Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma.

Abstract

Background:

Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric antigen receptor (CAR) T cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of 2 glioma antigens offsets antigen escape and enhances T-cell effector functions, the interpatient variability in surface antigen expression between patients hinders the clinical impact of targeting 2 antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application.

Methods:

We analyzed the surface expression of 3 targetable glioma antigens (human epidermal growth factor receptor 2 [HER2], interleukin-13 receptor subunit alpha-2 [IL13Rα2], and ephrin-A2 [EphA2]) in 15 primary GBM samples. Accordingly, we created a trivalent T-cell product armed with 3 CAR molecules specific for these validated targets encoded by a single universal (U) tricistronic transgene (UCAR T cells).

Results:

Our data showed that co-targeting HER2, IL13Rα2, and EphA2 could overcome interpatient variability by a tendency to capture nearly 100% of tumor cells in most tumors tested in this cohort. UCAR T cells made from GBM patients' blood uniformly expressed all 3 CAR molecules with distinct antigen specificity. UCAR T cells mediated robust immune synapses with tumor targets forming more polarized microtubule organizing centers and exhibited improved cytotoxicity and cytokine release over best monospecific and bispecific CAR T cells per patient tumor profile. Lastly, low doses of UCAR T cells controlled established autologous GBM patient derived xenografts (PDXs) and improved survival of treated animals.

Conclusion:

UCAR T cells can overcome antigenic heterogeneity in GBM and lead to improved treatment outcomes.

• Authors: Kevin Bielamowicz, Kristen Fousek, Tiara T Byrd, Hebatalla Samaha, Malini Mukherjee, Nikita Aware, Meng-Fen Wu, Jordan S Orange, Pavel Sumazin, Tsz-Kwong Man, Sujith K Joseph, Meenakshi Hegde, Nabil Ahmed
• Journal: Neuro-oncology (Neuro Oncol) Vol. 20 Issue 4 Pg. 506-518 (03 27 2018) ISSN: 1523-5866 [Electronic] England
• PMID: 29016929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-13 Receptor alpha2 Subunit
• Receptors, Antigen, T-Cell
• ERBB2 protein, human
• Receptor, EphA2
• Receptor, ErbB-2

Topics

• Animals
• Antigenic Variation (immunology)
• Apoptosis
• Cell Proliferation
• Glioblastoma (immunology, metabolism, pathology)
• Humans
• Interleukin-13 Receptor alpha2 Subunit (immunology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Receptor, EphA2 (immunology)
• Receptor, ErbB-2 (immunology)
• Receptors, Antigen, T-Cell (immunology)
• T-Lymphocytes (immunology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays