FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2912146309> ?p ?o ?g. }

• W2912146309 endingPage "3337" @default.
• W2912146309 startingPage "3337" @default.
• W2912146309 abstract "Abstract Adoptive cellular immunotherapy (ACT) using chimeric-antigen receptor (CAR)-modified T cells has shown unprecedented initial response rates in patients with advanced B cell malignancies and is emerging as a powerful tool for cancer treatment. However, there remains room for improvement in initial response rates, and relapse occurs in a significant fraction of those patients that do respond. Reasons for failure to respond are being elucidated. At least two mechanism of relapse - lack of persistence of infused CAR-T cells and the loss of antigen-expression by tumor cells - are well documented. We have developed a novel platform for ACT called Marrow-infiltrating Lymphocytes (MILs). MILs are a population of polyclonal T cells expanded from the bone marrow (BM) with distinct properties that set them apart from T cells expanded from peripheral blood lymphocytes (PBLs). MILs are enriched with memory T cells and contain tumor antigen-specific T cells that are typically not detected in PBLs. MILs are being developed for several tumor types, including both hematological and solid tumors. Distinguishing features of MILs compared to PBLs include their memory phenotype, inherent tumor antigen-specificity, and ability to persist long-term. As such, we hypothesized that MILs would provide a robust platform for CAR-T cell therapy with the potential to boost initial response rates and reduce the risk of relapse. Herein, data is presented demonstrating superior anti-tumor activity of CAR-modified MILs (CAR-MILs) compared to CAR-T cells generated from patient-matched PBLs (CAR-PBLs). We designed a 2nd generation 4-1BB-CD3z CD38 CAR using an scFv derived from Daratumumab. The CD38 CAR was linked to GFP by a T2a cleavage peptide so that GFP could be used as a marker of CAR expression. The CD38 CAR was expressed in a lentiviral construct and demonstrated equal transduction efficiencies and CAR expression levels in MILs and PBLs. The CAR modified MILs demonstrated superior antigen specific killing compared to PBLs against the 8226 myeloma (MM) cell line but not its isogenic CD38 knocked out line. More importantly, CAR-MILs retained their inherent tumor antigen-specificity and capacity to respond through their endogenous tumor antigen-specific T cell receptors - a property that PBL-CARs did not appear to possess. Tumor antigen-specific T cells were quantified by co-culturing MILs with autologous antigen-presenting cells pulsed with allogeneic multiple myeloma cell line lysates as a source of antigen and measuring IFNγ-production as a read-out. An equal or greater number of tumor antigen-specific IFNγ-producing T cells were measured in CD38 CAR-MILs compared to matched unmodified MILs. Finally, we compared the in vitro cytolytic potential of CD38 CAR-MILs to matched CD38 CAR-PBLs. Co-culture killing assays were performed at decreasing CAR-T effector: target (E:T) ratios. At high E:T ratios, CAR-MILs and CAR-PBLs lysed comparable percentages of CD38+ targets with similar kinetics. However, at lower E:T ratios, CAR-MILs killed a greater percentage of CD38+ targets with faster kinetics compared to CAR-PBLs. In conclusion, we have demonstrated 1) the feasibility of producing CAR-modified MILs, 2) that CAR-MILs retain their inherent tumor antigen-specificity and functional capacity - something that was lacking with CAR-PBLs, and 3) that CAR-MILs kill more efficiently in vitro than matched CAR-PBLs. These data suggest that CAR-MILs may provide both better antigen specific killing but more importantly by targeting the endogenous antigenic repertoire, they could also prevent or minimize the risk of relapse via antigen escape variants and thus increase the overall efficacy of adoptive CAR T cell therapy. Disclosures Lutz: WIndMIL Therapeutics: Employment, Patents & Royalties. Rudraraju:WIndMIL Therapeutics: Employment. DeOliveira:WIndMIL Therapeutics: Employment. Jana:WIndMIL Therapeutics: Employment. Weiss:WIndMIL Therapeutics: Employment. Borrello:WIndMIL Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Noonan:WIndMIL Therapeutics: Employment, Equity Ownership, Patents & Royalties." @default.
• W2912146309 created "2019-02-21" @default.
• W2912146309 creator A5011002242 @default.
• W2912146309 creator A5034547254 @default.
• W2912146309 creator A5039484714 @default.
• W2912146309 creator A5039638381 @default.
• W2912146309 creator A5078781359 @default.
• W2912146309 creator A5084994054 @default.
• W2912146309 creator A5085355136 @default.
