FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308376055> ?p ?o ?g. }

• W4308376055 abstract "<h3>Background</h3> Mesothelin (MSLN) is expressed on a variety of solid tumors, including mesothelioma and ovarian, uterine, gastric, pancreatic, and lung cancers.¹ However, efforts to target MSLN using cellular therapies have been hampered by severe on-target, off-tumor toxicities associated with damage to normal tissues expressing MSLN.² To avoid these toxicities, we have developed a logic-gated engineered cell therapy, Tmod™, which is composed of two chimeric antigen receptors (CARs): an activator that targets a tumor-associated antigen and an inhibitory receptor (blocker) gated by an antigen expressed on normal tissue but lost in tumor cells due to loss of heterozygosity (LOH). A2B694 is an MSLN-specific Tmod construct combining a third-generation MSLN CAR with an LIR-1-based inhibitory receptor specific for human leukocyte antigen A*02 (HLA-A*02). <h3>Methods</h3> Lentivirus encoding i) the CAR, ii) the blocker, and iii) an shRNA targeting β2M was used to transduce T cells from HLA-A*02 donors and generate MSLN Tmod cells. In vitro cytotoxicity measurements were performed using fluorescence-based imaging and luciferase readouts. In vivo assessments were performed in NSG mice subcutaneously implanted with “normal” cells (MSLN[+]A*02[+]), or tumor cells (MSLN[+]A*02[-]), in the left and right flanks, respectively. Following engraftment, mice were randomized and treated intravenously with MSLN Tmod cells or controls. Grafts were measured via caliper. <h3>Results</h3> MSLN Tmod cells preferentially killed tumor cells (MSLN[+]A*02[-]) over “normal” cells (MSLN[+]A*02[+]) in vitro, unlike clinically active comparator M5 CAR T cells, which indiscriminately killed both target cell types (figure 1A). Soluble MSLN, tested across a 0-2 µg/mL range, did not impact MSLN Tmod function. Additionally, in mixed cell cultures where T cells and tumor and “normal” cells were simultaneously cultured (1:1:1 ratio), MSLN Tmod cells selectively killed tumor targets while sparing “normal” cells. Further, MSLN Tmod cells cycled between activated and blocked states in vitro when repeatedly challenged with tumor or “normal” target cells. Finally, while MSLN CAR T cells killed both “normal” and tumor grafts in vivo, MSLN Tmod cells selectively killed tumor grafts while sparing “normal” grafts (figure 1B, C). <h3>Conclusions</h3> A2B694 is an autologous MSLN Tmod cell product that leverages LOH at the HLA locus in cancer cells, providing a mechanism to discriminate between normal and tumor cells. BASECAMP-1 (NCT04981119), an observational study that will identify patients with somatic HLA LOH, is currently recruiting. Eligible patients with metastatic colorectal, pancreatic, or non-small cell lung cancer will be apheresed for a future A2B694 interventional study (EVEREST-2). <h3>References</h3> Hassan R <i>et al</i>. Mesothelin immunotherapy for cancer: Ready for prime time? <i>J Clin Oncol</i>. 2016;<b>34</b>(34):4171-4179. Tanyi JL <i>et al</i>. Phase I study of autologous T cells bearing fully-humanized chimeric antigen receptors targeting mesothelin in mesothelin-expressing cancers. Presented at: Cellicon Valley ‘21: The Future of Cell and Gene Therapies; May 6-7, 2021; virtual symposium." @default.
• W4308376055 created "2022-11-11" @default.
• W4308376055 creator A5003368238 @default.
• W4308376055 creator A5007420253 @default.
• W4308376055 creator A5015190820 @default.
• W4308376055 creator A5016684714 @default.
• W4308376055 creator A5018257387 @default.
• W4308376055 creator A5018825816 @default.
• W4308376055 creator A5019199548 @default.
• W4308376055 creator A5030459924 @default.
• W4308376055 creator A5033680753 @default.
• W4308376055 creator A5035287097 @default.
• W4308376055 creator A5037958863 @default.
• W4308376055 creator A5038755935 @default.
• W4308376055 creator A5042326252 @default.
• W4308376055 creator A5048332817 @default.
• W4308376055 creator A5049156516 @default.
• W4308376055 creator A5049498138 @default.
• W4308376055 creator A5053252660 @default.
• W4308376055 creator A5055379755 @default.
• W4308376055 creator A5060287300 @default.
• W4308376055 creator A5066527544 @default.
• W4308376055 creator A5070734531 @default.
• W4308376055 creator A5071328253 @default.
• W4308376055 creator A5071944022 @default.
