Neoantigen-driven immunotherapeutic strategies for glioblastoma
| Therapeutic strategy | Mechanism | Application in GBM | Key challenges | Recent advances | Future directions | References |
|---|---|---|---|---|---|---|
| Personalized cancer vaccines | Prime the immune system with patient-specific neoantigens. | Induces tumor-specific immune responses by presenting identified neoantigens, activating both CD8+ T cells and helper T cells. | Limited immune response due to tumor heterogeneity and immune evasion mechanisms (e.g., checkpoint inhibition). | Development of combinatory approaches with checkpoint inhibitors to boost efficacy in GBM. | Expansion to other tumor types beyond GBM and improvement in neoantigen identification for higher immunogenicity. | [134] |
| Adoptive T cell therapies | Infuse patients with expanded T cells specifically targeting neoantigens. | Increases the quantity of tumor-specific T cells, improving tumor cell recognition and destruction through cytotoxic mechanisms. | Difficulty in maintaining T cell persistence and activity within the immunosuppressive GBM tumor microenvironment. | Use of IL-2 or other cytokines to support T cell expansion and persistence in vivo. | Optimizing T cell expansion methods and improving the persistence of T cells within the GBM microenvironment. | [264] |
| TCR-engineered lymphocytes | Modify T cells ex vivo to express receptors targeting specific neoantigens on tumor cells, then reinfuse them into the patient. | Improves T cell specificity and efficacy in targeting neoantigen-expressing tumor cells, enhancing tumor cell recognition and killing. | Off-target effects and T cell exhaustion in the hostile tumor environment can reduce efficacy. | Advances in TCR optimization to avoid off-target effects and increase the recognition of a broader range of neoantigens in GBM. | Developing next-generation TCR engineering techniques for targeting neoantigens more effectively, along with immune checkpoint blockers. | [149] |
| Immunotherapy combination therapy | Combine personalized vaccines, adoptive T cells, or TCR-engineered lymphocytes with other immunomodulatory agents (e.g., checkpoint inhibitors). | Provides synergistic effects, improving immune response and overcoming GBM’s immune evasion mechanisms (e.g., PD-1/PD-L1 axis). | Combination therapy may lead to increased toxicity, requiring careful patient monitoring and dosing. | Promising results combining anti-PD-1/PD-L1 with TCR-engineered T cells or vaccines to overcome immune suppression. | Expanding personalized combination therapies to include other immune modulators and identifying the most effective pairings. | [261] |
| Chimeric antigen receptor (CAR)-T cells | Engineer T cells with a CAR that targets a specific antigen on GBM cells, enhancing their ability to recognize and attack tumors. | Enhances tumor cell recognition and cytotoxicity against neoantigen-expressing GBM cells. | Limited by antigen escape, GBM’s heterogeneous nature, and CAR-T cell exhaustion in the tumor microenvironment. | Development of CAR-T cells targeting novel neoantigens and improving persistence through advanced cytokine support and genetic engineering. | Exploring multi-antigen CAR T cells targeting diverse neoantigens in GBM, along with methods to sustain CAR-T cell activity. | [265] |
| Oncolytic virus therapy | Use modified viruses that selectively infect and kill tumor cells while stimulating anti-tumor immune responses. | Induces tumor cell death and enhances immune responses to tumor neoantigens, potentially increasing efficacy of vaccines or T cell therapies. | Potential for oncolytic virus resistance and insufficient targeting specificity in the heterogeneous GBM tumor environment. | Oncolytic virus therapies combined with checkpoint inhibitors have shown early promise in preclinical models. | Investigating improved viral vectors that can better target GBM cells and enhance immune activation. | [123] |
| CRISPR-Cas9 gene editing | Modify the genome of T cells or tumor cells to enhance neoantigen targeting or create new therapeutic pathways for immune evasion. | Potential to enhance the precision and efficiency of T cell therapies or alter GBM’s immune evasion mechanisms to increase treatment efficacy. | Risks of off-target mutations, ethical concerns with gene-editing, and long-term effects of genetic modifications. | Successful use of CRISPR-Cas9 to engineer T cells for better targeting of neoantigens, with promising results in early-phase trials. | Expansion of CRISPR-based approaches to more effectively engineer immune cells and GBM cells for personalized therapies. | [175] |
| Peptide-based immunotherapies | Use synthetic peptides derived from identified neoantigens to activate immune cells in the tumor microenvironment. | Can specifically activate immune responses targeting neoantigens in GBM, enhancing tumor-specific immunity. | Limited by peptide delivery and the complexity of ensuring effective immune activation against heterogenous tumor populations. | Nanoparticle-mediated peptide delivery systems have enhanced peptide efficacy in preclinical models. | Optimizing delivery methods for peptide-based therapies to ensure efficient and targeted immune activation within GBM tumors. | [52] |
| Neoantigen-based biomarkers | Utilize identified neoantigens as biomarkers to predict treatment response and monitor therapy efficacy. | Can guide personalized therapy choices, monitor immune response, and track disease progression in GBM patients. | The complexity of tracking neoantigen responses in vivo, and the need for accurate biomarkers to predict treatment outcomes. | Development of liquid biopsy approaches using neoantigen biomarkers for non-invasive tracking of tumor progression and therapy response. | Continued refinement of non-invasive biomarkers for GBM treatment monitoring, including early detection of resistance. | [266] |
TCR: T-cell receptor; GBM: glioblastoma