HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma

A phase 1 dose-escalation trial

Nabil Ahmed, Vita Brawley, Meenakshi Hegde, Kevin Bielamowicz, Mamta Kalra, Daniel Landi, Catherine Robertson, Tara L. Gray, Oumar Diouf, Amanda Wakefield, Alexia Ghazi, Claudia Gerken, Zhongzhen Yi, Aidin Ashoori, Meng Fen Wu, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Jack Su & 13 others Yvonne Kew, David Baskin, Yi Jonathan Zhang, Pamela New, Bambi Grilley, Milica Stojakovic, John Hicks, Suzanne Z. Powell, Malcolm K. Brenner, Helen E. Heslop, Robert Grossman, Winfried S. Wels, Stephen Gottschalk

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

IMPORTANCE: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. OBJECTIVE: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. DESIGN, SETTING, AND PARTICIPANTS: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). INTERVENTIONS: Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). MAIN OUTCOMES AND MEASURES: Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. RESULTS: A total of 17 patients (8 females and 9 males; 10 patients 18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 10 6 /m 2 to 1 × 10 8 /m 2 ) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. CONCLUSIONS AND RELEVANCE: Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

Original languageEnglish (US)
Pages (from-to)1094-1101
Number of pages8
JournalJAMA Oncology
Volume3
Issue number8
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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Glioblastoma
Antigen Receptors
Viruses
T-Lymphocytes
Antigens
Poisons
Cytomegalovirus
Human Herpesvirus 4
Adenoviridae
Real-Time Polymerase Chain Reaction
Cohort Studies
Medicine
Outcome Assessment (Health Care)
Safety
Survival
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma : A phase 1 dose-escalation trial. / Ahmed, Nabil; Brawley, Vita; Hegde, Meenakshi; Bielamowicz, Kevin; Kalra, Mamta; Landi, Daniel; Robertson, Catherine; Gray, Tara L.; Diouf, Oumar; Wakefield, Amanda; Ghazi, Alexia; Gerken, Claudia; Yi, Zhongzhen; Ashoori, Aidin; Wu, Meng Fen; Liu, Hao; Rooney, Cliona; Dotti, Gianpietro; Gee, Adrian; Su, Jack; Kew, Yvonne; Baskin, David; Zhang, Yi Jonathan; New, Pamela; Grilley, Bambi; Stojakovic, Milica; Hicks, John; Powell, Suzanne Z.; Brenner, Malcolm K.; Heslop, Helen E.; Grossman, Robert; Wels, Winfried S.; Gottschalk, Stephen.

In: JAMA Oncology, Vol. 3, No. 8, 01.08.2017, p. 1094-1101.

