Preclinical development of CD126 CAR-T cells with broad antitumor activity.
Ameet K MishraIris KemlerDavid DingliPublished in: Blood cancer journal (2021)
Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive partly due to the restricted use of each CAR construct for specific tumors. Thus, a CAR construct with broad antitumor activity can be advantageous. We identified that CD126 is expressed by many hematologic and solid tumors, including multiple myeloma, lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer, and malignant melanoma among others. CAR-T cells targeting CD126 were generated and shown to kill many tumor cells in an antigen-specific manner and with efficiency directly proportional to CD126 expression. Soluble CD126 did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126 but caused no weight loss or hepatotoxicity in mice. In multiple myeloma and prostate adenocarcinoma xenograft models, intravenously injected CD126 CAR-T cells infiltrated within, expanded, and killed tumor cells without toxicity. Binding of soluble interleukin-6 receptor (sIL-6R) by CAR-T cells could mitigate cytokine release syndrome. Murine SAA-3 levels were lower in mice injected with CD126 CAR-T compared to controls, suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic target for CAR-T cells for many tumors with a low risk of toxicity.
Keyphrases
- cell therapy
- acute myeloid leukemia
- prostate cancer
- nk cells
- multiple myeloma
- weight loss
- squamous cell carcinoma
- stem cells
- type diabetes
- oxidative stress
- mesenchymal stem cells
- adipose tissue
- cell death
- bone marrow
- transcription factor
- rectal cancer
- induced apoptosis
- endoplasmic reticulum stress
- cancer therapy
- weight gain
- locally advanced
- young adults
- papillary thyroid