Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas

Friedman, Gregory K.; Johnston, James M.; Bag, Asim K.; Bernstock, Joshua D.; Li, Rong; Aban, Inmaculada; Kachurak, Kara; Li, Nan; Kang, Kyung-Don; Totsch, Stacie K.; Schlappi, Charles; Martin, Allison; Pastakia, Devang; McNall-Knapp, René; Sait, Sameer Farouk; Khakoo, Yasmin; Karajannis, Matthias A.; Woodling, Karina; Palmer, Joshua D.; Osorio, Diana S; Leonard, Jeffrey R.; AbdelBaki, Mohamed S.; Madan‐Swain, Avi; Atkinson, T. Prescott; Whitley, Richard J.; Fiveash, John B.; Markert, James M.; Gillespie, G. Yancey

doi:10.1056/nejmoa2024947

Cited by 189 publications

(136 citation statements)

References 35 publications

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“…Intra-tumoral injection of the oHSV G207 with 5Gy single dose focal irradiation has now been found to be safe and result in stable disease or partial reponse in a cohort of nine adult patients with HGG (149). A phase I study investigating the safety profile of delivering oHSV via surgically implanted catheters in 12 pediatric patients with recurrent or refractory supratentorial pHGG found that oHSV (10 7 or 10 8 plaque forming units, alone or in combination with a single 5 Gy dose of focal radiotherapy) was well tolerated and resulted in no identified peripheral blood virus shedding (150). The authors reported a median OS of 12.2 months (95% CI 8 to 16.4), which is longer than the median OS of 5.6 months in historical cohorts.…”

Section: Local Immunotherapiesmentioning

confidence: 99%

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

2021

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Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.

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Section: Local Immunotherapiesmentioning

confidence: 99%

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

2021

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“…Fatigue is a common complaint following stroke (Christensen et al, 2008;Duncan et al, 2012Duncan et al, , 2014Cumming et al, 2016) and interferes with health-related quality of life (Naess et al, 2006;van de Port et al, 2006), participation in daily activities (Röding et al, 2003;Naess et al, 2005;White et al, 2012;Maaijwee et al, 2015), and return to work (Lock et al, 2005;Andersen et al, 2012). The experience of fatigue is inherently subjective (Aaronson et al, 1999;Staub and Bogousslavsky, 2001a), and stroke survivors' perspectives reveal that fatigue is a heterogeneous condition with several characteristics (Eilertsen et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Response Processes to the Danish Version of the Dutch Multifactor Fatigue Scale in Stroke Using the Three-Step Test-Interview

Cour

Norup

Schow

et al. 2021

Front. Hum. Neurosci.

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Validated self-report measures of post-stroke fatigue are lacking. The Dutch Multifactor Fatigue Scale (DMFS) was translated into Danish, and response process evidence of validity was evaluated. DMFS consists of 38 Likert-rated items distributed on five subscales: Impact of fatigue (11 items), Signs and direct consequences of fatigue (9), Mental fatigue (7), Physical fatigue (6), and Coping with fatigue (5). Response processes to DMFS were investigated using a Three-Step Test-Interview (TSTI) protocol, and data were analyzed using Framework Analysis. Response processes were indexed on the following categories: (i) “congruent,” response processes were related to the subscale construct; (ii) “incongruent,” response processes were not related to the subscale construct; (iii) “ambiguous,” response processes were both congruent and incongruent or insufficient to evaluate congruency; and (iv) “confused,” participants did not understand the item. Nine adults were recruited consecutively 10–34 months post-stroke (median = 26.5) at an outpatient brain injury rehabilitation center in 2019 [five females, mean age = 55 years (SD = 6.3)]. Problematic items were defined as <50% of response processes being congruent with the intended construct. Of the 38 items, five problematic items were identified, including four items of Physical fatigue and one of Mental fatigue. In addition, seven items posed various response difficulties to some participants due to syntactic complexity, vague terms, a presupposition, and a double-barrelled statement. In conclusion, findings elucidate the interpretative processes involved in responding to DMFS post-stroke, strengthen the evidence base of validity, and guide revisions to mitigate potential problems in item performance.

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“…G207 demonstrated high safety profiles with post treatment evidence of significant infiltration of CD8+ T cells and macrophages/microglia into the TME [ 42 ]. Most recently, results from the first in-human trial of G207 for malignant pediatric cerebellar brain tumors were reported [ 43 , 44 ]. Patients had catheters introduced which allowed direct administration of virus to tumors.…”

Section: Tumor Microenvironment and Oncolytic Virotherapymentioning

confidence: 99%

“…Results were highly encouraging with only a single non-responder of 12 patients enrolled. There was substantial evidence of lymphocyte infiltration into tumors in some patients [ 44 ]. Interestingly, when patients who were HSV-1 seropositive were excluded from analysis, increased circulating numbers of natural killer (NK) cells was found to positively correlate with survival.…”

Section: Tumor Microenvironment and Oncolytic Virotherapymentioning

confidence: 99%

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

Uche

Kousoulas

Rider

2021

Viruses

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The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

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Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas

Cited by 189 publications

References 35 publications

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

Evaluation of Response Processes to the Danish Version of the Dutch Multifactor Fatigue Scale in Stroke Using the Three-Step Test-Interview

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

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