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Artif Intell Cancer. Jun 28, 2021; 2(3): 25-41
Published online Jun 28, 2021. doi: 10.35713/aic.v2.i3.25
Therapeutic tumor vaccines — a rising star to benefit cancer patients
Qian Wei, Zhao-Yuan Fang, Zi-Meng Zhang, Teng-Fei Zhang
Qian Wei, Zi-Meng Zhang, Teng-Fei Zhang, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Zhao-Yuan Fang, Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai 200031, China
ORCID number: Qian Wei (0000-0003-4391-7153); Zhao-Yuan Fang (0000-0002-0393-2052); Zi-Meng Zhang (0000-0003-1123-8543); Teng-Fei Zhang (0000-0002-0315-9506).
Author contributions: Wei Q and Zhang ZM wrote the manuscript; Zhang TF and Fang ZY designed the outline and coordinated the writing of the paper; Wei Q made the figures and tables; All authors read, revised and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Teng-Fei Zhang, MD, Associate Professor, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou 450052, Henan Province, China. fcczhangtf@zzu.edu.cn
Received: April 10, 2021
Peer-review started: April 10, 2021
First decision: April 28, 2021
Revised: May 11, 2021
Accepted: June 22, 2021
Article in press: June 22, 2021
Published online: June 28, 2021

Abstract

Malignant tumors are still a worldwide threat to human health. Tumor treatment strategies are constantly evolving, and the advent of tumor immunotherapy has brought up hope to many types of tumors, especially for those that are refractory to conventional therapies including surgery, radiotherapy, and chemotherapy. Tumor vaccines can initiate or amplify an anti-tumor immune response in tumor patients through active immunization, and therefore occupy an important position in tumor immunotherapy. The main types of tumor vaccines include tumor cell vaccines, dendritic cell vaccines, polypeptide vaccines and nucleic acid vaccines. Due to factors such as poor antigen selection and suppressive tumor microenvironment, earliest tumor vaccines on clinical trials failed to achieve satisfactory clinical effects. However, with the development of second-generation genome sequencing technologies and bioinformatics tools, it is possible to predict neoantigens generated by tumor-specific mutations and therefore prepare personalized vaccines. This article summarizes the global efforts in developing tumor vaccines and highlights several representative tumor vaccines in each category.

Key Words: Tumor vaccines, Tumor cell vaccines, Dendritic cell vaccines, Peptide vaccines, Nucleic acid vaccines

Core Tip: There are many advancements in the field of cancer immunotherapy in the past decade such as the application of immune checkpoint blockade and adoptive cell therapy. Tumor therapeutic vaccines have emerged as an additional effective treatment strategy due to their ability to trigger potent immune response. Typically, they are tumor cell vaccines, dendritic cell vaccines, peptide vaccines or nucleic acid vaccines. This article mainly reviews the current clinical status as well as research and development status of these four types of therapeutic tumor vaccines for those who are interested.



INTRODUCTION

Exploratory research on tumor vaccines can be traced back to 1891 when Dr. William B. Coley first proved that heat-inactivated Streptococcus pyogenes and Serratia marcescens (Coley toxin) are effective treatments for inoperable tumors[1]. Coley toxin is especially effective for osteosarcoma and soft tissue sarcoma, thus inspiring the subsequent development of various tumor vaccines. While Coley toxin has faded out of clinical application, its pioneering role cannot be erased. Therapeutic tumor vaccines represent a viable option for tumor immunotherapy, which aims to stimulate the patient's immune system to specifically kill tumor cells without damaging normal cells[2]. Therapeutic cancer vaccines are designed to induce enduring anti-tumor immunity, which enables active immunity to systematically prevent tumor recurrence or metastatic disease. Research on the exploration of approaches to therapeutic tumor vaccines has been ongoing and has been achieving varying degrees of success[3]. So far, the United States Food and Drug Administration (FDA) has approved the following two types of preventive tumor vaccines: Hepatitis B virus (HBV) vaccine-a recombinant HBV vaccine Recombivax HB® approved in 1983 and Engerix-B® approved in 1989, and human papillomavirus (HPV) vaccine: Recombinant HPV type 6, 11, 16, 18 (Gardasil®), recombinant HPV 9-valent vaccine (Gardasil® 9) and recombinant HPV type 16, 18 (Cervarix®).

