Dataset Information

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

ABSTRACT: BACKGROUNDThe 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.METHODSTwenty-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.RESULTSNo 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.CONCLUSIONData 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 REGISTRATIONanzctr.org.au: ACTRN12615000656538.FUNDINGPhilanthropic funding and the National Health and Medical Research Council (Australia).

SUBMITTER: Smith C

PROVIDER: S-EPMC7598048 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Smith Corey C Lineburg Katie E KE Martins J Paulo JP Ambalathingal George R GR Neller Michelle A MA Morrison Beth B Matthews Katherine K KK Rehan Sweera S Crooks Pauline P Panikkar Archana A Beagley Leone L Le Texier Laetitia L Srihari Sriganesh S Walker David D Khanna Rajiv R

The Journal of clinical investigation 20201101 11

BACKGROUNDThe 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.METHODSTwenty-eight patients w ...[more]

PMID: 32750039

Similar Datasets

Project description:Abstract In our translational research, an immunotherapeutic, ADCTA-G, has been developed to emphasize autologous tumor antigens, DC antigen processing/presentation, enhanced tumor immunogenicity and CTL induction. Two clinical trials, Phase I/II [2003-2005Taiwan DOH/MA 0910072504] and phase II [2005–2016 NIH NCT02772094], “Dendritic Cell(DC)-Based Tumor Vaccine Adjuvant Immunotherapy of Human Glioblastoma Multiforme”, respectively enrolled 17 and 42 WHO Grade-IV glioblastomas. Every patient received peripheral blood apheresis for PBMNCs. Monocytes were used for derivation of 3-7x108 phagocytic dendritic cells (iDC). Autologous glioma cells grown out of surgical tumor specimen were irradiated and co-cultivated 1 to 2:1 with iDC to make a ADCTA-G lot. After surgical tumor de-bulking, 10 vaccinations were given, each with 2-5x107 mature DC from the ADCTA lot, in a [4x biweekly and 6x monthly] scheduled s.c. injection in both axillar regions. The follow-up period has been 15 years. Primary endpoint is the overall survival (OS); phenotypes of tumor infiltrating T cells and tumor IDH mutation were also analyzed for long-term survivors. The ADCTA-G inoculations were tolerated well, and curtailed the grade-3/4 lymphopenia adverse effect of the temozolomide CCRT. The median OS is 22.9 months for the total 59 grade IV patients in the two trials. The median OS is 21.8 months for the 44 newly diagnosed patients and 28.1 months for the 15 recurrent patients; the difference is insignificant statistically. In this study, vaccinations were initiated early in the recurrent GBM patients while the newly diagnosed GBM patients had to wait till after external radiation therapy, leading to a comparable OS benefit of the ADCTA vaccination. Also, we demonstrated in vitro the earlier vaccinations in the recurrent decrease CD133+ tumor stem-like cells. In addition, the CD8(+) cells were susceptible to ionizing radiation. A phase 3 open-labelled randomized study will be initiated to improve the survival of this aggressive malignancy.

Project description:BackgroundGlioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. Dendritic cell (DC) vaccines have demonstrated promising results in GBM clinical trials. However, some patients do not respond well to DC therapy, with survival rates similar to those of conventional therapy. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment.MethodsForty-seven patients with de novo GBM were enrolled at China Medical University Hospital between 2005 and 2010 and divided into two subgroups. One subgroup of 27 patients received postsurgical adjuvant immunotherapy with autologous dendritic cell/tumor antigen vaccine (ADCTA) in conjunction with conventional treatment of concomitant chemoradiotherapy (CCRT) with temozolomide. The other 20 patients received only postsurgical conventional treatment without immunotherapy. Immunohistochemistry for CD45, CD4, CD8, programed death ligand 1 (PD-L1), and programed death 1 (PD-1) was performed on sections of surgical tumor specimens and peripheral blood mononuclear cells (PBMCs). Pearson's correlation, Cox proportional hazard model, and Kaplan-Meier analyses were performed to examine the correlations between the prognostic factors and survival rates.ResultsYounger age (<57 years), gross total resection, and CCRT and PD-1+ lymphocyte counts were significant prognostic factors of overall survival (OS) and progression-free survival (PFS) in the ADCTA group. Sex, CD45+ lymphocyte count, CD4+ or CD8+ lymphocyte count, tumor PD-L1 expression, isocitrate dehydrogenase 1 mutation, and O6 methylguanine-DNA methyltransferase promoter methylation status were not significant factors in both groups. In the ADCTA group, patients with tumor-infiltrating lymphocytes (TILs) with a lower PD-1+/CD8+ ratio (≤0.21) had longer OS and PFS (median OS 60.97 months, P < 0.001 and PFS 11.2 months, P < 0.008) compared to those with higher PD-1+/CD8+ ratio (>0.21) (median OS 20.07 months, P < 0.001 and PFS 4.43 months, P < 0.008). Similar results were observed in patients' PBMCs; lymphocyte counts with lower PD-1+/CD8+ ratio (≤0.197) had longer OS and PFS. There was a significant correlation of PD-1+/CD8+ ratio between TILs and PBMCs (Pearson's correlation R2 = 0.6002, P < 0.001). By contrast, CD4-, CD8-, but PD-1+, CD45+ tumor-infiltrating lymphocytes have no impact on OS and PFS (P = 0.073 and P = 0.249, respectively).ConclusionFor patients receiving DC vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets