A lentiviral vector targeting a KRAS neoepitope for cancer immunotherapy

Area of Science:

• Oncology
• Immunology
• Gene Therapy

Background:

• Mutated Kirsten rat sarcoma virus (KRAS) is a common oncogenic driver in various cancers, including pancreatic, colorectal, and lung cancers.
• KRAS mutations, particularly at positions 12 or 13, are frequent and drive tumor development, often expressed ubiquitously within tumors.

Purpose of the Study:

• To develop and evaluate novel immuno-oncotherapeutic non-integrative lentiviral vectors targeting KRAS G12D mutations.
• To assess the efficacy of these vectors, alone or with antigen carriers, in controlling tumor growth in preclinical cancer models.

Main Methods:

• Development of non-integrative lentiviral vectors encoding KRAS G12D antigen, with or without antigen carriers.
• Administration of immunotherapy using these vectors in colorectal and pulmonary preclinical cancer models across different murine backgrounds.
• Analysis of tumor growth, intra-tumoral immune cell infiltration (including CD8+ T cells), and combination therapy potential.

Main Results:

• Immunotherapy with the developed vectors demonstrated significant immune control of tumor growth in colorectal and pulmonary models.
• Antitumor effects were correlated with increased intra-tumoral hematopoietic cells, especially CD8+ T cells.
• The approach showed robust, reproducible partial antitumor effects and was combinable with conventional therapies.

Conclusions:

• The developed immuno-oncotherapeutic lentiviral vectors targeting KRAS G12D show promise for treating KRAS-mediated cancers.
• This approach offers a potential strategy to enhance antitumor immunity, particularly when combined with existing treatments.
• Further investigation is warranted to explore the full therapeutic potential in KRAS-driven malignancies.