Expanded question: What does the latest evidence suggest for the efficacy and safety of the messenger RNA vaccine for Glioblastoma?

Answered on September 13, 2024
The latest evidence on the efficacy and safety of messenger RNA (mRNA) vaccines for glioblastoma (GBM) is promising but still primarily in the preclinical and early clinical trial stages.
Recent studies have demonstrated that mRNA vaccines targeting tumor-specific neoantigens and tumor-associated antigens can elicit robust anti-tumor immune responses in preclinical models of GBM. For instance, Trivedi et al. showed that personalized mRNA vaccines could effectively target multiple tumor antigens, resulting in increased tumor-infiltrating lymphocytes and a favorable shift in the tumor microenvironment from immunologically cold to hot.[1] This suggests a potential for mRNA vaccines to overcome the immunosuppressive environment typical of GBM.
Chen et al. identified several potential tumor antigens suitable for mRNA vaccine development in gliomas, emphasizing the importance of selecting appropriate immune subtypes for vaccination to maximize efficacy.[2] This stratification could be crucial for tailoring mRNA vaccine therapies to individual patients based on their tumor's immunological profile.
Moreover, Mao et al. reviewed the progress of mRNA-based dendritic cell vaccines, highlighting their potential in both preclinical and early clinical trials. These vaccines have shown promise in generating strong immune responses and improving survival outcomes in GBM models.[3]
In terms of safety, the available data from early-phase clinical trials indicate that mRNA vaccines are generally well-tolerated, with common adverse events being mild and related to the injection site.[1][3] However, comprehensive safety profiles will require further validation in larger clinical trials.
In summary, mRNA vaccines for glioblastoma show promising efficacy in preclinical models and early clinical trials, with a favorable safety profile. Continued research and clinical trials are necessary to fully establish their therapeutic potential and optimize their use in clinical practice.

References

1.
mRNA-based Precision Targeting of Neoantigens and Tumor-Associated Antigens in Malignant Brain Tumors.

Trivedi V, Yang C, Klippel K, et al.

Genome Medicine. 2024;16(1):17. doi:10.1186/s13073-024-01281-z.

Leading Journal
New Research

Background: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.

Methods: Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.

Results: Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.

Conclusions: We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

2.
Identification of Tumor Antigens and Immune Subtypes of Glioma for mRNA Vaccine Development.

Chen Z, Wang X, Yan Z, Zhang M.

Cancer Medicine. 2022;11(13):2711-2726. doi:10.1002/cam4.4633.

Recent evidence suggested that the mRNA vaccine has been effective for many tumors, but its progress in gliomas was slow. In this study, we screened potential tumor antigens and suitable populations for mRNA vaccine to develop mRNA vaccine for glioma. We integrated the normalized RNA sequencing expression data and somatic mutation data from TCGA-GBM, TCGA-LGG, and CGGA datasets. Putative antigens in glioma were identified by selecting highly mutated genes with intimate correlation with clinical survival and immune infiltration. An unsupervised partition around medoids algorithm was utilized to stably cluster the patients into five different immune subtypes. Among them, IS1/2 was cold tumor with low tumor mutation burden (TMB), immunogenic cell death (ICDs), and immune checkpoints (ICPs), and IS4/5 was hot tumor with high TMB, ICDs, and ICPs. Monocle3 package was used to evaluate the immune status similarity and evolution in glioma, which identified cluster IS2A/2B within IS2 subtype to be more suitable vaccination receivers. Weighted gene co-expression network analysis identified five hub immune genes as the biomarkers of patients' immune status in glioma. In conclusion, NAT1, FRRS1, GTF2H2C, BRCA2, GRAP, NR5A2, ABCB4, ZNF90, ERCC6L, and ZNF813 are potential antigens suitable for glioma mRNA vaccine. IS1/2A/2B are suitable for mRNA vaccination.

3.
Current mRNA-based Vaccine Strategies for Glioma Treatment.

Mao M, Yang W, Zhang X.

Critical Reviews in Oncology/Hematology. 2024;202:104459. doi:10.1016/j.critrevonc.2024.104459.

New Research

Gliomas are one of the most aggressive types of brain tumors and are associated with high morbidity and mortality rates. Currently, conventional treatments for gliomas such as surgical resection, radiotherapy, and chemotherapy have limited effectiveness, and new approaches are needed to improve patient outcomes. mRNA-based vaccines represent a promising therapeutic strategy for cancer treatment, including gliomas. Recent advances in immunotherapy using mRNA-based dendritic cell vaccines have shown great potential in preclinical and clinical trials. Dendritic cells are professional antigen-presenting cells that play a crucial role in initiating and regulating immune responses. In this review, we summarize the current progress of mRNA-based vaccines for gliomas, with a focus on recent advances in dendritic cell-based mRNA vaccines. We also discuss the feasibility and safety of mRNA-based clinical applications for gliomas.

