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

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 55488

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Dr. So Young Yoo

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Guest Editor

BIO-IT Foundry Technology Institute, Pusan National University, Busan, Republic of Korea
Interests: cancer immunotherapy; virotherapy; regenerative therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vaccines have saved millions of people from infectious diseases. Despite advances in immunology and medicine, developing vaccines against cancers is still a challenge for researchers. Recent studies have shown some remarkable steps toward successful development. Vaccines are used to induce antitumor immunity through specific tumor-associated antigens. Cancer cells also express normal cells antigens, which limits therapeutic vaccine development. Targeting tumor-associated antigens and neoantigens on cancer cells is widely used to stimulate effective antitumor immunity in therapeutic vaccine approaches. In addition, various adjuvants have been used to enhance antitumor immunity with these targeting approaches. The tumor microenvironment comprises various immune cells and suppresses tumor antigen expression. In order to target the tumor microenvironment, combined therapeutic approaches using oncolytic viruses, immune checkpoint inhibitors, and adoptive T-cells therapy have been widely employed. This issue will specially focus on cancer vaccine development. Therefore, we welcome research articles as well as review articles, which would provide not only immense knowledge in these topics but also lead to new directions in cancer vaccine research.

Dr. So Young Yoo
Guest Editor

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Keywords

cancer immunotherapy
therapeutic vaccine
tumor-associated antigens
neoantigens
adjuvant
tumor microenviroment
oncolytic viruses
immune checkpoint inhibitors

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Published Papers (10 papers)

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Research

Jump to: Review

16 pages, 2827 KiB

Open AccessArticle

Intratumoral Combinatorial Administration of CD1c (BDCA-1)⁺ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial

by Julia Katharina Schwarze, Gil Awada, Louise Cras, Jens Tijtgat, Ramses Forsyth, Inès Dufait, Sandra Tuyaerts, Ivan Van Riet and Bart Neyns

Vaccines 2020, 8(4), 670; https://doi.org/10.3390/vaccines8040670 - 10 Nov 2020

Cited by 22 | Viewed by 3715

Abstract

Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG₁ monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)⁺ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)⁺ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 10⁶ CD1c (BDCA-1)⁺ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumonitis (n = 2), colitis (n = 1), and bullous pemphigoid (n = 1). The best response was a durable partial response in a patient with stage IV melanoma who previously progressed on checkpoint inhibitors. Our combinatorial therapeutic approach, including IT injection of CD1c (BDCA-1)⁺ myDCs, is feasible and safe, and it resulted in encouraging signs of antitumor activity in patients with advanced solid tumors. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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14 pages, 3640 KiB

Open AccessArticle

A Polypeptide of Tumor-Associated Antigen L6 with Intrinsic Adjuvant Activity Enhances Antitumor Immunity

by Yuh-Pyng Sher, Kit Man Chai, Wen-Ching Chen, Kuan-Yin Shen, I-Hua Chen, Ming-Hui Lee, Fang-Feng Chiu and Shih-Jen Liu

Vaccines 2020, 8(4), 620; https://doi.org/10.3390/vaccines8040620 - 21 Oct 2020

Cited by 1 | Viewed by 2670

Abstract

Peptide vaccines are safe, and aim to elicit and expand tumor-specific immunity so as to eradicate tumors. However, achieving strong and long-lasting anti-tumor immunity with peptide vaccines for the antigen-specific treatment of cancer is challenging, in part because their efficacy depends on strong adjuvants or immunomodulators. We approached this problem by conjugating an epitope-based cancer vaccine with a lipidated sequence (an immunomodulator) to elicit a strong immune response. Lipidated and non-lipidated polyepitope proteins were generated that contained the universal T helper cell epitope (pan-DR), B cell epitopes, and the extended loop sequence of extracellular domain 2 of tumor-associated antigen L6 (TAL6). We show that the lipidated polyepitope cancer vaccine can activate bone marrow-derived dendritic cells, and trigger effective antigen-specific antibody and T helper cell responses, more effectively than the non-lipidated vaccine. Moreover, potent T cell immune responses were elicited in mice inoculated with the lipidated polyepitope cancer vaccine, providing protective antitumor immunity in mice bearing TAL6 tumors. Our study demonstrates that a lipidated polyepitope cancer vaccine could be employed to generate potent anti-tumor immune responses, including humoral and cellular immunity, which could be beneficial in the treatment of TAL6⁺ cancer. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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17 pages, 2520 KiB

