Saule Nurmukhambetova

Optimized tandem BCMA-specific CAR T-cells designed to minimize tonic signaling and off-target toxicity

Xu Wang, Peirong Hu, Brittany Steimle, Michael Wagner et autres

ABSTRACT B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR) T-cell therapies induce high response rates in relapsed or refractory multiple myeloma but have been associated with distinct neurotoxicity profiles. The mechanisms underlying these events remain incompletely understood. Here, we describe a …

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Abstract 4281: Armoring ROR1 CAR T cells with IL18 improves CAR T cell function and cytotoxicity against pancreatic cancer cell-lines in vitro and in vivo

Bal Krishna Chand Thakuri, Saule Nurmukhambetova, Tri Tran, Ngoc Tran et autres

Abstract ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1) is a tumor-associated antigen widely expressed in solid tumors and is a promising target for CAR T cell therapy in pancreatic cancer. Cell-based immunotherapy has met with limited success due in part to the …

292 Optimized bi-paratopic BCMA-specific CAR T cells designed to minimize tonic signaling and off-target toxicity

Xu Wang, Peirong Hu, Brittany Steimle, Michael Wagner et autres

Background BCMA-targeted CAR T-cell therapy has demonstrated remarkable clinical efficacy in patients with relapsed or refractory multiple myeloma (MM). 1 2 Nevertheless, concerns remain regarding neurotoxicity, including Parkinsonism-like movement and cognitive disorders in patients receiving ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel).3 …

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208 A novel fully human MSLN CAR armored with dominant negative TGFβ receptor II demonstrates enhanced efficacy in xenograft models of pancreatic cancer

Bal Krishna Chand Thakuri, Tri Tran, Saule Nurmukhambetova, Peirong Hu et autres

Background Mesothelin (MSLN) is a tumor-associated antigen highly expressed in multiple solid tumors, including pancreatic cancer. A human second-generation MSLN-targeted CAR T-cell product was developed which demonstrated anti-tumor activity in vitro and in vivo, and was further engineered to express dominant-negative transforming …

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337 Dual role of CD276 as target antigen and putative activation marker in CD276-redirected CAR T cells for the treatment of solid tumors

Wei Xiong, Peirong Hu, Michael Wagner, Hamid Zarkesh et autres

Background CD276 (B7-H3) is an attractive pan-solid tumor target due to frequent overexpression in various solid tumors and tumor stroma, and its correlation with poor clinical outcomes. Despite published CAR T cell therapies targeting CD276 (376.96, MGA271, and B12) and numerous ongoing …

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Immune response profiles from humans experimentally exposed to Phlebotomus duboscqi bites

Fernanda Fortes de Araújo, Maha Abdeladhim, Clarissa Teixeira, Kelly A. Hummer et autres

Introduction Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease. Methods To characterize the human …

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Armored TGFβRIIDN ROR1-CAR T cells reject solid tumors and resist suppression by constitutively-expressed and treatment-induced TGFβ1

Tri Tran, Bal Krishna Chand Thakuri, Saule Nurmukhambetova, Jia‐Jye Lee et autres

Background Chimeric antigen receptor (CAR) T-cell therapy target receptor tyrosine kinase-like orphan receptor 1 (ROR1) is broadly expressed in hematologic and solid tumors, however clinically-characterized ROR1-CAR T cells with single chain variable fragment (scFv)-R12 targeting domain failed to induce durable remissions, in …

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Abstract 2913: Co-expression of extracellular matrix enzymes heparanase or PH-20 augments the anti-tumor efficacy of folate receptor 1-targeting CAR T cells in an ovarian cancer model

Brittany Steimle, Peirong Hu, Ngoc Tran, Jia‐Jye Lee et autres

Abstract Introduction: The tumor extracellular matrix (ECM) is a physical barrier which obstructs trafficking of CAR T cells to tumors. We hypothesize that co-expressing ECM remodeling/degrading enzymes heparanase (HPSE) or PH-20 with a CAR directed against folate receptor 1 (FolR1) will overcome …

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280 Multiplex immunofluorescence imaging of armored CAR T cells in pancreatic ductal adenocarcinoma mouse xenografts confirms potent anti-tumor response

Jia‐Jye Lee, Kathleen Baysac, Tri Tran, Bal Krishna Chand Thakuri et autres

Background Chimeric antigen receptor (CAR) T-cells are a promising modality for the treatment of solid tumors, however their functionality to date has been hampered by the immunosuppressive tumor microenvironment (TME). Armoring CAR T cells to overcome TME may improve clinical outcomes. We …

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287 Novel, boosted, fully human ROR1-targeting CAR T cells effectively eliminate hematologic and solid tumors, and resist tumor microenvironment

Tri Tran, Bal Krishna Chand Thakuri, Saule Nurmukhambetova, Brittany Steimle et autres

Background Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is widely expressed in various hematologic and solid tumors. A clinical trial employing ROR1-CAR T-cells with scFv-R12 binder showed poor tumor infiltration and dysfunctionality of CAR T-cells in NSCLC & TNBC patients,1 suggesting that …

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mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron

Matthew Gagné, Juan I. Moliva, Kathryn E. Foulds, Shayne F. Andrew et autres

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mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron

Matthew Gagné, Juan I. Moliva, Kathryn E. Foulds, Shayne F. Andrew et autres

Summary SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and …

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