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Case Reports
. 2021 May 7:11:669071.
doi: 10.3389/fonc.2021.669071. eCollection 2021.

Case Report: Prolonged Survival Following EGFRvIII CAR T Cell Treatment for Recurrent Glioblastoma

Joseph S Durgin  1   2   3 , Fraser Henderson Jr  4 , MacLean P Nasrallah  1   3 , Suyash Mohan  5 , Sumei Wang  5 , Simon F Lacey  2 , Jan Joseph Melenhorst  1   2   3 , Arati S Desai  1   6 , John Y K Lee  7 , Marcela V Maus  8 , Carl H June  2   3 , Steven Brem  1   7 , Roddy S O'Connor  2   3 , Zev Binder  1   7 , Donald M O'Rourke  1   7
Affiliations
Case Reports

Case Report: Prolonged Survival Following EGFRvIII CAR T Cell Treatment for Recurrent Glioblastoma

Joseph S Durgin et al. Front Oncol. .

Abstract

Autologous chimeric antigen receptor (CAR) T cells targeted to epidermal growth factor receptor variant III (CAR T-EGFRvIII) have been developed and administered experimentally to treat patients with IDH1 wildtype recurrent glioblastoma (rGBM) (NCT02209376). We report the case of a 59-year-old patient who received a single peripheral infusion of CAR T-EGFRvIII cells and survived 36 months after disease recurrence, exceeding expected survival for recurrent glioblastoma. Post-infusion histopathologic analysis of tissue obtained during a second stage surgical resection revealed immunosuppressive adaptive changes in the tumor tissue as well as reduced EGFRvIII expression. Serial brain imaging demonstrated a significant reduction in relative cerebral blood volume (rCBV), a measure strongly associated with tumor proliferative activity, at early time points following CAR T treatment. Notably, CAR T-EGFRvIII cells persisted in her peripheral circulation during 29 months of follow-up, the longest period of CAR T persistence reported in GBM trials to date. These findings in a long-term survivor show that peripherally administered CAR T-EGFRvIII cells can persist for years in the circulation and suggest that this cell therapy approach could be optimized to achieve broader efficacy in recurrent GBM patients.

Keywords: CAR (chimeric antigen receptor); CAR T cell therapy; EGFRvIII; glioblastoma; perfusion imaging; recurrent glioblastoma (rGBM).

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Conflict of interest statement

DO’R and ZB are inventors on patents related to CAR T cells that have been filed by the University of Pennsylvania. JJM consults with or serves on the board of directors of several companies developing CAR T technology. JM and SL are inventors of intellectual property related to CAR T cells that is licensed by the University of Pennsylvania to Novartis. CHJ reports receiving grants from Tmunity Therapeutics and holds founders stock in Tmunity Therapeutics and DeCART Therapeutics. CHJ also receives personal income from BluesphereBio, Cabaletta, Carisma, Cellares, Celldex Therapeutics, Viracta Therapeutics, Ziopharm and WIRB-Copernicus Group as well as royalties from Novartis. MCM is an inventor on patent applications related to CAR technology and has received licensing royalties from Novartis corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Serial MR images one week before (baseline) and three months after CAR T-EGFRvIII infusion. Left sided images are axial post contrast T1 weighted images and right sided images are axial FLAIR images. Note, minimal increase in size of the enhancing lesion in the left temporal lobe at follow-up time-points. (B) Serial MRI examinations after the patient’s second surgery. The baseline is one month after her second surgery. White arrows at 15, 21- and 25-month follow-up periods indicate the increasing signal abnormality in the right periventricular region on FLAIR images.
Figure 2
Figure 2
Timeline of disease progression and treatment. Black bordered months indicate diagnosis or definitive progression on surveillance MRI. The graph shows CAR T-EGFRvIII levels in the peripheral blood as measured by qPCR.
Figure 4
Figure 4
Percent change from baseline for MRI diffusion (MD, FA), perfusion (rCBVmax), and spectroscopy (Cho/Cr) parameters after CAR T-EGFRvIII infusion. No MR spectroscopy was performed at month -1, so the baseline for Cho/Cr is month 0. The arrow indicates the date of CAR T-EGFRvIII infusion. MD, mean diffusivity; FA, fractional anisotropy; rCBVmax, maximum relative cerebral blood volume; Cho/Cr, choline/creatine ratio.
Figure 3
Figure 3
Immunohistochemical (IHC) analysis of EGFRvIII, CD3, FoxP3, and PD1 expression in the patient’s tumor before and after CAR T infusion. The left panels show tissue from her original surgery, prior to any treatment. The right panels show tissue from her surgery 104 days after CAR T infusion. Scale bars are 200 µm. Percent positivity by area was calculated by ImageJ as described in the methods, and staining intensity is by pathologist assessment. a: Pre-treatment fields also contain scattered 1+ EGFRvIII positive cells of unknown type. b: The positive cells are of undetermined lineage.
See this image and copyright information in PMC

References

    1. Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. . Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New Engl J Med (2005) 352(10):987–96. 10.1056/NEJMoa043330 - DOI - PubMed
    1. Franceschi E, Ermani M, Bartolini S, Bartolotti M, Poggi R, Tallini G, et al. . Post Progression Survival in Glioblastoma: Where are We? J Neurooncol (2015) 121(2):399–404. 10.1007/s11060-014-1651-7 - DOI - PubMed
    1. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. . Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med (2015) 7(275):275ra22–275ra22. - PMC - PubMed
    1. Newick K, O’Brien S, Moon E, Albelda SM. Car T Cell Therapy for Solid Tumors. Annu Rev Med (2017) 68(1):139–52. 10.1146/annurev-med-062315-120245 - DOI - PubMed
    1. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJ, et al. . A Single Dose of Peripherally Infused EGFRvIII-directed Car T Cells Mediates Antigen Loss and Induces Adaptive Resistance in Patients With Recurrent Glioblastoma. Sci Trans Med (2017) 9(399):eaaa0984. 10.1126/scitranslmed.aaa0984 - DOI - PMC - PubMed

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