Compared with preventive tumor vaccines, therapeutic tumor vaccine development has lagged significantly. In terms of therapeutic tumor vaccines, the United States FDA so far only approved sipuleucel-T (Provenge®) in 2010 for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC) and an oncolytic virus-based vaccine talimogene laherparepvec for the treatment of advanced melanoma in 2015[4,5]. Other countries have also approved 5 therapeutic tumor vaccines, which are DCVax®-Brain and M-VaxTM approved by Switzerland, HybriCell approved by Brazil, Oncophage® approved by Russia and CIMAVax EGF® approved by Cuba and Peru[6]. However, 4 out of these 5 tumor vaccines (DCVax®-Brain, M-VaxTM, HybriCell and CIMAVax EGF®) had simply completed phase I and II clinical trials by the time of approval. The main goal of Oncophage®'s phase III clinical trial is to prolong relapse-free survival (RFS) and overall survival (OS) instead of efficacy. According to the data retrieved from ClinicalTrials.gov, there are 439 “therapeutic cancer vaccines” under development worldwide, of which North America accounts for the largest proportion of 301 (Figure 1, Source: https://ClinicalTrials.gov). This article mainly summarizes some tumor vaccines that have entered phase III clinical trials. Some tumor vaccines that are currently under recruitment in early clinical trials phase I and II are listed in Table 1.

