Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86-Positive B Cell Malignancies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor T (CAR T) cell therapy shows promise for hematological malignancies but faces challenges in solid tumors due to inhibitory microenvironments.
• Immune checkpoints, like CTLA4, often suppress T-cell function within the tumor microenvironment.

Purpose of the Study:

• To develop a novel CAR T-cell strategy by repurposing the immune checkpoint molecule CTLA4 to enhance anti-tumor activity against solid tumors.
• To investigate the efficacy and safety of CTLA4-modified CAR T cells (CTLA4-CAR T) in preclinical models.

Main Methods:

• Engineered novel CAR T cells (CTLA4-CAR T) using extracellular and transmembrane domains of CTLA4 combined with CD28 and CD3z cytoplasmic domains.
• Evaluated CTLA4-CAR T cell function, including cytokine secretion and cytotoxicity, in vitro and in vivo using xenograft models.

Main Results:

• CTLA4-CAR T cells demonstrated enhanced cytokine secretion and potent cytotoxicity against tumor cells.
• These engineered T cells effectively accumulated within tumors and showed toxicity towards myeloid-derived suppressor cells (MDSCs).
• Preclinical models showed no signs of severe graft-versus-host disease (GVHD) or cytokine release syndrome (CRS).

Conclusions:

• The developed chimeric CTLA4-CAR effectively enhances CAR T-cell antitumor activity.
• This strategy offers a promising approach for targeting the immunomodulatory tumor microenvironment in solid tumors using armed CAR T cells.