KRAS^G12V/HLA-A*02:01-targeted chimeric antigen receptor T cells exhibit potent preclinical activity against solid...

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Chimeric antigen receptor T cell (CAR T cell) therapy has shown success in blood cancers but faces challenges in solid tumors due to target specificity and safety.
• KRAS^G12V is a prevalent, undruggable mutation in solid tumors, offering a potential tumor-exclusive target.

Purpose of the Study:

• To develop and evaluate CAR T cells targeting the KRAS^G12V neoantigen in the context of the HLA-A*02:01 allele for solid tumor treatment.

Main Methods:

• Phage antibody display was used to identify high-affinity single-chain variable fragments against KRAS^G12V/HLA-A*02:01.
• Engineered B9 CAR T cells were tested for their ability to lyse tumor cells and patient-derived cancer organoids.
• In vivo efficacy and safety were assessed in mouse models of pancreatic ductal adenocarcinoma (PDAC).

Main Results:

• B9 CAR T cells demonstrated specific lysis of KRAS^G12V/HLA-A*02:01-expressing tumor cells and organoids.
• Significant control of tumor growth was observed in various PDAC mouse models, including subcutaneous, metastatic, and peritoneal models.
• No detectable in vivo toxicity was observed in safety assessments in mice.

Conclusions:

• Neoantigen-targeted CAR T cell therapy against KRAS^G12V/HLA-A*02:01 shows potent antitumor activity and a favorable safety profile.
• This approach holds significant potential for clinical translation in patients with KRAS^G12V-mutated solid tumors.