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Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition
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Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Cancer Vaccines and Immunotherapy".

Deadline for manuscript submissions: 20 March 2026 | Viewed by 9559

Special Issue Editor

Dr. Takumi Kumai

E-Mail Website
Guest Editor
Department of Otolaryngology Head and Neck Surgery, Asahikawa Medical University, Midorigaoka East 2-1-1-1, Asahikawa, Hokkaido 0788510, Japan
Interests: tumor vaccine; T-cells; peptides; adjuvants; head and neck cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy is now a standard therapy in addition to surgery, chemotherapy, and radiotherapy for treating cancer. Immune checkpoint blockades are a form of immunotherapy that have acceptable results in many types of tumors. However, it only works for around 20% of patients, as it depends on the immune cells already present in the tumor microenvironment. If these cells are lacking or exhausted, the treatment is not effective. Tumor vaccines can help by increasing the number of antitumor immune cells, including CD8 T cells and CD4 T cells. Peptide epitopes from tumor-associated antigens (TAAs) can be used to develop a tumor vaccine. In the past, vaccines using tumor-derived peptides and inadequate adjuvants (such as incomplete Freund’s adjuvant) failed to achieve clinical antitumor effects. However, with improvements in our understanding of the immune system, we can now use peptides, costimulatory molecules, and cytokines in combination with adequate adjuvants to expand T cells and impede the immune-suppressive environment. This Special Issue will gather the latest advances in the field of tumor immunology to optimize tumor vaccines.

This Special Issue aims to cover various topics related to immunotherapy for cancer treatment. Some of the potential areas include but are not limited to the following: developing immune adjuvants for a tumor vaccine; assessing the immunological aspects of the tumor microenvironment; exploring the benefits of combining immunotherapy with chemoradiotherapy; optimizing the administration route and formula for a tumor vaccine; studying the polarization of immune cells in immunotherapy; impeding immune suppression in the tumor microenvironment; and re-educating immune cells in the tumor microenvironment.

Dr. Takumi Kumai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor vaccine
  • immune adjuvants
  • tumor immune environment
  • peptide vaccine
  • chemoradiotherapy
  • cytokines
  • suppressive immune cells
  • checkpoint inhibitors

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Published Papers (7 papers)

