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1525 Initial clinical experience with chlorotoxin-redirected CAR T cells for patients with recurrent glioblastoma
  1. Maryam Aftabizadeh1,
  2. Marie Suzette Blanchard1,
  3. Tracey Stiller1,
  4. Heini M Natri2,
  5. Brenda Aguilar1,
  6. Jamie R Wagner1,
  7. Jinny A Paul1,
  8. Renate Starr1,
  9. Julie A Ressler1,
  10. Julie Kilpatrick1,
  11. Paige Myers-McNamara1,
  12. Massimo D’Apuzzo1,
  13. Nicholas Benovich2,
  14. Stephen J Forman1,
  15. Michael E Barish1,
  16. Behnam Badie1 and
  17. Christine E Brown1
  1. 1City of Hope, Duarte, CA, USA
  2. 2Translational Genomics Research Institute, Phoenix, AZ, USA

Abstract

Background A major barrier to achieving effective therapies for patients with glioblastoma multiforme (GBM) is the phenotypic heterogeneity seen both between patients and within individual tumors, the later creating multiple cell subpopulations contributing to disease recurrence. One strategy for creating more efficacious therapies is to design novel immunotherapies targeting higher proportions of tumors and tumor cells than current options. Chlorotoxin (CLTX) is a 36-amino acid peptide component of scorpion venom that selectively binds to glioma cells of all malignancy grades while sparing normal brain cells and non-malignant tissues.1 2 With this understanding, we developed chimeric antigen receptor (CAR) T cells incorporating the CLTX peptide as a tumor-recognizing ligand, thereby redirecting T cells to target GBM cells and tumors.3 Preclinical studies suggested broad yet specific CLTX binding to patient-derived GBM cells. Preclinical data also suggested a role for cell surface matrix metalloproteinase-2 (MMP-2) in CLTX-CAR T cell activation.

Methods We designed a non-randomized and dose escalating phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells to patients with recurrent/progressing GBM (NCT04214392; approved by the City of Hope National Medical Center protocol review committee, written consent obtained for leukapheresis and treatment), with the primary objectives of feasibility and safety.

Results Here we report clinical outcomes and correlative observations for four lead-in research participants, all of whom had a histopathological diagnosis of glioblastoma, idh wild type, grade 4, and who had received prior temozolomide as well as radiation and other treatments. The key enrollment criterion was MMP-2 expression in tissue biopsies at levels greater than 20% (moderate and/or high expression) as assessed by immunochemistry. Participants received three infusions of 4, 20, and 20 x 10^6 CLTX-CAR T cells at weekly intervals. There were no CRS events or DLTs observed. Three of the four participants (75%) achieved stable disease. Participants survived a median of 5.75 months (min = 2.4, max = 20.5) after CAR T cell infusion. The presence of CLTX-CAR T cells in tumor fluid collected before and one day after each infusion indicated persistence of CLTX-CAR T cells. IgG1 was absent in these samples, suggesting non-immunogenicity of CLTX-CAR T cells despite the presence of the exogenous CLTX peptide.

Conclusions Phase 1 clinical observations to date confirm the feasibility and safety of CLTX-CAR T cell immunotherapy for patients with GBM. These studies will lead to determination of a maximum tolerated dose/maximum feasible dose.

References

  1. Lyons SA, O’Neal J, Sontheimer H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia. 2022;39:162–173.

  2. Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC, Ravanpay AC, Stroud MR, Kusuma Y, Hansen SJ, Kwok D, Munoz NM, Sze RW, Grady WM, Greenberg NM, Ellenbogen RG, Olson JM. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci, Cancer Res. 2007;67:6882–6888.

  3. Wang D, Starr R, Chang WC, Aguilar B, Alizadeh D, Wright SL, Yang X, Brito A, Sarkissian A, Ostberg JR, Li L, Shi Y, Gutova M, Aboody K, Badie B, Forman SJ, Barish ME, Brown CE. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. 2020;12.

Ethics Approval We designed a non-randomized and dose escalating phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells to patients with recurrent/progressing GBM (NCT04214392; approved by the City of Hope National Medical Center protocol review committee, written consent obtained for leukapheresis and treatment), with the primary objectives of feasibility and safety.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

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