Research output: Contribution to journalArticle

Ahmed, N, Brawley, V, Hegde, M, Bielamowicz, K, Kalra, M, Landi, D, Robertson, C, Gray, TL, Diouf, O, Wakefield, A, Ghazi, A, Gerken, C, Yi, Z, Ashoori, A, Wu, MF, Liu, H, Rooney, C, Dotti, G, Gee, A, Su, J, Kew, Y, Baskin, D, Zhang, YJ, New, P, Grilley, B, Stojakovic, M, Hicks, J, Powell, SZ, Brenner, MK, Heslop, HE, Grossman, R, Wels, WS & Gottschalk, S 2017, 'HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial', JAMA Oncology, vol. 3, no. 8, pp. 1094-1101. https://doi.org/10.1001/jamaoncol.2017.0184
Ahmed, Nabil ; Brawley, Vita ; Hegde, Meenakshi ; Bielamowicz, Kevin ; Kalra, Mamta ; Landi, Daniel ; Robertson, Catherine ; Gray, Tara L. ; Diouf, Oumar ; Wakefield, Amanda ; Ghazi, Alexia ; Gerken, Claudia ; Yi, Zhongzhen ; Ashoori, Aidin ; Wu, Meng Fen ; Liu, Hao ; Rooney, Cliona ; Dotti, Gianpietro ; Gee, Adrian ; Su, Jack ; Kew, Yvonne ; Baskin, David ; Zhang, Yi Jonathan ; New, Pamela ; Grilley, Bambi ; Stojakovic, Milica ; Hicks, John ; Powell, Suzanne Z. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Grossman, Robert ; Wels, Winfried S. ; Gottschalk, Stephen. / HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma : A phase 1 dose-escalation trial. In: JAMA Oncology. 2017 ; Vol. 3, No. 8. pp. 1094-1101.
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abstract = "IMPORTANCE: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. OBJECTIVE: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. DESIGN, SETTING, AND PARTICIPANTS: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). INTERVENTIONS: Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). MAIN OUTCOMES AND MEASURES: Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. RESULTS: A total of 17 patients (8 females and 9 males; 10 patients 18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 10 6 /m 2 to 1 × 10 8 /m 2 ) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95{\%} CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95{\%} CI, 17.2-34.6 months) from diagnosis. CONCLUSIONS AND RELEVANCE: Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.",
author = "Nabil Ahmed and Vita Brawley and Meenakshi Hegde and Kevin Bielamowicz and Mamta Kalra and Daniel Landi and Catherine Robertson and Gray, {Tara L.} and Oumar Diouf and Amanda Wakefield and Alexia Ghazi and Claudia Gerken and Zhongzhen Yi and Aidin Ashoori and Wu, {Meng Fen} and Hao Liu and Cliona Rooney and Gianpietro Dotti and Adrian Gee and Jack Su and Yvonne Kew and David Baskin and Zhang, {Yi Jonathan} and Pamela New and Bambi Grilley and Milica Stojakovic and John Hicks and Powell, {Suzanne Z.} and Brenner, {Malcolm K.} and Heslop, {Helen E.} and Robert Grossman and Wels, {Winfried S.} and Stephen Gottschalk",
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TY - JOUR

T1 - HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma

T2 - A phase 1 dose-escalation trial

AU - Ahmed, Nabil

AU - Brawley, Vita

AU - Hegde, Meenakshi

AU - Bielamowicz, Kevin

AU - Kalra, Mamta

AU - Landi, Daniel

AU - Robertson, Catherine

AU - Gray, Tara L.

AU - Diouf, Oumar

AU - Wakefield, Amanda

AU - Ghazi, Alexia

AU - Gerken, Claudia

AU - Yi, Zhongzhen

AU - Ashoori, Aidin

AU - Wu, Meng Fen

AU - Liu, Hao

AU - Rooney, Cliona

AU - Dotti, Gianpietro

AU - Gee, Adrian

AU - Su, Jack

AU - Kew, Yvonne

AU - Baskin, David

AU - Zhang, Yi Jonathan

AU - New, Pamela

AU - Grilley, Bambi

AU - Stojakovic, Milica

AU - Hicks, John

AU - Powell, Suzanne Z.

AU - Brenner, Malcolm K.

AU - Heslop, Helen E.

AU - Grossman, Robert

AU - Wels, Winfried S.

AU - Gottschalk, Stephen

PY - 2017/8/1

Y1 - 2017/8/1

N2 - IMPORTANCE: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. OBJECTIVE: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. DESIGN, SETTING, AND PARTICIPANTS: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). INTERVENTIONS: Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). MAIN OUTCOMES AND MEASURES: Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. RESULTS: A total of 17 patients (8 females and 9 males; 10 patients 18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 10 6 /m 2 to 1 × 10 8 /m 2 ) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. CONCLUSIONS AND RELEVANCE: Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

AB - IMPORTANCE: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. OBJECTIVE: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. DESIGN, SETTING, AND PARTICIPANTS: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). INTERVENTIONS: Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). MAIN OUTCOMES AND MEASURES: Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. RESULTS: A total of 17 patients (8 females and 9 males; 10 patients 18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 10 6 /m 2 to 1 × 10 8 /m 2 ) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. CONCLUSIONS AND RELEVANCE: Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

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