• W2912146309 creator A5086599253 @default.
• W2912146309 date "2018-11-29" @default.
• W2912146309 modified "2023-09-27" @default.
• W2912146309 title "Marrow-Infiltrating Lymphocytes (MILs) Provide a Robust Platform for CAR-T Cell Therapy" @default.
• W2912146309 doi "https://doi.org/10.1182/blood-2018-99-118580" @default.
• W2912146309 hasPublicationYear "2018" @default.
• W2912146309 type Work @default.
• W2912146309 sameAs 2912146309 @default.
• W2912146309 citedByCount "2" @default.
• W2912146309 countsByYear W29121463092019 @default.
• W2912146309 countsByYear W29121463092020 @default.
• W2912146309 crossrefType "journal-article" @default.
• W2912146309 hasAuthorship W2912146309A5011002242 @default.
• W2912146309 hasAuthorship W2912146309A5034547254 @default.
• W2912146309 hasAuthorship W2912146309A5039484714 @default.
• W2912146309 hasAuthorship W2912146309A5039638381 @default.
• W2912146309 hasAuthorship W2912146309A5078781359 @default.
• W2912146309 hasAuthorship W2912146309A5084994054 @default.
• W2912146309 hasAuthorship W2912146309A5085355136 @default.
• W2912146309 hasAuthorship W2912146309A5086599253 @default.
• W2912146309 hasBestOaLocation W29121463091 @default.
• W2912146309 hasConcept C10882517 @default.
• W2912146309 hasConcept C147483822 @default.
• W2912146309 hasConcept C203014093 @default.
• W2912146309 hasConcept C2776090121 @default.
• W2912146309 hasConcept C2777701055 @default.
• W2912146309 hasConcept C2780007613 @default.
• W2912146309 hasConcept C28328180 @default.
• W2912146309 hasConcept C2908647359 @default.
• W2912146309 hasConcept C3875195 @default.
• W2912146309 hasConcept C502942594 @default.
• W2912146309 hasConcept C71924100 @default.
• W2912146309 hasConcept C86803240 @default.
• W2912146309 hasConcept C8891405 @default.
• W2912146309 hasConcept C90375314 @default.
• W2912146309 hasConcept C95444343 @default.
• W2912146309 hasConcept C99454951 @default.
• W2912146309 hasConceptScore W2912146309C10882517 @default.
• W2912146309 hasConceptScore W2912146309C147483822 @default.
• W2912146309 hasConceptScore W2912146309C203014093 @default.
• W2912146309 hasConceptScore W2912146309C2776090121 @default.
• W2912146309 hasConceptScore W2912146309C2777701055 @default.
• W2912146309 hasConceptScore W2912146309C2780007613 @default.
• W2912146309 hasConceptScore W2912146309C28328180 @default.
• W2912146309 hasConceptScore W2912146309C2908647359 @default.
• W2912146309 hasConceptScore W2912146309C3875195 @default.
• W2912146309 hasConceptScore W2912146309C502942594 @default.
• W2912146309 hasConceptScore W2912146309C71924100 @default.
• W2912146309 hasConceptScore W2912146309C86803240 @default.
• W2912146309 hasConceptScore W2912146309C8891405 @default.
• W2912146309 hasConceptScore W2912146309C90375314 @default.
• W2912146309 hasConceptScore W2912146309C95444343 @default.
• W2912146309 hasConceptScore W2912146309C99454951 @default.
• W2912146309 hasIssue "Supplement 1" @default.
• W2912146309 hasLocation W29121463091 @default.
• W2912146309 hasOpenAccess W2912146309 @default.
• W2912146309 hasPrimaryLocation W29121463091 @default.
• W2912146309 hasRelatedWork W2562658803 @default.
• W2912146309 hasRelatedWork W2901390118 @default.
• W2912146309 hasRelatedWork W2906766942 @default.
• W2912146309 hasRelatedWork W2917396455 @default.
• W2912146309 hasRelatedWork W2933273568 @default.
• W2912146309 hasRelatedWork W4221031414 @default.
• W2912146309 hasRelatedWork W4324026084 @default.
• W2912146309 hasRelatedWork W4328048881 @default.
• W2912146309 hasRelatedWork W4383998590 @default.
• W2912146309 hasRelatedWork W4385996357 @default.
• W2912146309 hasVolume "132" @default.
• W2912146309 isParatext "false" @default.
• W2912146309 isRetracted "false" @default.
• W2912146309 magId "2912146309" @default.
• W2912146309 workType "article" @default.