Ddel-06preliminary Safety of Toca 511, a Retroviral Replicating Vector, in Patients With Recurrent High Grade Glioma Across Three Separate Phase 1 Studies

Kalkanis, Steven N.; Aghi, Manish K.; Cloughsy, Timothy F.; Kaptain, George J.; Portnow, Jana; Vogelbaum, Michael A.; Kesari, Santosh; Mikkelsen, Tom; Elder, J. Bradley; Chen, Clark C.; Piccioni, David; Baskin, David S.; Engh, Jonathan; Bota, Daniela; Chiocca, E. Antonio; Foltz, Greg; Ostertag, Derek; Gammon, Dawn; Niethammer, Andreas G.; Landolfi, Joseph C.

doi:10.1093/neuonc/nov212.06

Cited by 3 publications

(1 citation statement)

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“…2) mOS: 7.1 mos. (HR, 0.45; 95% CI, 0.27 to 0.77; P = 0.003) [ 78 , 79 ] NCT01470794 Toca 511 + Toca FC I ( n = 56) Recurrent HGG mOS: 11.9 mos. (95% CI, 10.7 to 15.1) [ 80 ] NCT02414165 1) Toca 511 + Toca FC 2) SOC II/III ( n = 403) Recurrent HGG; IDH-mut stratified 1) mOS: 11.1 mos.…”

Section: Recent Advances In Immunotherapymentioning

confidence: 99%

Current Advances in Immunotherapy for Glioblastoma

et al. 2021

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Purpose of Review This review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system–specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction. Recent Findings The success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Summary Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.

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Section: Recent Advances In Immunotherapymentioning

confidence: 99%

Current Advances in Immunotherapy for Glioblastoma

et al. 2021

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Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma

Mozhei

Teschemacher

Kasparov

2020

Cancers

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In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells.

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Glioblastoma Immunotherapy: A Systematic Review of the Present Strategies and Prospects for Advancements

Agosti,

Zeppieri,

De Maria

et al. 2023

IJMS

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Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “glioblastomas,” “immunotherapies,” and “treatment.” The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.

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Ddel-06preliminary Safety of Toca 511, a Retroviral Replicating Vector, in Patients With Recurrent High Grade Glioma Across Three Separate Phase 1 Studies

Cited by 3 publications

References 0 publications

Current Advances in Immunotherapy for Glioblastoma

Current Advances in Immunotherapy for Glioblastoma

Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma

Glioblastoma Immunotherapy: A Systematic Review of the Present Strategies and Prospects for Advancements

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