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Research

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18 pages, 1960 KiB  
Article
Venous Thromboembolic Risk Does Not Increase After a Third Dose of SARS-CoV-2 mRNA-BNT162b2 Vaccine in Cancer Patients Receiving Active Systemic Therapies: Updated Results from the Vax-On-Third-Profile Study
by Fabrizio Nelli, Enzo Maria Ruggeri, Antonella Virtuoso, Diana Giannarelli, Jona Barbuta, Fabrizio Chegai, Armando Raso, Valentina Panichi, Julio Rodrigo Giron Berrios, Marta Schirripa, Cristina Fiore, Francesco Schietroma, Alessandro Strusi, Carlo Signorelli, Mario Giovanni Chilelli, Francesca Primi and Agnese Fabbri
Vaccines 2025, 13(4), 392; https://doi.org/10.3390/vaccines13040392 - 8 Apr 2025
Viewed by 556
Abstract
(1) Background: Clinical evidence has raised concerns regarding a potential link between COVID-19 mRNA-based vaccines and the occurrence of thromboembolic events. So far, no research has explored the effects of this possible interaction in cancer patients undergoing active treatment. We leveraged prospective monitoring [...] Read more.
(1) Background: Clinical evidence has raised concerns regarding a potential link between COVID-19 mRNA-based vaccines and the occurrence of thromboembolic events. So far, no research has explored the effects of this possible interaction in cancer patients undergoing active treatment. We leveraged prospective monitoring from the Vax-On-Third-Profile study to examine the development of venous thromboembolism (VTE) after the third dose of mRNA-BNT162b2 (tozinameran) and its association with antibody and lymphocyte responses. (2) Methods: Patients who had received a third dose of tozinameran and had not experienced any VTE in the previous 30 days were eligible. A serological evaluation was conducted before the booster vaccination (timepoint-1) and four weeks thereafter (timepoint-2) to measure antibody titers against the SARS-CoV-2 spike protein, as well as to determine the absolute counts of T-helper cells, T-cytotoxic cells, B cells, and NK cells. Data were acquired from November 2021 to October 2022 and analyzed from November 2022 to October 2023. (3) Results: The present study involved 429 patients who were given a third dose of tozinameran from 26 September to 30 October 2021. Among the active treatments of interest, 109 (25.4%) patients received targeted therapy, 111 (25.9%) received cytotoxic chemotherapy, 39 (9.1%) received immune checkpoint inhibitors, 21 (4.9%) received endocrine therapy, and 30 (7.0%) received a combination of chemotherapy and targeted agents in the eight weeks preceding the booster dosing. In addition, 119 (27.7%) patients who had discontinued any systemic therapy for at least 12 weeks accounted for the reference subgroup. After a median follow-up time of 10.6 (95% CI 8.1–11.7) months, we observed 31 venous thromboembolic events in the general population, for an overall incidence rate of 7.2% (95% CI 5.0–10.1). The median time to VTE development after booster immunization was 99 (95% CI 85–112) days. In a univariate comparison, patients exposed to targeted therapies (11.3% [95% CI 6.0–18.9]; p = 0.030) or immune checkpoint inhibitors (16.2% [95% CI 6.2–32.0]; p = 0.012) had a significantly higher incidence of VTE than the reference cohort (3.4% [95% CI 0.9–8.5]). Univariate analysis of immune responses showed that only dynamic changes pertaining to NK cell distributions correlated significantly with VTE occurrence. Multivariate regression analysis confirmed only a high-level NK cell response (OR 6.10 [9% CI 2.16–17.21]; p = 0.001), a history of thromboembolic events (OR 9.81 [3.99–24.13]; p < 0.001), and the presence of a central venous catheter (OR 5.02 [95% CI 1.84–13.67]; p = 0.002) as independently associated with an increased risk of VTE. (4) Conclusions: This prospective cohort study provides unprecedented evidence that cancer patients have no increased risk of developing VTE after the third dose of tozinameran, regardless of the type of active therapy. The specific pattern of lymphocyte response appears to increase thromboembolic risk, underlying immune dysregulation as a causal cofactor. These findings emphasize the need for additional monitoring after periodic COVID-19 vaccination in cancer patients. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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13 pages, 2789 KiB  
Article
Targeted Delivery of Personalized Cancer Vaccines Based on Antibody–Antigen Complexes
by Yaling Zhang, Lingling Yan, He Sun, Ziyi Zhang, Fengyun Shen and Lele Sun
Vaccines 2025, 13(3), 324; https://doi.org/10.3390/vaccines13030324 - 19 Mar 2025
Viewed by 530
Abstract
Background: Personalized cancer vaccines based on tumor neoantigens show great potential in cancer immunotherapy due to their high safety and specificity. However, it is inherently difficult to realize the efficiently targeted delivery of personalized cancer vaccines to antigen-presenting cells (APCs). Methods: This study [...] Read more.
