T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity

Sailer, Nadja; Fetzer, Ina; Salvermoser, Melanie; Braun, Monika; Brechtefeld, Doris; Krendl, Christian; Geiger, Christiane; Mutze, Kathrin; Noeßner, Elfriede; Schendel, Dolores J.; Bürdek, Maja; Wilde, Susanne; Sommermeyer, Daniel

doi:10.3390/cancers14081998

Cited by 12 publications

(18 citation statements)

References 50 publications

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“…Like in CAR-T cells, IL-7 and CCL19 were constructed into TCR-T cells to generate potent and durable antitumor immunity when synergizing with PD-1 blockade therapy [108] . Co-expressing PD1-41BB-modified PRAMEspecific TCR-T cells produced strong anti-tumor reactivity in an animal model [109] . After identifying TCR sequences that specifically targeting neoantigens, TCR-T cells were reconstructed so that they are equipped with the potential anti-tumor ability [110] .…”

Section: Improving the Safety And Efficacy Of Tcr-t Cell Therapymentioning

confidence: 95%

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Chen¹,

Li²,

Zhang³

et al. 2022

Gene Protein Dis

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Immunotherapy has achieved significant breakthroughs in patients with hematological diseases and various cancers. The adoptive transfer of T cells, especially gene-modified T cells such as chimeric antigen receptor T (CAR-T) cells and T cell receptor-engineered T (TCR-T) cells, is developing rapidly. Since 2017, eight CAR-T cell products have been approved for the treatment of hematological diseases, such as refractory or relapsed acute B lymphoblastic leukemia, specific subtypes of B cell lymphoma, and multiple myeloma. The first TCR-T cell product, Kimmtrak, was approved for the treatment of unresectable or metastatic uveal melanoma in March 2022. However, there are still many problems, including side effects, relapse, high demand for individualization, and expensive cost in hematological diseases, tumor heterogeneity, antigen escape, poor immune cell infiltration ability, immunosuppressive microenvironment, and low response in solid tumors. With the in-depth exploration of tumor immunology and the development of genetic engineering technology, many novel strategies for improving the anti-tumor effect and safety of gene-modified T cell immunotherapy have been attempted. This paper presents a systematic review of the literature on CAR-T cell and TCR-T cell therapy, focusing on applications, clinical trials, problems, and potential solutions.

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Section: Improving the Safety And Efficacy Of Tcr-t Cell Therapymentioning

confidence: 95%

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Chen¹,

Li²,

Zhang³

et al. 2022

Gene Protein Dis

View full text Add to dashboard Cite

show abstract

“…reported transducing a chimeric PD1-41BB receptor can enhance IFN-γ secretion, improve cytotoxic capacity, and prevent exhaustion in vitro without changing safety. Moreover, the addition of PD1-41BB could eradicate refrectory melanoma in mice that was resistant to TCR-T cells without PD1-41BB ( 101 ). The study supports the development of similar PRAME specific TCR-T cells for AML.…”

Section: Adoptive Immunotherapymentioning

confidence: 99%

Targeting PRAME for acute myeloid leukemia therapy

Yang,

Chen,

et al. 2024

Front. Immunol.

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Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit disease characteristics, and patients with adverse disease risk characteristics. Over the past 10 years, adaptive T-cell immunotherapy has been recognized as a strategy for treating various malignant tumors. However, it has faced significant challenges in AML, primarily because myeloid blasts do not contain unique surface antigens. The preferentially expressed antigen in melanoma (PRAME), a cancer-testis antigen, is abnormally expressed in AML and does not exist in normal hematopoietic cells. Accumulating evidence has demonstrated that PRAME is a useful target for treating AML. This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up, and its use in antigen-specific immunotherapy for AML.

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“…The cancer/testis antigen Preferentially Expressed Antigen in Melanoma (PRAME) is an encouraging target for TCR-Ts because it is highly expressed in several solid tumors and its expression in normal tissues is mainly restricted to the testis [77][78][79][80][81]. Recently, researchers combined the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB (PD-1-41BB) with PRAME-TCR to create an innovative product that repurposes an inhibitory pathway into a T-cell co-stimulatory pathway [82]. They cocultured MelA375_PD-L1 tumor cells with TCR-T cells with and without PD-1-41BB, and then profiled TCR-T cells by using the 32-plex human adaptive immune panel.…”

Section: T-cell Receptor (Tcr)-modified T-cell (Tcr-t) Is Another Pro...mentioning

confidence: 99%

Applying single‐cell highly multiplexed secretome proteomics to characterize immunotherapeutic products and predict clinical responses

Han

Cyr

et al. 2023

Proteomics

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Genetically and phenotypically identical immune cell populations can be highly heterogenous in terms of their immune functions and protein secretion profiles. The microfluidic chip-based single-cell highly multiplexed secretome proteomics enables characterization of cellular heterogeneity of immune responses at different cellular and molecular layers. Increasing evidence has demonstrated that polyfunctional T cells that simultaneously produce 2+ proteins per cell at the single-cell level are key effector cells that contribute to the development of potent and durable cellular immunity against pathogens and cancers. The functional proteomic technology offers a wide spectrum of cellular function assessment and can uniquely define highly polyfunctional cell subsets with cytokine signatures from live individual cells. This highdimensional single-cell analysis provides deep dissection into functional heterogeneity and helps identify predictive biomarkers and potential correlates that are crucial for immunotherapeutic product design optimization and personalized immunotherapy development to achieve better clinical outcomes.

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T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity

Cited by 12 publications

References 50 publications

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Targeting PRAME for acute myeloid leukemia therapy

Applying single‐cell highly multiplexed secretome proteomics to characterize immunotherapeutic products and predict clinical responses

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