• W4308376055 creator A5081851296 @default.
• W4308376055 creator A5085418536 @default.
• W4308376055 creator A5090083196 @default.
• W4308376055 date "2022-11-01" @default.
• W4308376055 modified "2023-09-30" @default.
• W4308376055 title "263 A2B694, an autologous logic-gated cell therapy targeting mesothelin" @default.
• W4308376055 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0263" @default.
• W4308376055 hasPublicationYear "2022" @default.
• W4308376055 type Work @default.
• W4308376055 citedByCount "0" @default.
• W4308376055 crossrefType "proceedings-article" @default.
• W4308376055 hasAuthorship W4308376055A5003368238 @default.
• W4308376055 hasAuthorship W4308376055A5007420253 @default.
• W4308376055 hasAuthorship W4308376055A5015190820 @default.
• W4308376055 hasAuthorship W4308376055A5016684714 @default.
• W4308376055 hasAuthorship W4308376055A5018257387 @default.
• W4308376055 hasAuthorship W4308376055A5018825816 @default.
• W4308376055 hasAuthorship W4308376055A5019199548 @default.
• W4308376055 hasAuthorship W4308376055A5030459924 @default.
• W4308376055 hasAuthorship W4308376055A5033680753 @default.
• W4308376055 hasAuthorship W4308376055A5035287097 @default.
• W4308376055 hasAuthorship W4308376055A5037958863 @default.
• W4308376055 hasAuthorship W4308376055A5038755935 @default.
• W4308376055 hasAuthorship W4308376055A5042326252 @default.
• W4308376055 hasAuthorship W4308376055A5048332817 @default.
• W4308376055 hasAuthorship W4308376055A5049156516 @default.
• W4308376055 hasAuthorship W4308376055A5049498138 @default.
• W4308376055 hasAuthorship W4308376055A5053252660 @default.
• W4308376055 hasAuthorship W4308376055A5055379755 @default.
• W4308376055 hasAuthorship W4308376055A5060287300 @default.
• W4308376055 hasAuthorship W4308376055A5066527544 @default.
• W4308376055 hasAuthorship W4308376055A5070734531 @default.
• W4308376055 hasAuthorship W4308376055A5071328253 @default.
• W4308376055 hasAuthorship W4308376055A5071944022 @default.
• W4308376055 hasAuthorship W4308376055A5081851296 @default.
• W4308376055 hasAuthorship W4308376055A5085418536 @default.
• W4308376055 hasAuthorship W4308376055A5090083196 @default.
• W4308376055 hasBestOaLocation W43083760551 @default.
• W4308376055 hasConcept C147483822 @default.
• W4308376055 hasConcept C1491633281 @default.
• W4308376055 hasConcept C185592680 @default.
• W4308376055 hasConcept C203014093 @default.
• W4308376055 hasConcept C2777045440 @default.
• W4308376055 hasConcept C502942594 @default.
• W4308376055 hasConcept C553184892 @default.
• W4308376055 hasConcept C55493867 @default.
• W4308376055 hasConcept C71924100 @default.
• W4308376055 hasConceptScore W4308376055C147483822 @default.
• W4308376055 hasConceptScore W4308376055C1491633281 @default.
• W4308376055 hasConceptScore W4308376055C185592680 @default.
• W4308376055 hasConceptScore W4308376055C203014093 @default.
• W4308376055 hasConceptScore W4308376055C2777045440 @default.
• W4308376055 hasConceptScore W4308376055C502942594 @default.
• W4308376055 hasConceptScore W4308376055C553184892 @default.
• W4308376055 hasConceptScore W4308376055C55493867 @default.
• W4308376055 hasConceptScore W4308376055C71924100 @default.
• W4308376055 hasLocation W43083760551 @default.
• W4308376055 hasOpenAccess W4308376055 @default.
• W4308376055 hasPrimaryLocation W43083760551 @default.
• W4308376055 hasRelatedWork W2048555387 @default.
• W4308376055 hasRelatedWork W2054529397 @default.
• W4308376055 hasRelatedWork W2157511196 @default.
• W4308376055 hasRelatedWork W2220102944 @default.
• W4308376055 hasRelatedWork W2414745257 @default.
• W4308376055 hasRelatedWork W2748952813 @default.
• W4308376055 hasRelatedWork W2887391094 @default.
• W4308376055 hasRelatedWork W2899084033 @default.
• W4308376055 hasRelatedWork W3083781026 @default.
• W4308376055 hasRelatedWork W2014181924 @default.
• W4308376055 isParatext "false" @default.
• W4308376055 isRetracted "false" @default.
• W4308376055 workType "article" @default.