Enhanced solid tumor cell targeting by a neoepitope-encoding oncolytic measles virus combined with CAR therapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Solid tumor treatment faces challenges from the tumor microenvironment (TME) and lack of specific antigens.
• Cellular therapies like CAR-T cells are effective against hematological malignancies but struggle with solid tumors.
• Identifying and targeting unique tumor antigens is crucial for effective solid tumor immunotherapy.

Purpose of the Study:

• To investigate a novel octapeptide neoepitope derived from MICB for solid tumor targeting.
• To develop and evaluate chimeric antigen receptor (CAR) constructs for enhanced T and NK cell activity against solid tumors.
• To explore the synergistic potential of combining neoepitope-based CAR therapy with oncolytic virotherapy.

Main Methods:

• Generated and characterized high-affinity antibodies against a specific octapeptide neoepitope.
• Engineered CAR constructs with optimized linker designs for improved antigen accessibility and cell surface expression.
• Utilized oncolytic measles virus (MV) as a vector to deliver the neoepitope and enhance CAR-T/NK cell-mediated cytotoxicity.

Main Results:

• CAR constructs demonstrated antigen-specific cytotoxicity against tumor cells, with improved efficacy using a rigid linker.
• Oncolytic MV selectively infected tumor cells, enhancing the antitumor activity of CAR-T cells.
• Combined CAR-T/NK cell therapy with MV infection resulted in increased immune cell persistence and potent, sustained antitumor effects.

Conclusions:

• Neoepitope-based CAR therapy holds significant potential for targeting solid tumors.
• Combining cell therapy with virotherapy offers a synergistic approach for enhanced and durable antitumor responses.
• This strategy represents a promising avenue for overcoming solid tumor treatment challenges.