Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• Targeting co-stimulatory receptors like 4-1BB (CD137/TNFSF9) enhances anti-tumor lymphocyte function.
• Agonistic antibodies targeting 4-1BB show therapeutic promise in clinical trials.
• The 4-1BB ligand (4-1BBL) plays a crucial role in T cell activation and effector functions.

Purpose of the Study:

• To evaluate engineered soluble 4-1BBL formats for their ability to induce 4-1BB co-stimulation.
• To assess the therapeutic potential of s4-1BBL-TriXVIII as an immunomodulatory payload in oncolytic viruses.
• To investigate the efficacy of oncolytic measles virus encoding s4-1BBL-TriXVIII in a humanized mouse model.

Main Methods:

• Utilized a T cell reporter system to assess 4-1BBL variants.
• Engineered a soluble 4-1BBL ectodomain with a collagen-derived trimerization domain (s4-1BBL-TriXVIII).
• Constructed oncolytic measles viruses encoding s4-1BBL-TriXVIII and evaluated their anti-tumor activity in a CD34+ humanized mouse model.

Main Results:

• s4-1BBL-TriXVIII demonstrated potent induction of 4-1BB co-stimulation and T cell proliferation, comparable to the agonistic antibody urelumab.
• Oncolytic measles viruses encoding s4-1BBL-TriXVIII significantly reduced tumor burden.
• Measles viruses without s4-1BBL-TriXVIII showed no significant anti-tumor effect.

Conclusions:

• Engineered soluble 4-1BBL, specifically s4-1BBL-TriXVIII, is a potent stimulator of 4-1BB co-stimulation and T cell responses.
• s4-1BBL-TriXVIII serves as an effective immunomodulatory payload for therapeutic viral vectors, particularly oncolytic viruses.
• Targeted delivery of 4-1BBL, such as via oncolytic viruses, may offer a promising strategy for tumor therapy, warranting further investigation into potential systemic toxicities like liver toxicity.