Unlabelled: Chimeric antigen receptor (CAR) T cells are efficacious in patients with B-cell malignancies, while their activity is limited in patients with solid tumors. We developed a novel heterodimeric TCR-like CAR (TCAR) designed to achieve optimal chain pairing and integration into the T-cell CD3 signaling complex. The TCAR mediated high antigen sensitivity and potent antigen-specific T-cell effector functions in short-term assays. Both persistence and functionality of TCAR T cells were augmented by provision of costimulatory signals, which improved proliferation and . Combination with a nanoparticulate RNA vaccine, developed for expansion of CAR T cells, promoted tightly controlled expansion, survival, and antitumor efficacy of TCAR T cells .
Significance: A novel TCAR is tightly controlled by RNA vaccine-mediated costimulation and may provide an alternative to second-generation CARs for the treatment of solid tumors.
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http://dx.doi.org/10.1158/2767-9764.CRC-21-0154 | DOI Listing |
Int J Mol Sci
December 2024
Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing a recombinant complete TCR (TCR-T cell), a chimeric antigen receptor (CAR) with the variable domains of a neoepitope-reactive TCR as a binding domain (TCR-CAR-T cell) or a TCR-like antibody as a binding domain (TCR-like CAR-T cell). Furthermore, the synthetic T cell receptor and antigen receptor (STAR) and heterodimeric TCR-like CAR (T-CAR) are designed as a double-chain TCRαβ-based receptor with variable regions of immunoglobulin heavy and light chains (VH and VL) fused to TCR-Cα and TCR-Cβ, respectively, resulting in TCR signaling.
View Article and Find Full Text PDFFront Immunol
December 2024
Laboratory of Molecular Immunology and Immunotherapy, Faculty of Biology Technion - Israel Institute of Technology, Haifa, Israel.
The clinical success of cancer immunotherapy has driven ongoing efforts to identify novel targets that can effectively guide potent effector functions to eliminate malignant cells. Traditionally, immunotherapies have focused on surface antigens; however, these represent only a small fraction of the cancer proteome, limiting their therapeutic potential. In contrast, the majority of proteins within the human proteome are intracellular, yet they are represented on the cell surface as short peptides presented by MHC class I molecules.
View Article and Find Full Text PDFCurr Opin Biotechnol
December 2024
Nextera AS, Gaustadalléen 21, N-0349 Oslo, Norway. Electronic address:
A major prevailing challenge limiting our ability to fully harness the potential of the latest-generation therapeutic antibodies is the scarcity of clinically established disease-specific targets. A major next step forward will therefore be to expand this target space. The recent clinical success of immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibition, and chimeric antigen receptor (CAR) T-cell therapy strongly supports focusing on the immunopeptidome of peptides presented by human leukocyte antigen (pHLA) that are normally surveilled by T-cell receptors (TCRs).
View Article and Find Full Text PDFRes Sq
April 2024
Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes.
View Article and Find Full Text PDFHu8F4 is a T cell receptor (TCR)-like antibody with high affinity for leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is comprised of the Hu8F4 scFv, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain, and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from AML patients .
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