B cell–based therapy produces antibodies that inhibit glioblastoma growth

Si Wang; Brandyn A. Castro; Joshua L. Katz; Victor Arrieta; Hinda Najem; Gustavo I. Vazquez-Cervantes; Hanxiao Wan; Ian E. Olson; David Hou; Mark Dapash; Leah K. Billingham; Tzu Yi Chia; Chao Wei; Aida Rashidi; Leonidas C. Platanias; Kathleen McCortney; Craig M. Horbinski; Roger Stupp; Peng Zhang; Atique U. Ahmed; Adam M. Sonabend; Amy B. Heimberger; Maciej S. Lesniak; Cécile Riviere-Cazaux; Terry Burns; Jason Miska; Mariafausta Fischietti; Catalina Lee-Chang

doi:10.1172/JCI177384

B cell–based therapy produces antibodies that inhibit glioblastoma growth

Si Wang, Brandyn A. Castro, Joshua L. Katz, Victor Arrieta, Hinda Najem, Gustavo I. Vazquez-Cervantes, Hanxiao Wan, Ian E. Olson, David Hou, Mark Dapash, Leah K. Billingham, Tzu Yi Chia, Chao Wei, Aida Rashidi, Leonidas C. Platanias, Kathleen McCortney, Craig M. Horbinski, Roger Stupp, Peng Zhang, Atique U. AhmedAdam M. Sonabend, Amy B. Heimberger, Maciej S. Lesniak, Cécile Riviere-Cazaux, Terry Burns, Jason Miska, Mariafausta Fischietti^*, Catalina Lee-Chang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the B_Vax (B cell–based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of B_Vax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that B_Vax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by B_Vax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of B_Vax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

Original language	English (US)
Article number	e177384
Journal	Journal of Clinical Investigation
Volume	134
Issue number	20
DOIs	https://doi.org/10.1172/JCI177384
State	Published - Oct 15 2024

Funding

BC is supported by the Neurosurgery Research and Education Foundation (NREF), the Stach Strong Foundation, and the Glioblastoma Foundation. CLC is supported by National Cancer Institute (NCI), NIH (R37CA258426 and P50CA221747) and the Cancer Research Institute (CR68036). MSL is supported by the NCI, NIH (P50CA221747 and R35CA197725) and the National Institute of Neurological Diseases (NINDS), NIH (R01NS115955) DH is supported by the American Brain Tumor Association (ABTA) Jack and Fay Netchin Medical Student Fellowship in honor of Paul Fabbri and a Northwestern RISE research fellowship award. CRC is supported by the NIH (T32 GBM145408). TCB is supported by the NCI, NIH (R37 CA276851). The authors of this project are supported by the Cancer Research Institute and the Mal-nati Brain Tumor Institute. The Northwestern Nervous System Tumor Bank is supported by the Specialized Program of Research Excellence (SPORE) for Translational Approaches to Brain Cancer (P50CA221747). The spatial multiplex analysis is supported by NIH grants CA120813 and NS120547. The Flow Cytometry Core Facility is supported by a NCI Cancer Center Support grant (CA060553). Proteomics services were performed by the North-western Proteomics Core Facility, generously supported by a grant from the NCI, NIH (CCSG P30 CA060553), awarded to the Robert H. Lurie Comprehensive Cancer Center; an instrumentation award (S10OD025194) from NIH Office of the Director; and the National Resource for Translational and Developmental Proteomics, supported by P41 GM108569. The Mayo Clinic Cancer Center is supported by the NCI, NIH (P30 CA15083). BC is supported by the Neurosurgery Research and Education Foundation (NREF), the Stach Strong Foundation, and the Glioblastoma Foundation. CLC is supported by National Cancer Institute (NCI), NIH (R37CA258426 and P50CA221747) and the Cancer Research Institute (CR68036). MSL is supported by the NCI, NIH (P50CA221747 and R35CA197725) and the National Institute of Neurological Diseases (NINDS), NIH (R01NS115955) DH is supported by the American Brain Tumor Association (ABTA) Jack and Fay Netchin Medical Student Fellowship in honor of Paul Fabbri and a Northwestern RISE research fellowship award. CRC is supported by the NIH (T32 GBM145408). TCB is supported by the NCI, NIH (R37 CA276851). The authors of this project are supported by the Cancer Research Institute and the Malnati Brain Tumor Institute. The Northwestern Nervous System Tumor Bank is supported by the Specialized Program of Research Excellence (SPORE) for Translational Approaches to Brain Cancer (P50CA221747). The spatial multiplex analysis is supported by NIH grants CA120813 and NS120547. The Flow Cytometry Core Facility is supported by a NCI Cancer Center Support grant (CA060553). Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by a grant from the NCI, NIH (CCSG P30 CA060553), awarded to the Robert H. Lurie Comprehensive Cancer Center; an instrumentation award (S10OD025194) from NIH Office of the Director; and the National Resource for Translational and Developmental Proteomics, supported by P41 GM108569. The Mayo Clinic Cancer Center is supported by the NCI, NIH (P30 CA15083). Schematic illustrations were created using BioRender.com and Adobe illustrator. The Lunaphore COMET system for multiplex IF was enabled by a gift from the Stephen M. Coffman trust to the Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Cancer Center. We give special thanks to Bella Najem, BA in Fashion Design and Media, for her media and animated video generation expertise. We also acknowledge the assistance of the Mayo Clinic Proteomics Core, a shared resource of the Mayo Clinic Cancer Center. Authorship note: SW and BAC contributed equally to this work. Conflict of interest: ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of the patent \u201CBiomarkers and combination therapies using oncolytic virus and immunomodulation\u201D (no. 11,065,285); is supported by research grants from Celularity, Alnylam, and AbbVie; and receives consulting fees from Novocure and Istari Oncology. She additionally has active granted patents titled \u201CmiRNA for treating cancer and for use with adoptive immunotherapies\u201D (no. 9,675,633) and \u201CConcurrent chemotherapy and immunotherapy\u201D (no. 9,399,662), with a patent-pending titled \u201CLow-intensity ultrasound combination cancer therapies\u201D (international applications PCT/US2022/019435 and US 63/158,642). MF is currently employed as a principal scientist at Grove Biopharma Inc. CLC has pending patents titled \u201CB cell\u2013based immunotherapy for the treatment of glioblastoma and other cancer\u201D (PCT/US2021/046331 and US 62/936,867) and \u201CB cell production and expansion\u201D (US63/590,202). Copyright: \u00A9 2024, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: December 1, 2023; Accepted: August 20, 2024; Published: August 29, 2024. Reference information: J Clin Invest. 2024;134(20):e177384. https://doi.org/10.1172/JCI177384.