Open AccessArticle

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

by Insu Jeon, Jeong-Mi Lee, Kwang-Soo Shin, Taeseung Kang, Myung Hwan Park, Hyungseok Seo, Boyeong Song, Choong-Hyun Koh, Jeongwon Choi, Young Kee Shin, Byung-Seok Kim and Chang-Yuil Kang

Vaccines 2020, 8(3), 403; https://doi.org/10.3390/vaccines8030403 - 22 Jul 2020

Cited by 3 | Viewed by 3735

Abstract

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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17 pages, 4355 KiB

Open AccessArticle

Overcoming Tumor Resistance to Oncolyticvaccinia Virus with Anti-PD-1-Based Combination Therapy by Inducing Antitumor Immunity in the Tumor Microenvironment

by So Young Yoo, Narayanasamy Badrinath, Su-Nam Jeong, Hyun Young Woo and Jeong Heo

Vaccines 2020, 8(2), 321; https://doi.org/10.3390/vaccines8020321 - 19 Jun 2020

Cited by 20 | Viewed by 4482

Abstract

The tumor microenvironment (TME) comprises different types of immune cells, which limit the therapeutic efficacy of most drugs. Although oncolytic virotherapy (OVT) boosts antitumor immunity via enhanced infiltration of tumor-infiltrated lymphocytes (TILs), immune checkpoints on the surface of tumors and TILs protect tumor cells from TIL recognition and apoptosis. OVT and immune checkpoint blockade (ICB)-based combination therapy might overcome this issue. Therefore, combination immunotherapies to modify the immunosuppressive nature of TME and block immune checkpoints of immune cells and tumors are considered. In this study, cancer-favoring oncolytic vaccinia virus (CVV) and anti–programmed cell death protein-1 (anti-PD-1) were used to treat mouse colorectal cancer. Weekly-based intratumoral CVV and intraperitoneal anti-PD-1 injections were performed on Balb/c mice with subcutaneous CT26 tumors. Tumor volume, survival curve, and immunohistochemistry-based analysis demonstrated the benefit of co-treatment, especially simultaneous treatment with CVV and anti-PD-1. Infiltration of CD8⁺PD-1⁺ T-cells showed correlation with these results. Splenocytes enumeration also suggested CD4⁺ and CD8⁺ T-cell upregulation. In addition, upregulated CD8, PD-1, and CD86 messenger RNA expression was observed in this combination therapy. Therefore, CVV+anti-PD-1 combination therapy induces antitumor immunity in the TME, overcoming the rigidity and resistance of the TME in refractory cancers. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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13 pages, 2847 KiB

Open AccessArticle

PD-1 Immune Checkpoint Blockade Promotes Therapeutic Cancer Vaccine to Eradicate Lung Cancer

