Lenalidomide improves the antitumor activity of CAR-T cells directed toward the intracellular Wilms Tumor 1 antigen.

Abstract

OBJECTIVES:

CAR-based immunotherapies represent a potentially curative strategy for hematological malignancies. However, there are a number of intracellular antigens that CAR-T cells are unable to target. Furthermore, CAR-T cells often suffer from insufficient expansion in part because of the immunosuppressive mechanisms. Lenalidomide (LEN), an immunomodulatory drug, can potentiate T cell functionality. Therefore, it is necessary to investigate combinatorial therapy using CAR-T cells and LEN for enhancing function.

METHODS:

We redirected T cells to express HLA-A*2402+-restricted-CAR capable of recognizing WT1235-243 peptide and adoptively transferred them into tumor-bearing mice to test their anti-tumor activity. Then we assessed the combinatorial efficacy using CAR-T cells and LEN in vitro and in vivo.

RESULTS:

Using an anti-WT1 CAR-T, we showed that LEN enhances CAR-T cell function in a concentration-dependent manner. Our data demonstrated that LEN improved the anti-tumor activity of CAR-T cells in vivo by increasing the infiltration of tumors with CD3+ and CD8+ T cells. Proteomics studies supported LEN enhanced the efficacy of CAR-T cells, including T-cell activation, mitochondrial activity and immune synapse formation.

CONCLUSION:

These results demonstrate that lenalidomide potentiates WT1 CAR-T activity and paves the way to evaluate the combination of LEN with CAR-T for a planned clinical trial.

• Authors: Li Zhang, Guangyi Jin, Ziren Chen, Changhua Yu, Yonghui Li, Yisheng Li, Jinghong Chen, Li Yu
• Journal: Hematology (Amsterdam, Netherlands) (Hematology) Vol. 26 Issue 1 Pg. 818-826 (Dec 2021) ISSN: 1607-8454 [Electronic] England
• PMID: 34674611 (Publication Type: Journal Article)

Chemical References

• Immunologic Factors
• WT1 Proteins
• Lenalidomide

Topics

• Animals
• Hematologic Neoplasms (immunology, therapy)
• Humans
• Immunologic Factors (therapeutic use)
• Immunotherapy, Adoptive (methods)
• K562 Cells
• Lenalidomide (therapeutic use)
• Lymphocyte Activation (drug effects)
• Mice
• WT1 Proteins (immunology)