Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme
Corey Smith, … , David Walker, Rajiv Khanna
Corey Smith, … , David Walker, Rajiv Khanna
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6041-6053. https://doi.org/10.1172/JCI138649.
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Clinical Research and Public Health Immunology Oncology

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

Abstract

BACKGROUND The recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.METHODS Twenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro–expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution.RESULTS No participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMV-specific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7–65 vs. median 14 months, range 5–19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival.CONCLUSION Data presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.TRIAL REGISTRATION anzctr.org.au: ACTRN12615000656538.FUNDING Philanthropic funding and the National Health and Medical Research Council (Australia).

Authors

Corey Smith, Katie E. Lineburg, J. Paulo Martins, George R. Ambalathingal, Michelle A. Neller, Beth Morrison, Katherine K. Matthews, Sweera Rehan, Pauline Crooks, Archana Panikkar, Leone Beagley, Laetitia Le Texier, Sriganesh Srihari, David Walker, Rajiv Khanna

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Figure 8

Gene expression profile and clustering of CMV-specific ACT products.

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Gene expression profile and clustering of CMV-specific ACT products. In ...
In vitro–expanded patient CMV-specific ACT products were restimulated and IFN-γ–producing cells were used for gene expression analysis using the NanoString nCounter gene expression platform. (A) Expression heatmap of de novo patient clusters C1 and C3, identified using unsupervised hierarchical clustering of 46 differentially expressed genes (P < 0.05). (B) Volcano plot of genes that were significantly differentially expressed between patient clusters C1 and C3. Labeled differentially expressed genes have P < 0.05 and log2FC > 0.6 (~1.5 FC). Overall survival rates based on 72 months of follow-up from diagnosis of (C) all patients in clusters C1 and C3 and (D) patients that had no progression of disease before their first ACT infusion. C1 vs. C3: hazard ratio = 8.5 (P = 0.05); difference in mean survival using restricted mean survival time = 14.12 months (P = 0.001). Multivariate overall survival analysis was undertaken by incorporating MGMT methylation status (E) and IDH1 mutation status (F). NR, not recorded.