CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma.

Larson, Sarah; Walthers, Christopher M.; Ji, Brenda; Ghafouri, Sanaz N.; Naparstek, Jacob; Trent, Jacqueline; Harris, Caitlin; Khericha, Mobina; Schweppe, Thomas; Auerbach, Martin; Said, Jonathan W.; Nawaly, Karla; Mead, Monica; Vos, Sven de; Young, Patricia A.; Oliai, Caspian; Schiller, Gary J.; Timmerman, John M.; Ribas, Antoni; Chen, Yvonne Y.

doi:10.1200/jco.2022.40.16_suppl.2543

Cited by 8 publications

(8 citation statements)

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“…Having a more consistent and favorable phenotype (higher expression of CD62L, CCR7, and CD27) of the nal product across all patients may have contributed to the observed higher CAR T detection in blood and increased survival for Arm 5. This is consistent with previous reports of Tn/mem-derived CAR T cell products outperforming Tcm-derived CAR T cell products and mediating encouraging clinical bene t against hematological tumors 18, 19,21,23 .…”

Section: Discussionsupporting

confidence: 92%

“…In addition, two manufacturing platforms were evaluated differing in T cell subsets enriched for CAR engineering: Arms 1-4 utilized CD62L+, CD45RA-central memory T cells (Tcm); and Arm 5 utilized CD62L + enriched naïve, stem cell memory, and central memory T cells (Tn/mem). This manufacturing change was based on challenges with generating su cient Tcm-derived CAR products for treating at the highest dose schedule (DS3), along with data suggesting superior preclinical and clinical activity against hematological cancers by Tn/mem-derived CAR T cell products [18][19][20][21][22][23] .…”

Section: Trial Design and Patient Characteristicsmentioning

confidence: 99%

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Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Brown,

Hibbard,

Alizadeh

et al. 2023

Preprint

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Chimeric antigen receptor (CAR) T cell therapy is at early stages of clinical testing for solid tumors. We report here a completed phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM; 2 + recurrences). Primary endpoints were safety and feasibility, with secondary endpoints measuring therapy-related bioactivity. Weekly intratumoral (ICT) and/or intraventricular (ICV) administration of IL13Rα2-CAR T cells was well-tolerated with clinically manageable adverse events. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off-protocol therapy. Patients with rGBM treated with dual ICT/ICV delivery and an optimized manufacturing process exhibited superior overall median survival of 10.2 months, compared to 6.1 months for other treatment arms. Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, indicating an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Trial Design and Patient Characteristicsmentioning

confidence: 99%

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Brown,

Hibbard,

Alizadeh

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…1a ). The protocol was amended to include the Tn/mem manufacturing platform (arm 5) based on data suggesting superior activity against hematological malignancies for Tn/mem- versus Tcm-derived CAR-T cell products 22 – 27 , along with feasibility challenges with generating sufficient Tcm-derived CAR products for the highest dose schedule (DS3) in arm 4 (refs. 22 – 27 ).…”

Section: Resultsmentioning

confidence: 99%

“…The protocol was amended to include the Tn/mem manufacturing platform (arm 5) based on data suggesting superior activity against hematological malignancies for Tn/mem- versus Tcm-derived CAR-T cell products 22 – 27 , along with feasibility challenges with generating sufficient Tcm-derived CAR products for the highest dose schedule (DS3) in arm 4 (refs. 22 – 27 ). Arm 5, (Tn/mem manufacturing and dual ICT/ICV delivery), therefore, represents the foundation for ongoing and future clinical testing ( NCT04003649 , NCT04510051 and NCT04661384 ).…”

Section: Resultsmentioning

confidence: 99%

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

Brown,

Hibbard,

Alizadeh

et al. 2024

Nat Med

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Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362.

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“…Similarly, CD123/CD19 dual-CAR and CD20/CD19 bi-specific tandem CAR T cells prevented escape of CD19-negative disease 10,11 . However, clinical trials have documented escape of antigen-low or multi-antigen-negative B cell leukemia and lymphoma populations following treatment with tandem CAR and dual-CAR T cells or sequential infusions of different singleantigen-targeting CAR T cells [12][13][14][15] . These findings suggest that T cells possessing greater than two antigen specificities may better resist escape of antigen-negative or antigen-low tumor cells.…”

mentioning

confidence: 99%

Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

James,

Chen,

et al. 2023

Preprint

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Resistance to chimeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms including antigen-loss escape and tumor-induced immune suppression. Expression of multiple CARs may overcome multi-antigen-loss escape. Similarly, expression of switch receptors that convert inhibitory immune checkpoint signals into positive costimulatory signals may enhance CAR T cell activity in the tumor microenvironment. Engineering multiple features into one cell product, however, is limited by transgene packaging constraints of current vector systems. Here, we describe a leucine zipper-based cell sorting methodology that enables selective single-step immunomagnetic purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This “Zip-sorting” system facilitated generation of T cells simultaneously expressing up to four CARs and co-expressing up to three switch receptors. These multi-CAR multi-Switch receptor arrays enabled T cells to eliminate antigenically heterogeneous syngeneic leukemia populations co-expressing multiple inhibitory ligands. Zip-sorted multi-CAR multi-Switch receptor T cells represent a potent therapeutic strategy to overcome multiple mechanisms of CAR T cell resistance.

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CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma.

Cited by 8 publications

References 0 publications

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

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