Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

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

doi:10.1172/JCI76739

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

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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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 (MGMT^hi). 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. Patientspecific 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.

Original language	English (US)
Pages (from-to)	4082-4092
Number of pages	11
Journal	Journal of Clinical Investigation
Volume	124
Issue number	9
DOIs	https://doi.org/10.1172/JCI76739
State	Published - Sep 2 2014

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General Medicine

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10.1172/JCI76739

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Adair, J. E., Johnston, S. K., Mrugala, M. M., Beard, B. C., Guyman, L. A., Baldock, A. L., Bridge, C. A., Hawkins-Daarud, A., Gori, J. L., Born, D. E., Gonzalez-Cuyar, L. F., Silbergeld, D. L., Rockne, R. C., Storer, B. E., Rockhill, J. K., Swanson, K. R., & Kiem, H. P. (2014). Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. Journal of Clinical Investigation, 124(9), 4082-4092. https://doi.org/10.1172/JCI76739

Adair, JE, Johnston, SK, Mrugala, MM, Beard, BC, Guyman, LA, Baldock, AL, Bridge, CA, Hawkins-Daarud, A, Gori, JL, Born, DE, Gonzalez-Cuyar, LF, Silbergeld, DL, Rockne, RC, Storer, BE, Rockhill, JK, Swanson, KR & Kiem, HP 2014, 'Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients', Journal of Clinical Investigation, vol. 124, no. 9, pp. 4082-4092. https://doi.org/10.1172/JCI76739

@article{b10b7ecf2ef44fa4af8f13d0c0d6fef4,

title = "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. Patientspecific 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.",

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

year = "2014",

month = sep,

day = "2",

doi = "10.1172/JCI76739",

language = "English (US)",

volume = "124",

pages = "4082--4092",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "9",

}

TY - JOUR

T1 - Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

AU - Adair, Jennifer E.

AU - Johnston, Sandra K.

AU - Mrugala, Maciej M.

AU - Beard, Brian C.

AU - Guyman, Laura A.

AU - Baldock, Anne L.

AU - Bridge, Carly A.

AU - Hawkins-Daarud, Andrea

AU - Gori, Jennifer L.

AU - Born, Donald E.

AU - Gonzalez-Cuyar, Luis F.

AU - Silbergeld, Daniel L.

AU - Rockne, Russell C.

AU - Storer, Barry E.

AU - Rockhill, Jason K.

AU - Swanson, Kristin R.

AU - Kiem, Hans Peter

PY - 2014/9/2

Y1 - 2014/9/2

N2 - 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. Patientspecific 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.

AB - 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. Patientspecific 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.

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Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

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