Dr João Gonçalves PhD provides expert commentary on a recent study demonstrating real-world evidence of the feasibility and efficacy of a personalised peptide vaccine for glioblastoma – one of the most malignant primary brain tumours in adults.
The goal for cancer vaccines is straightforward: to harness what has been achieved for infectious diseases and their antigens to focus the immune system on eradicating cancer cells.1
A better understanding of the range of tumour-associated antigens and technological advances in neoantigen prediction, in vivo genetic and pharmacological models, and spectroscopic methods have facilitated improved designs for therapeutic cancer vaccines over the last decade.2,3
Despite these developments, glioblastoma remains one of the most formidable challenges in oncology, with current treatment modalities offering limited survival benefits. Regardless of advances in surgery, radiotherapy and chemotherapy, the prognosis for glioblastoma patients remains poor, with nearly all patients experiencing recurrence.
Previous studies for glioblastoma therapeutic vaccines have suggested that few neoantigens could be targeted in glioblastoma due to low mutation burden. However, a recent study by Latzer and colleagues offers real-world evidence and a promising glimpse into the potential of personalised peptide vaccines targeting tumour-specific neoantigens to extend survival in glioblastoma patients.3
Overview and significance
This retrospective study involved 173 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma, treated with a personalised neoantigen-derived peptide vaccine between 2015 and 2023.3
The personalised approach, tailored to the specific somatic mutations within each patient’s tumour, aims to harness the immune system by inducing a targeted T-cell response against the tumour. The median overall survival (OS) for the entire cohort was 31.9 months – a notable improvement compared with the historical median of approximately 15 months observed with the current standard of care.
The importance of this study lies in its demonstration of the feasibility, safety and potential efficacy of such personalised vaccines in a real-world setting.
The ability to generate a vaccine within 16 weeks of tumour tissue acquisition and observe a robust immune response in 88% of the patients underscores the practicality of this approach. Moreover, the study shows a clear correlation between the strength of the vaccine-induced immune response and patient survival, with those exhibiting multiple vaccine-induced T-cell responses achieving a median OS of 53 months.
Clinical implications and challenges of personalised peptide vaccines
This study provides compelling evidence for clinicians and researchers that personalised peptide vaccines could significantly advance the treatment of glioblastoma. The fact that most patients tolerated the vaccine well, with only grade 1 or 2 adverse events, suggests that this approach could be integrated into clinical practice without adding undue toxicity.
However, the study also highlights several challenges. First, the heterogeneity of the patient population, including primary and recurrent glioblastoma cases, introduces variability that could confound the interpretation of results. Additionally, the study’s retrospective nature and the absence of a randomised control group limit the ability to draw definitive conclusions about the vaccine’s efficacy relative to standard therapies.
The study’s reliance on patients who could afford the cost of the vaccine and travel to Germany introduces a potential socio-economic bias, which may limit the generalisability of the findings.
Mechanistic insights and future directions
The study’s focus on the immunogenicity of personalised vaccines provides valuable mechanistic insights. The detection of vaccine-induced T-cell responses in most patients and the association of these responses with prolonged survival support the hypothesis that effective anti-tumour immunity can be achieved through personalised vaccination strategies.
This is particularly relevant in glioblastoma, a tumour type often considered immunologically ‘cold’ due to its low mutational burden and immunosuppressive microenvironment.
Moving forward, exploring the factors contributing to variability in patients’ immune responses will be critical. The study noted that 10% of patients did not mount a detectable T-cell response, which raises questions about the potential barriers to effective immunisation in these individuals. Understanding the role of factors such as the tumour microenvironment, immune checkpoint expression and patient-specific immunogenetic factors will be essential in refining this approach.
Additionally, the study opens the door to further exploration of combination therapies. The observation that adding bevacizumab, a vascular endothelial growth factor inhibitor, was associated with reduced survival suggests that careful consideration is needed when integrating personalised vaccines with other therapies. Combining immune checkpoint inhibitors or other immune response modulators to enhance the vaccine’s efficacy may be beneficial.
Future clinical development of personalised peptide vaccines
The promising results of this real-world study set the stage for prospective, randomised clinical trials that can more rigorously assess the efficacy of personalised neoantigen vaccines.1,2,4 Such trials should aim to control for the heterogeneity seen in this study by focusing on more homogeneous patient populations. Moreover, they should investigate the optimal timing and sequencing of vaccine administration relative to other treatments, such as surgery, radiotherapy and chemotherapy.
Given the significant resources required for the development of personalised vaccines, future efforts should also focus on streamlining the production process. Advances in next-generation sequencing and bioinformatics will be vital in reducing the time and cost associated with vaccine development, making this approach more accessible to a broader patient population.5,6
Another critical area of investigation will be the long-term immune monitoring of patients who respond to the vaccine.7 The durability of the immune response and its ability to prevent recurrence in the long term are essential considerations for the overall success of this treatment strategy. The study’s indication that vaccine-specific T-cells can persist and continue to provide protection suggests that long-term benefits may be achievable.
Conclusion
The study by Latzer et al represents a significant step forward in the development of personalised cancer immunotherapies.3
Demonstrating the feasibility and potential efficacy of neoantigen-targeted peptide vaccines in a real-world setting provides a foundation for future clinical trials that could transform the treatment landscape for glioblastoma and potentially other solid tumours.
However, as with any pioneering approach, further research is needed to address the challenges and refine the strategies that will enable the widespread adoption of this promising therapeutic modality. If successful, personalised peptide vaccines could offer a new avenue of hope for patients with glioblastoma, a disease that has long been synonymous with poor prognosis.
Author
João Gonçalves PharmD PhD
Faculty of Pharmacy, University of Lisbon, Portugal
References
- Latzer P et al. A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine. Nat Commun 2024;15:6870.
- Saxena M et al. Therapeutic cancer vaccines. Nat Rev Cancer 2021;21:360–78.
- Sellars M., Wu CJ, Fritsch EF. Cancer vaccines: building a bridge over troubled waters. Cell 2022;185:2770–88.
- Dunn GP et al. Considerations for personalized neoantigen vaccination in malignant glioma. Adv Drug Deliv Rev 2022;186:114312.
- Grassl N et al. A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nat Med 2023;29:2586–92.
- Hilf N et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 2019;565:240–5.
- Keskin DB et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 2019;565:234–9.
