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Updated: Jan 8, 2026
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
A KRASG12V-targeted bispecific T cell engager promotes immunity against colorectal solid tumor
Nhan Huynh1,2, Thu-My Thi Nguyen1,2, Ngoc Thi Bui1,2
1Medical Genetics Institute, Ho Chi Minh City 740500, Vietnam.
Abstract:
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been detected at high rates in various tumor types, making them one of the most commonly mutated oncogenes. Limited relevant binding pockets have rendered these mutants undruggable for many decades, particularly the KRASG12V mutant. Recent advances in T cell receptor (TCR) profiling have provided a new strategy for overcoming this limitation by recognizing neoantigens presented by human lymphocyte antigen (HLA) and inducing T cell-mediated killing responses. Using the previously identified KRASG12V-targeting TCR, we engineered bispecific T cell engager receptors (TCERs) with high efficiency and specificity for the KRASG12V/HLA-A∗11:01 tetramer. Specifically, TCER01 and TCER02 effectively induced T cell-mediated tumor killing in 2D and 3D in vitro models of solid colorectal tumor cells. The binding and functional assessment of TCER01 and TCER02 exhibited high specificity for the KRASG12V 9-mer peptide while showing minimal cross-reactivity to other homologs. TCER01 activity is unique for HLA-A∗11:01, which is distinct from other KRASG12V-presenting HLAs. Our study proposes a potential new therapeutic option for KRASG12V colorectal cancer and extends our knowledge for developing TCER-based tumor immunotherapies.
Insights
Engineered T cell receptor engagers (TCERs) specifically target KRASG12V mutations in colorectal cancer. These novel therapies demonstrate potent tumor cell killing, offering a promising new treatment avenue for KRASG12V-mutated cancers.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are prevalent in many cancers, with the KRASG12V mutant historically being undruggable.
- T cell receptor (TCR) profiling offers a novel approach to target cancer neoantigens presented by human lymphocyte antigen (HLA).
Purpose of the Study:
- To engineer bispecific T cell engager receptors (TCERs) targeting the KRASG12V neoantigen presented by HLA-A∗11:01.
- To evaluate the efficacy and specificity of these TCERs in preclinical models of KRASG12V-mutated colorectal cancer.
Main Methods:
- Utilized a previously identified KRASG12V-targeting TCR to engineer TCERs (TCER01 and TCER02).
- Assessed TCER binding specificity for the KRASG12V/HLA-A∗11:01 tetramer and KRASG12V 9-mer peptide.
- Evaluated T cell-mediated tumor killing in 2D and 3D in vitro colorectal cancer models.
Main Results:
- Engineered TCER01 and TCER02 demonstrated high efficiency and specificity for the KRASG12V/HLA-A∗11:01 tetramer.
- TCERs effectively induced T cell-mediated killing of KRASG12V-mutated colorectal tumor cells in vitro.
- TCER01 and TCER02 showed high specificity for the KRASG12V peptide with minimal cross-reactivity, and TCER01 activity was unique to HLA-A∗11:01.
Conclusions:
- Engineered TCERs represent a potential new therapeutic strategy for KRASG12V-mutated colorectal cancer.
- This study advances the development of TCER-based immunotherapies for KRASG12V-driven malignancies.
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