A vector-encoded bispecific killer engager to harness virus-activated NK cells as anti-tumor effectors

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Oncolytic measles vaccines (MV) activate immune cells like natural killer (NK) cells.
• However, MV-activated NK cells exhibit limited direct tumor cell cytotoxicity.
• Targeting NK cells specifically to tumor cells is crucial for effective immunotherapy.

Purpose of the Study:

• To develop and evaluate oncolytic measles vaccines encoding bispecific killer engagers (MV-BiKE).
• To assess MV-BiKE's ability to direct NK cells against tumor cells expressing carcinoembryonic antigen (CEA).
• To demonstrate the potential of MV-BiKE as a novel immunovirotherapy approach.

Main Methods:

• Engineered oncolytic measles virus to express bispecific killer engagers (MV-BiKE) targeting CD16A on NK cells and CEA on tumor cells.
• Tested MV-BiKE in co-cultures of colorectal and pancreatic cancer cells with primary human NK cells.
• Evaluated MV-BiKE efficacy in patient-derived tumor explants and colorectal carcinoma specimens.

Main Results:

• MV-BiKE infected tumor cells secreted functional BiKE, enhancing NK cell effector functions.
• MV-BiKE induced NK cell degranulation, cytokine expression, and specific anti-tumor cytotoxicity.
• Efficacy varied based on tumor virus permissiveness, but activity was confirmed in patient specimens.

Conclusions:

• MV-BiKE represents a proof-of-concept for a novel immunovirotherapy.
• This approach effectively harnesses virus-activated NK cells as targeted anti-tumor effectors.
• MV-BiKE demonstrates potential for treating CEA-expressing cancers like colorectal and pancreatic cancer.