Membrane-bound IL-15 co-expression powers a potent and persistent CD70-targeted TRuC T-cell therapy

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• T-cell immunotherapies show promise for hematological malignancies but face challenges in solid tumors due to immunosuppressive microenvironments and limited target antigens.
• CD70, a ligand overexpressed in several solid tumors with limited healthy tissue expression, is a potential immunotherapeutic target.

Purpose of the Study:

• To describe the generation and preclinical characterization of ADP-520, a CD70-targeted T-cell receptor fusion construct (TRuC) T-cell therapy.
• To evaluate the efficacy of ADP-520, enhanced with membrane-bound IL-15 (mbIL-15), in overcoming solid tumor treatment challenges.

Main Methods:

• ADP-520 TRuC T cells were engineered with fratricide resistance and co-expressed mbIL-15.
• Phenotypic distribution, expansion, persistence, exhaustion resistance, and anti-tumor potency were assessed in vitro and in vivo.
• TCR and IL-15 signaling pathway contributions were analyzed using inhibition assays.

Main Results:

• ADP-520 demonstrated potent, antigen-specific activity against CD70-expressing hematological and solid tumors without fratricide.
• mbIL-15 co-expression enhanced T-cell expansion, persistence, and exhaustion resistance, improving tumor infiltration and antitumor efficacy.
• ADP-520 exhibited tumor-autonomous, exogenous cytokine-free persistence and bolstered resistance to chronic stimulation.

Conclusions:

• ADP-520 is a first-in-class, CD70-targeted, fratricide-resistant TRuC T-cell therapy combining TCR and constitutive IL-15 signaling.
• The therapy enhances T-cell persistence, tumor penetration, and antitumor efficacy, addressing key challenges in solid tumor treatment.
• ADP-520 represents a promising candidate for clinical development in solid tumor immunotherapy.