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

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.