Related Experiment Video

Updated: Jun 30, 2026

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
12:04

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells

Published on: March 10, 2023

Dual-degenerate TCRs target multiple KRAS hotspot and HLA-A3 family combinations

Minying Zhang1, Barbara Nassif Rausseo1, Peixin Jiang1

  • 1The University of Texas MD Anderson Cancer Center.

Research Square
|June 29, 2026
PubMed

Insights

Researchers engineered T cell receptors (TCRs) to target KRAS mutations in lung cancer. These novel TCRs successfully identified and destroyed cancer cells, showing promise for KRAS-targeted immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Oncogenic KRAS mutations are prevalent in lung adenocarcinoma, correlating with poor patient prognosis.
  • KRAS mutations, particularly G12C, G12V, and G12D, represent a significant therapeutic target.
  • Cellular immunotherapy offers a promising strategy for targeting KRAS-driven lung cancers.

Purpose of the Study:

  • To develop novel T cell receptors (TCRs) targeting KRAS G12C and G12V mutations in lung adenocarcinoma.
  • To validate the efficacy and specificity of these TCRs in recognizing and eliminating tumor cells.
  • To explore the potential for broad applicability of TCR-based therapies by assessing cross-reactivity.

Main Methods:

  • Development of HLA-A*03:01- and HLA-A*11:01-restricted TCRs against KRAS G12C and G12V hotspot mutations.
  • Screening of high-affinity peptides using a TCR discovery and validation pipeline.
  • Functional assessment of TCR-engineered T cells for sensitivity, specificity, and cytotoxic activity.

Main Results:

  • Five novel TCRs targeting KRAS G12C and G12V 9-mers were discovered and validated.
  • TCRs demonstrated the ability to recognize and lyse lung tumor cells presenting endogenous mutant KRAS.
  • Several TCRs exhibited cross-reactivity across different KRAS G12 variants and/or HLA types, expanding potential patient populations.
  • KRAS hotspot shared sequence motifs recognized by TCRs were identified in lung cancer patients.

Conclusions:

  • Successful generation of multi-valent KRAS-specific TCRs targeting common lung cancer mutations.
  • Demonstrated feasibility of targeting shared KRAS neoantigens via TCR engineering for lung cancer treatment.
  • Highlights the potential of TCR-based immunotherapy for KRAS-mutated lung adenocarcinomas.

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