Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma

Catalina Lee-Chang*, Jason Miska, David Hou, Aida Rashidi, Peng Zhang, Rachel A. Burga, Ignacio Torres Jusúe, Ting Xiao, Victor A. Arrieta, Daniel Y. Zhang, Aurora Lopez-Rosas, Yu Han, Adam M. Sonabend, Craig M. Horbinski, Roger Stupp, Irina V. Balyasnikova, MacIej S. Lesniak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient-derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

Original languageEnglish (US)
JournalJournal of Experimental Medicine
Volume218
Issue number1
DOIs
StatePublished - Jan 4 2021

Funding

This study was supported by the National Institutes of Health (grants P50CA221747, R35CA197725, R01NS093903, and R01 NS087990; to M.S. Lesniak). C. Lee-Chang received support from the Brain Tumor SPORE Career Enhancement Program (grant P50CA221747). Live animal imaging was performed at the Northwestern University Center for Advanced Microscopy, which is supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Mouse histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is also supported by the National Cancer Institute (grant P30-CA060553; awarded to the Robert H. Lurie Comprehensive Cancer Center). This study was also supported in part by the National Institute of Neurological Disorders and Stroke (grants R33 NS101150 and R01 NS106379 to I.V. Balyasnikova). The Northwestern Nervous System Tumor Bank is supported by the SPORE for Translational Approaches to Brain Cancer (grant P50CA221747). The Flow Cytometry Core Facility is supported by the National Cancer Institute Cancer Center Support Grant CA060553. This study was supported by the National Institutes of Health (grants P50CA221747, R35CA197725, R01NS093903, and R01 NS087990; to M.S. Lesniak). C. Lee-Chang received support from the Brain Tumor SPORE Career Enhancement Program (grant P50CA221747). Live animal imaging was performed at the Northwestern University Center for Advanced Microscopy, which is supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Mouse histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is also supported by the National Cancer Institute (grant P30-CA060553; awarded to the Robert H. Lurie Comprehensive Cancer Center). This study was also supported in part by the National Institute of Neurological Disorders and Stroke (grants R33 NS101150 and R01 NS106379 to I.V. Balyasnikova). The Northwestern Nervous System Tumor Bank is supported by the SPORE for Translational Approaches to Brain Cancer (grant P50CA221747). The Flow Cytometry Core Facility is supported by the National Cancer Institute Cancer Center Support Grant CA060553. Author contributions: C. Lee-Chang and M.S. Lesniak designed the study. C. Lee-Chang, J. Miska, D. Hou, A. Rashidi, P. Zhang, R.A. Burga, I. Jus?e-Torres, V.A. Arrieta, and D.Y. Zhang were involved in acquisition of data. C. Lee-Chang, T. Xiao, and I. Jus?e-Torres performed statistical analysis. C.M. Horbinski performed and interpreted mouse histopathological evaluations. C. Lee-Chang, A.M. Sonabend, R. Stupp, I.V. Balyasnikova, and M.S. Lesniak were involved in interpretation of data. A. Lopez- Rosas was responsible for the mice colonies. Y. Han helped with animal surgery. C. Lee-Chang and M.S. Lesniak prepared the manuscript. Disclosures: C. Lee-Chang and M. Lesniak reported a patent to a B cell-based vaccine for glioma and other cancers, which is pending. No other disclosures were reported.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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