging, with 48% of patients treated across target dose levels of 150-450 obtaining ≥VGPR. The presence of T cell markers associated with memory and the absence of T cells markers associated with differentiation/senescence in DP correlated positively with peak expansion and DOR. These preliminary correlative data support the mechanistic hypothesis that enrichment for memory like T cells in bb21217 DP may result in improved clinical outcomes. Data for approximately 14 additional patients at the 450 target dose will be presented. Disclosures Alsina: Janssen: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Raje:Janssen: Consultancy; Celgene: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Astrazeneca: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Karyopharm: Consultancy; BMS: Consultancy; Amgen: Consultancy. Jagannath:Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy. Kaufman:Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Celulatiry: Consultancy. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Timm:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Turka:bluebird bio: Current Employment. Mao:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences: Divested equity in a private or publicly-traded company in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses, Patents & Royalties: Numerous, Research Funding. Bitter:Novartis AG, Predicant Biosciences, Biospect, F Hofmann-La Roche: Ended employment in the past 24 months; bluebird bio: Current Employment, Current equity holder in publicly-traded company; Novartis: Ended employment in the past 24 months, Patents & Royalties. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Berdeja:Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Kesios: Research Funding; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Vivolux: Research Funding.
Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell maturation antigen (BCMA) directed CAR T cell therapy which uses the same CAR molecule as ide-cel, with the addition of a PI3K inhibitor (bb007) during ex vivo culture to enrich the drug product (DP) for memory-like T cells and decrease the proportion of highly differentiated or senescent T cells. We hypothesize that DPs enriched for memory like CAR T cells will persist and function longer than non-enriched DPs and this increased persistence will positively influence duration of response (DOR). We previously demonstrated patients with sustained response are more likely to have drug product enriched for naïve gene signatures and depleted of effector gene signatures compared to patients without a sustained response. Methods: CRB-402 (NCT03274219) is a multi-center phase 1 trial of bb21217 in RRMM patients who received ≥3 prior lines of antimyeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory to both classes. In expansion, patients were required to have prior exposure to an anti-CD38 antibody and were required to be refractory to their last line of therapy. Patients underwent lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days, then received a single infusion of bb21217 at 150, 300 or 450 x 10 6 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. Exploratory analyses include correlation of outcome with the molecular characteristics of materials collected temporally through the treatment course, including PBMCs at apheresis, CAR+ T cells from drug product and CAR+ T cells collected from patients around the time of peak expansion. Results: Asof Feb 16, 2021, 72 patients received bb21217, 12 at 150, 14 at 300 and 46 at 450 x 10 6 CAR+ T cells; median follow up for all patients is 9.0 (<1-36) months (M). Patients had a median of 6 (3-17) prior lines of therapy with 49/72 (68%) triple refractory. Cytokine release syndrome (CRS) developed in 54/72 (75%) patients and was predominately G1/2 (51 pts), with 1 G3 event and 2 deaths (previously reported). Median time to first onset of CRS was 2 days (1-20); tocilizumab (38 pts) + corticosteroids (12 pts) was used to manage CRS. Eleven (15%) patients developed neurotoxicity [8 G1/G2, 2 G3, 1 G4] with median time to first onset of 7 (2-24) days. Response was assessed per investigator for 72 patients treated with bb21217 (Table). CAR+ T cells remained detectable in 30/37 (81%) patients and 9/15 (60%) patients at 6 and 12 M respectively, post bb21217 infusion. Of the 15 patients evaluable for MRD with ≥CR, 14 (93%) were MRD negative at 10 -5 by NGS. Analysis of peripheral blood samples collected 15 days post bb21217 infusion demonstrated patients with higher than the median number of CD8+ CAR+ T cells expressing CD27 and CD28 had significantly longer DOR (p=0.0024), compared to patients with lower than the median values. This suggests less differentiated, more proliferative CAR+ T cells at peak expansion are associated with prolonged disease response (median DOR in high vs low: 27.2M (95% CI; 16.8, NE) vs 9.4M (95% CI; 5.1, NE). Conclusions: Adverse events are consistent with known toxicities of CAR T cell therapies. Efficacy results are encouraging with a median DOR estimate of 17M, CR rate continues to mature. Patients with higher levels of proliferative, less differentiated memory like CAR+ T cells at peak expansion are more likely to experience prolonged DOR, continuing to support the hypothesis that the memory like T cell phenotype associated with bb21217 results in prolonged DOR. Figure 1 Figure 1. Disclosures Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Shah: Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Kite: Consultancy; Nektar: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CSL Behring: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; Teneobio: Research Funding. Kaufman: BMS: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Siegel: Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria, Speakers Bureau. Munshi: Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Legend: Consultancy; Adaptive Biotechnology: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Karyopharm: Consultancy; Pfizer: Consultancy. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Lin: Sorrento: Consultancy; Takeda: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Timm: bluebird bio: Current Employment. Yeri: bluebird bio: Current Employment. Martin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Finney: bluebird bio: Current Employment, Current equity holder in publicly-traded company. Truppel-Hartmann: bluebird bio: Current Employment. Petrocca: blue bird bio: Ended employment in the past 24 months. Berdeja: Abbvie, Acetylon, Amgen: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding.
ATM plays a critical role in cellular responses to DNA double-strand breaks (DSBs). We describe a new ATM–mediated DSB–induced DNA damage response pathway involving microRNA (miRNA): irradiation (IR)-induced DSBs activate ATM, which leads to the downregulation of miR-335, a miRNA that targets CtIP, which is an important trigger of DNA end resection in homologous recombination repair (HRR). We demonstrate that CREB is responsible for a large portion of miR-335 expression by binding to the promoter region of miR-335. CREB binding is greatly reduced after IR, corroborating with previous studies that IR-activated ATM phosphorylates CREB to reduce its transcription activity. Overexpression of miR-335 in HeLa cells resulted in reduced CtIP levels and post-IR colony survival and BRCA1 foci formation. Further, in two patient-derived lymphoblastoid cell lines with decreased post-IR colony survival, a “radiosensitive” phenotype, we demonstrated elevated miR-335 expression, reduced CtIP levels, and reduced BRCA1 foci formation. Colony survival, BRCA1 foci, and CtIP levels were partially rescued by miRNA antisense AMO-miR-335 treatment. Taken together, these findings strongly suggest that an ATM–dependent CREB–miR-335–CtIP axis influences the selection of HRR for repair of certain DSB lesions.
IntroductionGM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids.ObjectiveIn this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover.ResultsUsing tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well.ConclusionsOur studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.