- |||||||||| Next-generation immunocompetent and humanized neuroblastoma murine models for the discovery and validation of novel immunotherapies (Section 43) - Mar 5, 2024 - Abstract #AACR2024AACR_6550;
We have shown the ability to stably engraft both lymphoid and myeloid populations in various human cytokine transgenic NSG variants (i.e. SGM3, Flt3L), allowing for T/B cell and APC crosstalk, thus providing a robust means to study targeted interventions. We are currently using this autologously humanized PDX model to test the ability of multivalent, personalized neoantigen vaccines developed specific to the neoantigen landscape of individual PDXs, with a focus on endogenous T cell responses of patient PBMC against their own PDX in vivo.
- |||||||||| Neuroblastoma extracellular vesicles present GPC2 and activate GPC2 CAR T cells in an antigen-dependent manner (Section 43) - Mar 5, 2024 - Abstract #AACR2024AACR_6547;
To further capitalize on these findings, we engineered GPC2Hi EVs to have an extended circulation half-life through albumin binding or tumor targeting via GD2 binding that are currently being tested in vivo and results will be reported. EVs offer a versatile platform for CAR antigen presentation and should be further validated as a strategy to enhance CAR T cell efficacy for solid tumors.
- |||||||||| TmGPC2 01 CAR-T / Gilead
Enrollment open, Trial initiation date, CAR T-Cell Therapy: 22CT012: GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma (clinicaltrials.gov) - May 24, 2023
P1, N=30, Recruiting,
Demonstration of GPC2 CAR efficacy in these models could lead to inclusion of RMS in our ongoing phase 1 clinical trial (NCT05650749) in a planned expansion phase. Not yet recruiting --> Recruiting | Initiation date: Oct 2023 --> May 2023
- |||||||||| Journal, IO biomarker: Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors. (Pubmed Central) - Oct 5, 2022
Given the robust preclinical activity of CT3.28H.BBζ, these results form a promising basis for further clinical testing in children with NB. Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.
- |||||||||| Journal, CAR T-Cell Therapy: GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. (Pubmed Central) - Feb 22, 2022
Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.
- |||||||||| Journal, CAR T-Cell Therapy: Development of Glypican-2 Targeting Single-Domain Antibody CAR T Cells for Neuroblastoma. (Pubmed Central) - Feb 22, 2022
We also present a methodology for assessing the efficiency of CAR expression on human T cells and their ability to kill GPC2-positive neuroblastoma cells in vitro and in vivo. The method described here is applicable to the production of CAR T cells derived from all types of sdAbs including VHHs and VNARs.
- |||||||||| Clinical, Review, Journal: Advances in immunotherapeutic targets for childhood cancers: a focus on glypican-2 and B7-H3. (Pubmed Central) - Jan 15, 2022
While cell surface antigens are normally targeted in a major histocompatibility complex (MHC)-independent manner using antibody-based therapies, intracellular antigens are normally targeted with MHC-dependent T cell therapies. Glypican 2 (GPC2) and B7-H3 (CD276) are two cell surface antigens that are expressed by a variety of pediatric tumors such as neuroblastoma and potentially can have a positive impact on the treatment of pediatric cancers in the clinic.
- |||||||||| Preclinical, Journal, CAR T-Cell Therapy: CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice. (Pubmed Central) - Jul 2, 2021
Genomic sequencing of T cells recovered from mice reveals the CAR integration sites that may contribute to CAR T cell proliferation and persistence. These studies demonstrate how RNA-seq data can be exploited to help identify tumor-associated exons that can be targeted by CAR T cell therapies.
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