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HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

ABSTRACT: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited.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.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).Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.?-signaling endodomain (HER2-CAR VSTs).Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity.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?×?106/m2 to 1?×?108/m2) 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.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.

SUBMITTER: Ahmed N

PROVIDER: S-EPMC5747970 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

Ahmed Nabil N Brawley Vita V Hegde Meenakshi M Bielamowicz Kevin K Kalra Mamta M Landi Daniel D Robertson Catherine C Gray Tara L TL Diouf Oumar O Wakefield Amanda A Ghazi Alexia A Gerken Claudia C Yi Zhongzhen Z Ashoori Aidin A Wu Meng-Fen MF Liu Hao H Rooney Cliona C Dotti Gianpietro G Gee Adrian A Su Jack J Kew Yvonne Y Baskin David D Zhang Yi Jonathan YJ New Pamela P Grilley Bambi B Stojakovic Milica M Hicks John J Powell Suzanne Z SZ Brenner Malcolm K MK Heslop Helen E HE Grossman Robert R Wels Winfried S WS Gottschalk Stephen S

JAMA oncology 20170801 8

<h4>Importance</h4>Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited.<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Chil ...[more]

PMID: 28426845

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Project description:BACKGROUND:Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. METHODS:This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3?+?3 design to establish the maximum tolerated dose, patients received either 1?×?10(6) CAR-transduced T cells per kg (dose 1), 3?×?10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. FINDINGS:Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1?×?10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). INTERPRETATION:CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. FUNDING:National Institutes of Health Intramural funds and St Baldrick's Foundation.

Project description:BackgroundTherapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80.MethodsWe did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984.FindingsWe completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%.InterpretationThe use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC.FundingUS National Institutes of Health.

Dataset Information

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

Publications

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

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