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Will cancer vaccines be the direction of curing cancer?
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Will cancer vaccines be the direction of curing cancer?
Antitumor immunity is initiated by tumor antigens released by dying tumor cells, which are then taken up, processed, and presented by antigen-presenting cells (APCs).
Under optimal co-stimulation and appropriate signaling conditions, tumor antigen-specific T cells are activated, proliferated , and transported into tumors for targeted killing.
Spontaneous anti-tumor immune responses can occur in some individuals, and cancer vaccines are designed to promote these same effects and can be used for broader clinical impact.
What has been missing from cancer vaccines so far? In short, robust clinical outcomes . Some studies suggest that cancer vaccination alone may not be effective enough in advanced and metastatic tumor settings , but may have a positive clinical impact in lower tumor burden settings.
Recently, “Science Translational Medicine” magazine published an article: What’s next for cancer vaccines , the author discussed the challenges and solutions encountered in tumor vaccine antigen targets, vaccine platforms, rational combination and immune monitoring, etc., for the next The development of tumor vaccines pointed out the direction.
What are the antigenic properties of tumors?
Ideally, cancer vaccines require targeted tumor-specific antigens (TSAs) to avoid potential autoimmune responses and central tolerance issues.
Tumors can be detected by the immune system, but vaccines with epitopes of mutant proteins cannot be efficiently presented by the major histocompatibility complex (MHC) .
About 15% of tumors are virally driven, and proteins from viruses, such as human papillomavirus (HPV) proteins E6 and E7, are TSAs that have been successfully targeted .
In addition, malignant transformation of cells depends on the accumulation of DNA damage . The immune system often responds to neoantigens caused by this DNA damage .
Recognition of neoantigens also appears to be an important driver of T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapy in the clinic.
Many research groups use proprietary and unique algorithms to select epitopes that tumors can present, such as high-resolution mass spectrometry that can directly identify MHC-bound surface peptides, process and present them to the immune system.
Mutated neoantigens increase the specificity of tumor targeting and stimulate T cells , but no experiments have yet determined whether they have more efficient antigen targeting.
As neoantigens have emerged as targets for potent tumor-directed T-cell responses, three clinical trials of neoantigen-based vaccines in melanoma patients used dendrites loaded with short peptides, long pep peptides, or RNA. cells (dc), demonstrating the safety, feasibility and robust immunogenicity of this approach.
How should tumor antigens be delivered ?
The most critical components of cancer vaccines are tumor antigens (signal 1), co-stimulatory (signal 2) and cytokines (signal 3) .
Antigens are often combined with adjuvants, which stabilize immunogenic molecules and can stimulate responses mediated by APCs and T cells.
Adjuvants currently used include oil and water emulsions, cytokines, toll-like) signal-inducing molecules, CD40 co-stimulatory triggers, and the like.
mRNA vaccines have also emerged as viable vaccine platforms and package RNA molecules into lipid nanoparticles for optimized delivery and immunostimulatory properties.
How to improve T cell activation and anti-tumor activity?
For DC vaccines, various combinations have been tested, including the addition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and/or programmed cell death protein 1 (PD-1)/PD ligand 1 blockade Drugs, adoptive transfer of T cells, low IL-2, interferon-α (IFN-α), and chemotherapy have made some improvements.
Initial clinical success of an HPV16 peptide encoding a synthetic long peptide (SLP) vaccine in early-stage cervical cancer, but did not produce the same efficacy in advanced patients, led to a combination trial with cisplatin and SLP combined with checkpoint blockade testing.
A key issue is the timing and sequence of vaccinations . Mouse studies showing that vaccines preceded by checkpoint blockade are more effective than the reverse sequence are also supported by data from human trials. Complicated by further examination of checkpoint combinations by FDA approval, for example a trial of patients eligible for an experimental vaccine may have received a checkpoint blockade as an SOC.
Lessons Learned and Future Outlook
Currently, the new product is enjoying greater success. FixVac, an intravenous liposomal RNA vaccine, mediates durable responses in checkpoint inhibitor-experienced unresectable melanoma patients, with responses improving in individuals given higher doses.
Furthermore, neoantigen vaccines were able to boost intratumoral T cell responses in microglioblastoma (GBM), and neoantigen-specific T cells from peripheral blood were detected in intracranial GBM tumor tissues.
The best responses were among dexamethasone-naïve patients, revealing SOC drugs that may limit the efficacy of combination therapy.
Cancer vaccination is a method that can safely boost anti-tumor T cell responses in vivo and can be therapeutically effective in cancer patients at many disease stages.
While the basic structure of a successful vaccine is well understood, optimization of each component is still being developed.
Immune monitoring reveals key efficacy mechanisms, particularly epitope spread induction, that can be applied to new cancer vaccine approaches.
Optimized treatment regimens and a better mechanistic understanding of how to induce effective responses are critical to the success of cancer vaccines.
Reference and image source: Science Translational Medicine
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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.