Expanded question: How does the efficacy of the mRNA vaccine for Glioblastoma compare to existing treatments, considering its promising results in preclinical models and early clinical trials?

Answered on September 13, 2024
The efficacy of mRNA vaccines for glioblastoma (GBM) is still under investigation, primarily in preclinical models and early clinical trials. These vaccines have shown promising results in eliciting robust anti-tumor immune responses and improving survival outcomes in preclinical models.[1-2] However, when compared to existing standard treatments, such as the Stupp protocol (surgical resection followed by radiotherapy and temozolomide), mRNA vaccines are not yet established as a superior or equivalent option.
The Stupp protocol remains the gold standard for GBM treatment, with median overall survival (OS) of approximately 14.6 months and progression-free survival (PFS) of 6.9 months.[3] In contrast, mRNA vaccines have demonstrated potential in preclinical settings but lack extensive clinical data to confirm their efficacy in improving OS and PFS in a comparable manner.
For instance, personalized mRNA vaccines targeting tumor-specific neoantigens have shown the ability to increase tumor-infiltrating lymphocytes and shift the tumor microenvironment from immunologically cold to hot, which is promising for future therapeutic applications.[1] However, these findings are preliminary and require validation in larger, controlled clinical trials.
In summary, while mRNA vaccines for glioblastoma show promising preclinical efficacy, they are not yet proven to be more effective than existing treatments like the Stupp protocol. Further clinical trials are necessary to establish their role in the therapeutic landscape of GBM.

References

1.
mRNA-based Precision Targeting of Neoantigens and Tumor-Associated Antigens in Malignant Brain Tumors.

Trivedi V, Yang C, Klippel K, et al.

Genome Medicine. 2024;16(1):17. doi:10.1186/s13073-024-01281-z.

Leading Journal
New Research

Background: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.

Methods: Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.

Results: Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.

Conclusions: We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

2.
Current mRNA-based Vaccine Strategies for Glioma Treatment.

Mao M, Yang W, Zhang X.

Critical Reviews in Oncology/Hematology. 2024;202:104459. doi:10.1016/j.critrevonc.2024.104459.

New Research

Gliomas are one of the most aggressive types of brain tumors and are associated with high morbidity and mortality rates. Currently, conventional treatments for gliomas such as surgical resection, radiotherapy, and chemotherapy have limited effectiveness, and new approaches are needed to improve patient outcomes. mRNA-based vaccines represent a promising therapeutic strategy for cancer treatment, including gliomas. Recent advances in immunotherapy using mRNA-based dendritic cell vaccines have shown great potential in preclinical and clinical trials. Dendritic cells are professional antigen-presenting cells that play a crucial role in initiating and regulating immune responses. In this review, we summarize the current progress of mRNA-based vaccines for gliomas, with a focus on recent advances in dendritic cell-based mRNA vaccines. We also discuss the feasibility and safety of mRNA-based clinical applications for gliomas.

3.
Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline.

Mohile NA, Messersmith H, Gatson NT, et al.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2022;40(4):403-426. doi:10.1200/JCO.21.02036.

Leading Journal

Clinical trials that specifically enrolled older (defined in some trials as anywhere from ≥ 60 to ≥ 70 years) or frail patients with the goal of identifying an attenuated therapeutic regimen are discussed separately in the Literature Review and Analysis section for recommendations 2.5 and 2.6. No trials were identified that compared RT alone to chemotherapy alone in patients that were not categorized as older or frail.
Prior to 2005, fractionated RT was considered the standard of care for the treatment of glioblastoma. TMZ given concurrently with RT followed by adjuvant TMZ versus RT alone has been studied in two randomized trials: the EORTC 26981-22981 trial reported by Stupp et al in 2005 and 2009 and the trial reported by Athanassiou et al in 2005. The EORTC 26981-22981 trial used 60 Gy in 2 Gy fractions at five fractions a week in both arms. Stupp et al, reported statistically significant differences in OS (median OS 14.6 months _v_ 12.1 months; HR, 0.63; 95% CI, 0.53 to 0.75; _P_ < .0001) and PFS (median PFS 6.9 months _v_ 5.0 months; HR, 0.56; 95% CI, 0.47 to 0.66; _P_ < .0001) in favor of the addition of TMZ. Improvements in OS were retained with long-term follow-up, demonstrating benefits in both 2-year and 5-year survival. Grade 3 or worse adverse events were only reported with TMZ, and no persistent health-related quality of life (HRQOL) differences were reported. _MGMT_ promoter methylation status was known in 206 out of 573 (36%) patients in this study and was associated with longer survival.