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Wang, S., Castro, B. A., Katz, J. L., Arrieta, V., Najem, H., Vazquez-Cervantes, G. I., Wan, H., Olson, I. E., Hou, D., Dapash, M., Billingham, L. K., Chia, T. Y., Wei, C., Rashidi, A., Platanias, L. C., McCortney, K., Horbinski, C. M., Stupp, R., Zhang, P., ... Lee-Chang, C. (2024). B cell–based therapy produces antibodies that inhibit glioblastoma growth. Journal of Clinical Investigation, 134(20), Article e177384. https://doi.org/10.1172/JCI177384

@article{50be156b9f56427582e13bd21e8660de,

title = "B cell–based therapy produces antibodies that inhibit glioblastoma growth",

abstract = "Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell–based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.",

author = "Si Wang and Castro, {Brandyn A.} and Katz, {Joshua L.} and Victor Arrieta and Hinda Najem and Vazquez-Cervantes, {Gustavo I.} and Hanxiao Wan and Olson, {Ian E.} and David Hou and Mark Dapash and Billingham, {Leah K.} and Chia, {Tzu Yi} and Chao Wei and Aida Rashidi and Platanias, {Leonidas C.} and Kathleen McCortney and Horbinski, {Craig M.} and Roger Stupp and Peng Zhang and Ahmed, {Atique U.} and Sonabend, {Adam M.} and Heimberger, {Amy B.} and Lesniak, {Maciej S.} and C{\'e}cile Riviere-Cazaux and Terry Burns and Jason Miska and Mariafausta Fischietti and Catalina Lee-Chang",

note = "Publisher Copyright: Copyright: {\textcopyright} 2024, Wang et al.",

year = "2024",

month = oct,

day = "15",

doi = "10.1172/JCI177384",

language = "English (US)",

volume = "134",

journal = "Journal of Clinical Investigation",

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Wang, S, Castro, BA, Katz, JL, Arrieta, V, Najem, H, Vazquez-Cervantes, GI, Wan, H, Olson, IE, Hou, D, Dapash, M, Billingham, LK, Chia, TY, Wei, C, Rashidi, A, Platanias, LC, McCortney, K, Horbinski, CM , Stupp, R, Zhang, P, Ahmed, AU , Sonabend, AM , Heimberger, AB , Lesniak, MS, Riviere-Cazaux, C, Burns, T, Miska, J, Fischietti, M & Lee-Chang, C 2024, 'B cell–based therapy produces antibodies that inhibit glioblastoma growth', Journal of Clinical Investigation, vol. 134, no. 20, e177384. https://doi.org/10.1172/JCI177384

TY - JOUR

T1 - B cell–based therapy produces antibodies that inhibit glioblastoma growth

AU - Wang, Si

AU - Castro, Brandyn A.

AU - Katz, Joshua L.

AU - Arrieta, Victor

AU - Najem, Hinda

AU - Vazquez-Cervantes, Gustavo I.

AU - Wan, Hanxiao

AU - Olson, Ian E.

AU - Hou, David

AU - Dapash, Mark

AU - Billingham, Leah K.

AU - Chia, Tzu Yi

AU - Wei, Chao

AU - Rashidi, Aida

AU - Platanias, Leonidas C.

AU - McCortney, Kathleen

AU - Horbinski, Craig M.

AU - Stupp, Roger

AU - Zhang, Peng

AU - Ahmed, Atique U.

AU - Sonabend, Adam M.

AU - Heimberger, Amy B.

AU - Lesniak, Maciej S.

AU - Riviere-Cazaux, Cécile

AU - Burns, Terry

AU - Miska, Jason

AU - Fischietti, Mariafausta

AU - Lee-Chang, Catalina

PY - 2024/10/15

Y1 - 2024/10/15

N2 - Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell–based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

AB - Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell–based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

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ER -

B cell–based therapy produces antibodies that inhibit glioblastoma growth

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