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Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy

Alexander Benton1, Jiageng Liu2, Mathilde A Poussin3

  • 1Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cancer Cell
|June 6, 2025
PubMed

Insights

This study developed a novel chimeric antigen receptor (CAR)-T cell therapy targeting KRAS G12V mutations in solid tumors. The engineered mKRAS NeoCARs showed efficacy in preclinical models, improving safety and effectiveness.

Area of Science:

  • Oncology
  • Immunotherapy
  • Genetic Engineering

Background:

  • Chimeric antigen receptor (CAR)-T cell therapy shows promise in blood cancers but faces challenges in solid tumors due to efficacy and toxicity.
  • Developing targeted immunotherapies for heterogeneous and immunosuppressive solid tumors requires novel strategies.
  • Oncogenic KRAS mutations, like KRAS G12V, are common drivers in many solid tumors.

Purpose of the Study:

  • To develop and evaluate a novel CAR-T cell therapy targeting oncogenic KRAS G12V mutations in solid tumors.
  • To engineer CAR-T cells with enhanced efficacy and safety profiles for treating metastatic lung, pancreatic, and renal cell cancers.
  • To establish a modular platform for creating advanced cellular immunotherapies against cancer.

Main Methods:

  • Screening of binders targeting KRAS G12V mutations presented by peptide-MHC complexes.
  • Development of KRAS-specific CAR-T cells (mKRAS NeoCARs) incorporating identified binders.
  • Enhancement of in vivo efficacy and safety through inducible IL-12 secretion and T cell receptor deletion in xenograft models.

Main Results:

  • Demonstrated efficacy of mKRAS NeoCARs in xenograft models of metastatic lung, pancreatic, and renal cell cancer.
  • Successfully enhanced the in vivo efficacy and safety profile of mKRAS NeoCARs.
  • Validated a modular platform for developing targeted cancer immunotherapies.

Conclusions:

  • The developed mKRAS NeoCARs represent a promising cellular immunotherapy for KRAS G12V-mutated solid tumors.
  • The combination of neoantigen targeting and genetic engineering enhances the therapeutic index of CAR-T cells.
  • This platform offers a versatile approach for expanding the application of cellular immunotherapies in oncology.
Keywords:
CARTCRISPRIL-12KRAST cellarmored CARcellular immunotherapyneo-antigenpeptidesolid tumorstherapeutic index

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