by Pournima Kadam and Sherven Sharma

Vaccines 2020, 8(2), 317; https://doi.org/10.3390/vaccines8020317 - 18 Jun 2020

Cited by 20 | Viewed by 4044

Abstract

(1) Background: Targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the activation of immune responses against cancer. Therapeutic vaccination, which induces specific immune responses against tumor antigens (Ags), is an attractive option. (2) Methods: Utilizing a K-RasG12Dp53null murine lung cancer model we determined tumor burden, tumor-infiltrating T cell (TIL) cytolysis, immunohistochemistry, flow cytometry, and CD4 and CD8 depletion to evaluate the efficacy of PD-1 blockade combined with CCL21-DC tumor lysate vaccine. (3) Results: Anti-PD-1 plus CCL21-DC tumor lysate vaccine administered to mice bearing established tumors (150 mm³) increased expression of perforin and granzyme B in the tumor microenvironment (TME), increased tumor-infiltrating T cell (TIL) activity, and caused 80% tumor eradication. Mice with treatment-induced tumor eradication developed immunological memory, enabling tumor rejection upon challenge and cancer-recurrence-free survival. The depletion of CD4 or CD8 abrogated the antitumor activity of combined therapy. PD-1 blockade or CCL21-DC tumor lysate vaccine monotherapy reduced tumor burden without tumor eradication. (4) Conclusion: Immune checkpoint blockade promotes the activity of the therapeutic cancer vaccine. PD-1 blockade plus CCL21-DC tumor lysate vaccine therapy could benefit lung cancer patients. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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16 pages, 2640 KiB

Open AccessArticle

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

by Marc Bach-Griera, Víctor Campo-Pérez, Sandra Barbosa, Sara Traserra, Sandra Guallar-Garrido, Laura Moya-Andérico, Paula Herrero-Abadía, Marina Luquin, Rosa Maria Rabanal, Eduard Torrents and Esther Julián

Vaccines 2020, 8(2), 198; https://doi.org/10.3390/vaccines8020198 - 25 Apr 2020

Cited by 10 | Viewed by 5740

Abstract

Intravesical Mycobacterium bovis Bacillus Calmette–Guérin (BCG) immunotherapy remains the gold-standard treatment for non-muscle-invasive bladder cancer patients, even though half of the patients develop adverse events to this therapy. On exploring BCG-alternative therapies, Mycolicibacterium brumae, a nontuberculous mycobacterium, has shown outstanding anti-tumor and immunomodulatory capabilities. As no infections due to M. brumae in humans, animals, or plants have been described, the safety and/or toxicity of this mycobacterium have not been previously addressed. In the present study, an analysis was made of M. brumae- and BCG-intravenously-infected severe combined immunodeficient (SCID) mice, M. brumae-intravesically-treated BALB/c mice, and intrahemacoelic-infected-Galleria mellonella larvae. Organs from infected mice and the hemolymph from larvae were processed to count bacterial burden. Blood samples from mice were also taken, and a wide range of hematological and biochemical parameters were analyzed. Finally, histopathological alterations in mouse tissues were evaluated. Our results demonstrate the safety and non-toxic profile of M. brumae. Differences were observed in the biochemical, hematological and histopathological analysis between M. brumae and BCG-infected mice, as well as survival curves rates and colony forming units (CFU) counts in both animal models. M. brumae constitutes a safe therapeutic biological agent, overcoming the safety and toxicity disadvantages presented by BCG in both mice and G. mellonella animal models. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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18 pages, 3322 KiB

Open AccessArticle

Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model

by Agnieszka Gąbka-Buszek, Eliza Kwiatkowska-Borowczyk, Jakub Jankowski, Anna Karolina Kozłowska and Andrzej Mackiewicz

