Journal of Vaccine Research, 2025, Vol.15, No.1, 45-55 http://medscipublisher.com/index.php/jvr 50 Therapeutic vaccines and other therapies, especially when used in combination with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies, have more promising effects. For instance, early trials of the combination of PDC*lung01 vaccine and pentiumab have shown that compared with previous treatment methods, the proportion of tumor shrinkage is higher (with an objective response rate of 63.2%), the disease is better controlled, the time without disease progression in patients is longer, and the safety is controllable (Awad et al., 2022; Theelen et al., 2024). Personalized neoantigen vaccines combined with chemotherapy and anti-PD-1 treatment can also strongly activate the immune response and produce clinical efficacy. This indicates that vaccines can be combined with existing immunotherapies to better combat tumors. 4.3 Evaluation methods and data for survival benefits Clinical trials of therapeutic vaccines for non-small cell lung cancer commonly use tumor reduction ratio (objective response rate ORR), time without disease progression in patients (progression-free survival PFS), and overall survival (OS). The effect is judged by immune response indicators (such as the proliferation of T cells against antigens and the production of cytokines) and other indicators (Awad et al., 2022; Gu et al., 2022; Wang et al., 2024; Theelen et al., 2024). Researchers will use IFN-γ ELISPOT, flow cytometry, single-cell analysis and other methods to monitor the immune response triggered by the vaccine to see if its effect is good and how long it can last (Brunsvig et al., 2011; Kjeldsen et al., 2018; Ingels et al., 2024). In some studies, patients with vaccine-specific T cells in their bodies and normal cytokine levels had better treatment outcomes and longer survival periods. Although some trials have provided data indicating that patients have a relatively good survival situation, for instance, 20% of patients who received the IDO peptide vaccine were still alive within six years, and patients who responded to the telomerase vaccine did not have cancer recurrence for a long time, most studies still have not been able to precisely prove that the vaccine can prolong patients' lives (Brunsvig et al., 2011; Kjeldsen et al., 2018). Early research and analysis have found that combining multiple treatment methods can prevent patients' conditions from deteriorating for a longer period of time, and the number of patients with tumor shrinkage has also increased. However, large-scale randomized controlled trials still need to be conducted to confirm these conclusions and figure out exactly how much therapeutic vaccines can extend the lifespan of patients with non-small cell lung cancer (Awad et al., 2022; Theelen et al., 2024). The ongoing research mainly aims to identify patients suitable for vaccination, develop more effective vaccines, and optimize the combined use of multiple treatments, thereby enhancing the therapeutic effect (Baka et al., 2024; Chen et al., 2024; Wang et al., 2024). 5 Challenges and Limitations 5.1 Tumors vary greatly, making it difficult to find suitable targets for attack The tumors of non-small cell lung cancer vary greatly, which brings great trouble to the development of therapeutic vaccines. Due to the diverse gene mutations and antigen expressions within and between tumors, it is difficult to identify attack targets that all tumors have (Saxena et al., 2021; Fan et al., 2023; Chen et al., 2024; Wang et al., 2024). This difference leads to the fact that the same antigen or the same group of antigens are not present in all tumor cells, thus making the immune attack incomplete and the tumor more likely to escape. Moreover, tumors can change under immune stress, causing the original antigens to disappear or alter, thereby reducing the efficacy of vaccines. It is also difficult to select the most suitable antigen because a balance needs to be struck between stimulating immunity and ensuring safety. Some tumor-associated antigens are also present in normal tissues. Using them as vaccines may cause autoimmune problems (Saxena et al., 2021; Fan et al., 2023). Although neoantigen-based methods are promising, they require individual search and validation for each patient, have high technical requirements, and are particularly time-consuming (Chen et al., 2024). Therefore, choosing the right antigen remains the biggest challenge in developing an effective and universal vaccine for non-small cell lung cancer. 5.2 The current vaccines have weak immune stimulation capabilities and their effects are not satisfactory Many therapeutic vaccines for non-small cell lung cancer have limited ability to stimulate immunity, and only a few patients can produce a strong and long-lasting immune response (Fan et al., 2023; Chen et al., 2024). This is
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