Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients
Jennifer E. Adair, … , Kristin R. Swanson, Hans-Peter Kiem
Jennifer E. Adair, … , Kristin R. Swanson, Hans-Peter Kiem
Published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):4082-4092. https://doi.org/10.1172/JCI76739.
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Clinical Medicine Clinical trials

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

Abstract

BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.

METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.

RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57+) months and OS of 20 (range 13–57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG.

CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.

TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669.

FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

Authors

Jennifer E. Adair, Sandra K. Johnston, Maciej M. Mrugala, Brian C. Beard, Laura A. Guyman, Anne L. Baldock, Carly A. Bridge, Andrea Hawkins-Daarud, Jennifer L. Gori, Donald E. Born, Luis F. Gonzalez-Cuyar, Daniel L. Silbergeld, Russell C. Rockne, Barry E. Storer, Jason K. Rockhill, Kristin R. Swanson, Hans-Peter Kiem

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Figure 2

Chemoresistance of wbc in vivo after infusion of P140K gene-modified CD34+ cells and O6BG/TMZ chemotherapy.

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Chemoresistance of wbc in vivo after infusion of P140K gene-modified CD3...
(A) Schematic of the P140K-encoding gammaretrovirus vector used for transduction of autologous human CD34+ cells. (B–H) Blood cell counts for chemotherapy treatment per protocol (ANC and PLTs) for case patients 1 to 7 (B–H, respectively). Each graph shows ANC (white circles) and PLT counts (black squares) as measured from peripheral blood (y axis) over time (x axis) and chemotherapy with O6BG/TMZ (inverted triangles). Black inverted triangles in B (case patient 1) and H (case patient 7) represent dose-escalated chemotherapy cycles with TMZ dose of 590 mg/m2. Upper and lower dashed lines represent the threshold counts for each hematopoietic cell type required for chemotherapy retreatment in the study.