Coexpression of IL15 Promotes Effector Differentiation and Sustained Proliferative Capacity in ALPPL2-Specific Human...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cells demonstrate efficacy in hematologic cancers but face challenges in solid tumors, including immune rejection and limited persistence.
• Murine protein recognition and the tumor microenvironment's lack of homeostatic cytokines hinder CAR T-cell expansion and survival.
• Utilizing fully human CAR sequences and incorporating cytokines like interleukin-15 (IL15) can potentially overcome these limitations.

Purpose of the Study:

• To develop and evaluate a fully human CAR T-cell construct targeting the antigen ALPPL2 for solid tumor therapy.
• To investigate the impact of co-expressing IL15 on the expansion, persistence, and effector function of human ALPPL2-specific CAR T cells.

Main Methods:

• A human antibody-derived phage-displayed scFv library was screened to identify a binder specific to ALPPL2, forming the basis of the ABBz CAR construct.
• ABBz CAR T cells were engineered with or without co-expressed IL15.
• Antigen specificity, cytolytic function, cytokine production, NK-like effector differentiation, proliferative capacity, and antitumor activity in vitro and in vivo were assessed.

Main Results:

• The ABBz CAR construct, derived from human sequences, demonstrated antigen specificity and effective cytotoxic function.
• Co-expression of IL15 induced NK-like effector differentiation in ABBz CAR T cells, enhancing proliferative capacity and reducing apoptosis.
• ABBz CAR T cells exhibited robust antitumor activity, which was significantly augmented by IL15 co-expression, leading to improved cytotoxicity and expansion.

Conclusions:

• Co-expression of IL15 promotes effector differentiation and enhances the proliferative capacity of human ALPPL2-CAR T cells.
• The developed huALPPL2-CAR T cells, particularly with IL15 co-expression, show promising antitumor activity and potential for clinical development in solid tumors.