Vaccines 2020, 8(2), 147; https://doi.org/10.3390/vaccines8020147 - 26 Mar 2020

Cited by 14 | Viewed by 3670

Abstract

Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they are targets for various cancer therapies, including immunotherapy. Here, we demonstrate the effectiveness of melanoma vaccines composed of genetically modified tumor cells admixed with melanoma stem-like cells (MSC) or induced pluripotent stem cells (iPSCs). Two vaccines were constructed. The first vaccine contained cells derived from B16F10 melanospheres (SFs) with CSC characteristics. The second vaccine contained syngeneic murine induced pluripotent stem cells (miPSCs). iPSCs or SF cells were admixed with B16F10 cells, modified with the designer cytokine Hyper-IL6(H6) (B16/H6). Control mice received B16/H6 cells, B16F10 cells or PBS. Immunization with either vaccine significantly inhibited tumor growth and increased disease-free survival (DFS) and overall survival (OS) in C57BL/6 mice. Mice treated with the SF or iPSC vaccine demonstrated increased activation of the immune response in the vaccination site and tumor microenvironment compared to those treated with B16/H6, B16F10 or PBS. Higher infiltration of dendritic cells (DCs) monocytes, and natural killer (NK) cells; lower numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); higher levels of the cytokines INFγ and IL-12 were observed with the novel vaccines than with the control treatments. In vitro restimulation of splenocytes derived from mice immunized with B16F10 cell, SF cell or miPSC lysates increased the proliferation of CD4+ T helper lymphocytes and secretion of cytokines. An increased serum titer of antibodies directed against B16F10 cells was found in mice immunized with the SF vaccine. The most effective DFS and OS extensions were reached with the miPSCs vaccine. The described results form the basis for a novel platform for the next generation of cancer vaccines composed of allogeneic cancer-specific cells modified with a molecular adjuvant gene and admixed with allogeneic miPSCs or SFs. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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Review

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18 pages, 490 KiB

Open AccessReview

Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

by Robin Park, Fariha Eshrat, Mohammed Al-Jumayli, Azhar Saeed and Anwaar Saeed

Vaccines 2020, 8(3), 447; https://doi.org/10.3390/vaccines8030447 - 8 Aug 2020

Cited by 21 | Viewed by 6792

Abstract

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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15 pages, 336 KiB

Open AccessReview

Human Papillomavirus Vaccines: An Updated Review

by Liqin Cheng, Yan Wang and Juan Du

Vaccines 2020, 8(3), 391; https://doi.org/10.3390/vaccines8030391 - 16 Jul 2020

Cited by 152 | Viewed by 15216

Abstract

Human papillomavirus (HPV) vaccines, which were introduced in many countries in the past decade, have shown promising results in decreasing HPV infection and related diseases, such as warts and precancerous lesions. In this review, we present the updated information about current HPV vaccines, focusing on vaccine coverage and efficacy. In addition, pan-gender vaccination and current clinical trials are also discussed. Currently, more efforts should be put into increasing the vaccine’s coverage, especially in low- and middle-income countries. Provision of education on HPV and vaccination is one of the most important methods to achieve this. Vaccines that target HPV types not included in current vaccines are the next stage in vaccine development. In the future, all HPV-related cancers, such as head and neck cancer, and anal cancer, should be tracked and evaluated, especially in countries that have introduced pan-gender vaccination programs. Therapeutic vaccines, in combination with other cancer treatments, should continue to be investigated. Full article

(This article belongs to the Special Issue Cancer Vaccine)

17 pages, 792 KiB

Open AccessReview

The Landscape of Tumor-Specific Antigens in Colorectal Cancer

by Nurul Ainaa Adilah Rus Bakarurraini, Nurul Syakima Ab Mutalib, Rahman Jamal and Nadiah Abu

Vaccines 2020, 8(3), 371; https://doi.org/10.3390/vaccines8030371 - 10 Jul 2020

Cited by 19 | Viewed by 4664

Abstract

Over the last few decades, major efforts in cancer research and treatment have intensified. Apart from standard chemotherapy approaches, immunotherapy has gained substantial traction. Personalized immunotherapy has become an important tool for cancer therapy with the discovery of immune checkpoint inhibitors. Traditionally, tumor-associated antigens are used in immunotherapy-based treatments. Nevertheless, these antigens lack specificity and may have increased toxicity. With the advent of next-generation technologies, the identification of new tumor-specific antigens is becoming more important. In colorectal cancer, several tumor-specific antigens were identified and functionally validated. Multiple clinical trials from vaccine-based and adoptive cell therapy utilizing tumor-specific antigens have commenced. Herein, we will summarize the current landscape of tumor-specific antigens particularly in colorectal cancer. Full article

(This article belongs to the Special Issue Cancer Vaccine)

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