Background: Personalized cancer vaccines based on tumor neoantigens show great potential in cancer immunotherapy due to their high safety and specificity. However, it is inherently difficult to realize the efficiently targeted delivery of personalized cancer vaccines to antigen-presenting cells (APCs). Methods: This study aimed to address these challenges by developing and evaluating a personalized cancer vaccine based on antibody–antigen complexes, which was designed to enhance antitumor effects by increasing the utilization of tumor neoantigens by APCs. Mice were immunized with a carrier protein, keyhole limpet hemocyanin (KLH), to induce the production of antibodies against KLH. Subsequently, mice were immunized with KLH loaded with tumor neoantigens and the immunoadjuvant CpG ODN and underwent immunological analysis to evaluate the immune and antitumor effects. Results: The results showed that preimmunization with KLH could promote the uptake of the personalized KLH-based tumor vaccine, which was enhanced by dendritic cells (DCs) and macrophages (Mφs), by strengthening the T-cell immune responses to tumors. Conclusions: Collectively, this work provides a new idea for the targeted delivery of personalized cancer vaccines. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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12 pages, 2054 KiB  
Article
Type I Interferon Modulates the Function of Ly6C High-Expressing Naïve CD8+ T Cells to Promote an Antitumor Response
by Hsin-Fang Tu, Julia Tao, Ming-Hung Hu, Darrell Fan, Ya-Chea Tsai, Tzyy-Choou Wu and Chien-Fu Hung
Vaccines 2025, 13(3), 246; https://doi.org/10.3390/vaccines13030246 - 27 Feb 2025
Viewed by 720
Abstract
Background: Ly6C expression in naïve CD8+ T cells plays a crucial role in enhancing their effector activity, suggesting potential implications for cancer immunotherapy. This study investigates the functional impact of Ly6C expression on CD8+ T cells and explores albumin-conjugated IFNβ (Alb-IFNβ) as [...] Read more.
Background: Ly6C expression in naïve CD8+ T cells plays a crucial role in enhancing their effector activity, suggesting potential implications for cancer immunotherapy. This study investigates the functional impact of Ly6C expression on CD8+ T cells and explores albumin-conjugated IFNβ (Alb-IFNβ) as a strategy to modulate Ly6C expression and improve cancer vaccine efficacy. Methods: We analyzed the functional differences between Ly6C high-expressing (Ly6Chi) and Ly6C low-expressing (Ly6Clo) naïve CD8+ T cells in tumor suppression. To assess the role of type I interferon signaling, we administered Alb-IFNβ in C57BL/6J and IFNAR−/− mice and measured Ly6C expression in CD8+ T cells. The therapeutic potential of Alb-IFNβ was further evaluated in combination with a vaccinia virus encoding the HPV-16 E7 antigen (CRT-E7 vaccine) in a syngeneic TC-1 tumor model, assessing tumor growth, survival, and antigen-specific CD8+ T cell responses. Results: Naïve CD8+ T cells with elevated Ly6C expression exhibited enhanced tumor-suppressive capacity and required lower activation thresholds for effector function. Alb-IFNβ treatment selectively increased Ly6Chi naïve CD8+ T cells in C57BL/6J mice but not in IFNAR−/− mice, confirming type I interferon’s role in Ly6C regulation. Combining Alb-IFNβ pretreatment with the CRT-E7 vaccine significantly enhanced antigen-specific CD8+ T cell immunity, reducing tumor growth and prolonging survival in TC-1 tumor-bearing mice. Conclusions: Our findings suggest that Alb-IFNβ may enhance the antitumor activity of naïve CD8+ T cells by modulating Ly6C expression. Alb-IFNβ could potentially improve the efficacy of HPV vaccinia-based cancer vaccines, warranting further investigation as an adjuvant strategy in cancer immunotherapy. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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19 pages, 3006 KiB  
Article
Intranodal Injection of Immune Activator Demonstrates Antitumor Efficacy in an Adjuvant Approach
by Romano Josi, Anete Ogrina, Dominik Rothen, Ina Balke, Arnau Solé Casaramona, Simone de Brot and Mona O. Mohsen
Vaccines 2024, 12(4), 355; https://doi.org/10.3390/vaccines12040355 - 26 Mar 2024
Viewed by 2062
Abstract
The tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed [...] Read more.
The tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed as an attempt to turn a cold, unresponsive tdLN into a hot, responsive site. The adjuvant antitumor efficacy of our novel intranodal injection was evaluated in an aggressive metastatic mammary carcinoma murine model. The cancer cells were inoculated subcutaneously in the lower quadrant of the mouse to provoke the tdLN (inguinal lymph node). The study encompasses a range of methodologies, including in vivo and in vitro assays and high-dimensional flow cytometry analysis. Our findings demonstrated that intranodal administration of ImmAct following the dissection of the primary tumor led to improved tumor-free survival and minimized weight loss. ImmAct led to both local and systemic alterations in the cellular and humoral immunity. Additionally, after ImmAct treatment, non-responders showed a higher rate of exhausted CD8+ T cells compared to responders. Indeed, our innovative approach surpassed the gold standard surgery of sentinel lymph node excision. Overall, intranodal administration of ImmAct yielded a robust antitumor immune response, offering protection against micrometastases and relapse. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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Review

