The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma

Neth, Bryan J.; Webb, Mason; Parney, Ian F.; Şener, Uğur

doi:10.3390/pharmaceutics15041134

Cited by 8 publications

(6 citation statements)

References 141 publications

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“…In addition, a comprehensive review of vaccine therapies for GBM is available for further reading. [ 137 ]…”

Section: Immune Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions

Ser,

Webb,

Sener

et al. 2024

Journal of Immunotherapy and Precision Oncology

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Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

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“…In addition, a comprehensive review of vaccine therapies for GBM is available for further reading. [ 137 ]…”

Section: Immune Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions

Ser,

Webb,

Sener

et al. 2024

Journal of Immunotherapy and Precision Oncology

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“…Actually, although there is no clear SOC salvage therapy for rGB [ 289 ], patients who received no salvage treatment had poorer survival than those who received radiation and/or chemotherapy [ 356 ]. Therefore, re-resection, re-irradiation and systemic chemotherapy with TMZ rechallenge, nitrosoureas, BEV, and TTFields or clinical trial enrolment to test experimental drugs are considered for all recurrent patients [ 295 , 357 , 358 , 359 , 360 ]. Unfortunately, fewer than 43% of rGB patients were fit enough to be included in clinical trials [ 361 ].…”

Section: Present Therapy and Challengesmentioning

confidence: 99%

“…Up to now, therapeutic vaccines have generally yielded limited efficacy, despite their theoretical basis [ 360 , 789 ]. Combining diverse antigens, including tumor-associated antigens, neoantigens, and pathogen-derived antigens, and optimizing vaccine design or vaccination strategy may help with clinical efficacy improvement [ 790 , 791 ].…”

Section: Immunotherapiesmentioning

confidence: 99%

Glioblastoma Therapy: Past, Present and Future

Obrador,

Moreno-Murciano,

Oriol-Caballo

et al. 2024

IJMS

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Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood–brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

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“…However, despite aggressive treatment, GBM often recur, and the prognosis for patients is generally poor. The median survival time after diagnosis is relatively short (15 months), with the worst 5-year life expectancy among all human cancers (less than 7%), emphasizing the need for continued research into more effective treatment strategies [3].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

Lofiego,

Piazzini,

Caruso

et al. 2024

J Transl Med

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Background Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM. Methods Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients’ cohort. Results The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways. Conclusions Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.

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The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma

Cited by 8 publications

References 141 publications

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions

Glioblastoma Therapy: Past, Present and Future

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

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