Recurrent Glioblastoma Treated with Recombinant Poliovirus

Desjardins, Annick; Gromeier, Matthias; Herndon, James E.; Beaubier, Nike; Bolognesi, Dani P.; Friedman, Allan H.; Friedman, Henry S.; McSherry, Frances; Muscat, Andrea; Nair, Smita K.; Peters, Katherine B.; Randazzo, Dina; Sampson, John H.; Vlahović, Gordana; Harrison, William T.; McLendon, Roger E.; Ashley, David M.; Bigner, Darell D.

doi:10.1056/nejmoa1716435

Cited by 609 publications

(477 citation statements)

References 24 publications

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“…These therapies can induce the regression of injected and distal tumors in experimental models. Very promising results have been reported in clinical trials with local injection of oncolytic viruses in melanoma lesions (Tang et al, 2018) and brain tumors (Desjardins et al, 2018; Lang et al, 2018). The roles of local therapies in long-term survival and the regression of distal metastases remain to be studied in the clinic.…”

Section: The Principles To Combine Other Therapeutics With Anti-pd Thmentioning

confidence: 99%

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed

Chen

2018

Cell

997

557

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Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed “immune normalization,” which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.

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Section: The Principles To Combine Other Therapeutics With Anti-pd Thmentioning

confidence: 99%

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed

Chen

2018

Cell

997

557

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“…While only destruction of the virus would eliminate any risk of accidental release, a switch to alternative, hyper‐attenuated PV strains that are unable to infect humans may equally minimize the risks of transmission and disease in the event of facility‐associated dissemination into the environment, a strategy that was already proposed by the WHO and FDA more than a decade ago . Replication incompetent pseudoviruses or hyper‐attenuated PV strains have been developed and their use in vaccine production, immunogenicity studies, immunotherapy, monitoring of the environment, or neutralizing antibody titers has been proposed. The feasibility to use such hyper‐attenuated strains for vaccine production has been shown and was confirmed for the monitoring of PV neutralizing antibody titers in the QC of immunoglobulin, another essential medicinal, in this work.…”

Section: Discussionmentioning

confidence: 99%

Continued use of poliovirus after eradication: hyper‐attenuated strains as a safe alternative for release testing of human immunoglobulins

Farcet¹,

Modrof²,

Rabel³

et al. 2018

Transfusion

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BACKGROUND Wild‐type poliovirus may be eradicated soon and under WHO GAPIII guidance, laboratory use will be discontinued or subject to strict containment. Per US Code of Federal Regulations, however, immunoglobulin lot release testing will still require use of replicating poliovirus. The suitability of S19 hyper‐attenuated and apathogenic poliovirus strains as alternatives to the currently used wild‐type virus in such a release assay was investigated. STUDY DESIGN AND METHODS S19 poliovirus strains were propagated in a commercial setting using good virological practices and maintenance of the S19 hyper‐attenuated genotype was confirmed by massively parallel sequencing. RESULTS The attenuated phenotype of the produced S19 stocks was confirmed in a highly sensitive mouse‐model. Equivalency in performance was seen in the lot release assay for the S19 and wild‐type polioviruses. CONCLUSION The deployment of such hyper‐attenuated and thoroughly characterized S19 stocks in these and other essential activities might reconcile final containment measures with continued safe use of poliovirus.

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“…Immune checkpoint inhibitors have demonstrated little efficacy as monotherapy in GBM, and studies of other immunotherapeutic approaches, including oncolytic viral therapy and dendritic cell vaccination, have generally failed to produce rates of response or stable disease above 20% [4,12,13,25,26]. Immunologically, GBM is characterized by a highly suppressive tumor microenvironment [12], and for most patients, there is scant intratumoral infiltration of effector T cells [27,28].…”

Section: Discussionmentioning

confidence: 99%

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

et al. 2018

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Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p=0.003), CD137 (p=0.042), VEGF-A (p<0.001), CTLA4 (p=0.028), CD40 (p=0.023), GITR (p=0.020), IL6 (p=0.02), and OX40 (p<0.001). In CGCG (n=52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

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Recurrent Glioblastoma Treated with Recombinant Poliovirus

Cited by 609 publications

References 24 publications

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Continued use of poliovirus after eradication: hyper‐attenuated strains as a safe alternative for release testing of human immunoglobulins

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

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