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14 pages, 1170 KiB  
Review
Emerging Immunotherapies in Lung Cancer: The Latest Advances and the Future of mRNA Vaccines
by Raquel Ramos and Nuno Vale
Vaccines 2025, 13(5), 476; https://doi.org/10.3390/vaccines13050476 - 28 Apr 2025
Viewed by 491
Abstract
Lung cancer is the most lethal malignancy worldwide, having the highest incidence rate. This is a heterogeneous disease classified according to its histological and molecular characteristics. Depending on these, different therapeutic approaches have already been approved for lung cancer treatment targeting genetic alterations [...] Read more.
Lung cancer is the most lethal malignancy worldwide, having the highest incidence rate. This is a heterogeneous disease classified according to its histological and molecular characteristics. Depending on these, different therapeutic approaches have already been approved for lung cancer treatment targeting genetic alterations or even the immune system. Nonetheless, other therapies are being studied to continuously improve the care and survival of lung cancer patients. Among them, immunotherapies are one of the main targets of investigation to try and combat the ability of some malignant cells to evade anti-tumor responses mediated by the immune system. Cancer vaccine development has emerged as a promising approach to strengthen the patient’s immune system and combat the disease, especially mRNA vaccines. Currently, there are several ongoing studies investigating the therapeutic efficacy of mRNA vaccines in lung cancer treatment alone or combined with other therapeutic drugs. This review aims to highlight the importance of immunotherapy in lung cancer treatment, presenting the most recent advances particularly in mRNA-based vaccines as well as the challenges and future perspectives. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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51 pages, 2702 KiB  
Review
Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges
by Marco Palma
Vaccines 2025, 13(4), 344; https://doi.org/10.3390/vaccines13040344 - 24 Mar 2025
Viewed by 1283
Abstract
Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body’s immune system to precisely target and eliminate cancer cells. However, several [...] Read more.
Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body’s immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody–drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines—including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines—aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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17 pages, 1191 KiB  
Review
Exosome-like Systems: From Therapies to Vaccination for Cancer Treatment and Prevention—Exploring the State of the Art
by Hamid Heydari Sheikhhossein, Francesca Iommelli, Natalia Di Pietro, Maria Cristina Curia, Adriano Piattelli, Rosanna Palumbo, Giovanni N. Roviello and Viviana De Rosa
Vaccines 2024, 12(5), 519; https://doi.org/10.3390/vaccines12050519 - 9 May 2024
Cited by 6 | Viewed by 3330
Abstract
Cancer remains one of the main causes of death in the world due to its increasing incidence and treatment difficulties. Although significant progress has been made in this field, innovative approaches are needed to reduce tumor incidence, progression, and spread. In particular, the [...] Read more.
Cancer remains one of the main causes of death in the world due to its increasing incidence and treatment difficulties. Although significant progress has been made in this field, innovative approaches are needed to reduce tumor incidence, progression, and spread. In particular, the development of cancer vaccines is currently ongoing as both a preventive and therapeutic strategy. This concept is not new, but few vaccines have been approved in oncology. Antigen-based vaccination emerges as a promising strategy, leveraging specific tumor antigens to activate the immune system response. However, challenges persist in finding suitable delivery systems and antigen preparation methods. Exosomes (EXs) are highly heterogeneous bilayer vesicles that carry several molecule types in the extracellular space. The peculiarity is that they may be released from different cells and may be able to induce direct or indirect stimulation of the immune system. In particular, EX-based vaccines may cause an anti-tumor immune attack or produce memory cells recognizing cancer antigens and inhibiting disease development. This review delves into EX composition, biogenesis, and immune-modulating properties, exploring their role as a tool for prevention and therapy in solid tumors. Finally, we describe future research directions to optimize vaccine efficacy and realize the full potential of EX-based cancer immunotherapy. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy and Vaccines Research: 2nd Edition)
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