Figure 1
Figure 1 According to resources downloaded from the open access website (https://ClinicalTrials.gov, cited April 9, 2021), clinical trials of tumor vaccines are unevenly distributed in the world, with the United States occupying the largest proportion, followed by Europe and East Asia. Overall, the number of North America far exceeds that of the rest regions in the world. There is little difference in the number of clinical trials conducted in other regions.
Table 1 Selected list of tumor vaccine under recruitment in clinical trials.
Vaccine typeDiseaseCombinationPhaseNCT ID
Tumor cell vaccineGVAXNeuroblastoma. Pediatric Solid TumorNivolumab. IpilimumabPhase INCT04239040
Locally Advanced Pancreatic Ductal AdenocarcinomaNivolumab CCR2/CCR5 dual antagonistPhase I; Phase IINCT03767582
Metastatic Pancreatic AdenocarcinomaEpacadostat. Pembrolizumab CRS-207 CYPhase IINCT03006302
Colorectal CancerPhase INCT01952730
GVAX Pancreas VaccinePancreatic CancerCyclophosphamide NivolumabPhase IINCT03161379
Pancreatic CancerCyclophosphamide Nivolumab UrelumabPhase I; Phase IINCT02451982
GM-CSF vaccineMultiple MyelomaLenalidomide Prevnar13Phase IINCT03376477
DC VaccineAST-VAC2NSCLC in the Advanced and Adjuvant SettingsPhase INCT03371485
MIDRIXNEONSCLCAntigen-specific DTH. Control DTHPhase INCT04078269
Autologous Dendritic Cell-Adenovirus CCL21 VaccineNSCLC Stage IV, IVA, IVB Lung Cancer AJCC v8PembrolizumabPhase INCT03546361
Autologous DCs: MESOVAXMesothelioma. Malignant PD-L1 Negative Advanced Cancer Progressive DiseasePembrolizumab. Interleukin-2Phase INCT03546426
PEP-DC vaccinePancreatic AdenocarcinomaPhase INCT04627246
ME TARP vaccineProstate CancerPhase IINCT02362451
DC/AML Fusion VaccineAcute Myelogenous LeukemiaDecitabinePhase INCT03679650
Acute Myelogenous LeukemiaPhase IINCT03059485
mDC3/8-KRAS VaccinePancreatic Ductal AdenocarcinomaPhase INCT03592888
Autologous DC vaccine: RaC-AdHead Neck Tumors, Neuroendocrine Tumors, Soft Tissue Sarcoma Rare CancerInterleukin-2Phase IINCT04166006
COREVAX-1Stage IV Colorectal Cancer Curative ResectionInterleukin-2Phase IINCT02919644
Autologous DCs + Prevnar 13Stage III, IIIA, IIIB, IV, IVA, IVB Hepatocellular Carcinoma AJCC v8, Stage III, IIIA, IIIB, IV Intrahepatic Cholangiocarcinoma AJCC v8, Unresectable Hepatocellular Carcinoma, Unresectable Intrahepatic CholangiocarcinomaRadiation: External Beam Radiation TherapyEarly Phase INCT03942328
DC Tumor Cell Lysate Vaccine: ATL-DCRecurrent GlioblastomaPembrolizumab poly-ICLCPhase INCT04201873
Dendritic Cell/Tumor Fusion VaccineGlioblastoma, Neuroectodermal TumorsInterleukin-12 TemozolomidePhase I; Phase IINCT04388033
DC1 Vaccine+ WOKVAC VaccineFemale Breast Cancer, Male Breast Cancer, Stage I, II, III Breast Cancer, HER2-positive Breast CancerPhase IINCT03384914
neoantigen-primed DC vaccineGastric Cancer, Hepatocellular Carcinoma, NSCLC, Colon Rectal CancerPhase INCT04147078
MG-7-DC vaccineLater stage of gastric cancerSintilimabPhase I; Phase IINCT04567069
IKKb matured, RNA-loaded DC vaccineMelanoma, Uveal MetastaticPhase IINCT04335890
Peptide vaccineUCPVax: VolATILSquamous Cell Carcinoma of the Head and Neck, Anal Canal Cancer, Cervical CancerAtezolizumabPhase IINCT03946358
UCPVax-GlioGlioblastomaPhase I; Phase IINCT04280848
UCPVaxMetastatic NSCLCPhase I; Phase IINCT02818426
MUC1NSCLCPolyICLCPhase I; Phase IINCT01720836
SVN53-67/M57-KLHLung Atypical Carcinoid Tumor, Lung Typical Carcinoid Tumor, Metastatic Pancreatic Neuroendocrine TumorIncomplete Freund's Adjuvant Octreotide Acetate SargramostimPhase INCT03879694
NSABP FB-14/AE37Triple-negative Breast CancerPembrolizumabPhase IINCT04024800
KRAS peptide vaccineColorectal Cancer, Pancreatic CancerNivolumab IpilimumabPhase INCT04117087
da VINc/OTSGC-A24Gastric CancerNivolumab IpilimumabPhase INCT03784040
ARG1-18, 19, 20NSCLC, Urothelial Carcinoma, Malignant Melanoma, Ovarian Cancer, Colorectal Cancer, Breast Cancer, Squamous Cell Carcinoma of the Head and Neck, Metastatic CancerPhase INCT03689192
Personalized peptide vaccineStage IV, IVA, IVB Colorectal Cancer AJCC v7, Stage IV Pancreatic Cancer AJCC v6 and v7Imiquimod PembrolizumabPhase INCT02600949
WT1/NY-ESO-1Ovarian Cancer, Fallopian Tube Primary Peritoneal Cancer, Recurrent Ovarian CancerNivolumabPhase INCT02737787
IMU-131/HER-VaxxGastrointestinal Neoplasms, AdenocarcinomaCisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and capecitabinePhase I; Phase IINCT02795988
ESR1Breast CancerPhase INCT04270149
DNAJB1-PRKACAFibrolamellar, Hepatocellular CarcinomaNivolumab IpilimumabPhase INCT04248569
H3.3K27MDiffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-MutantNivolumabPhase I; Phase IINCT02960230
H2NVACDuctal Breast Carcinoma In SituGranulocyte Macrophage Colony Stimulating FatorPhase INCT04144023
IDH1R132H/AMPLIFY-NEOVACMalignant GliomaAvelumabPhase INCT03893903
DNA VaccinepTVG-HP/pTVG-ARCRPC, Metastatic CancerPembrolizumab rhGM-CSFPhase IINCT04090528
Mammaglobin-ABreast CancerPhase INCT02204098
pTVG-HPProstate CancerNivolumab GM-CSFPhase IINCT03600350
pNGVL4a-Sig/E7(detox)/HSP70Cervical Cancer, Precancerous Condition, HPV Disease, Human Papilom-virusImiquimodPhase INCT00788164
Salmonella oral vaccineRelapsed NeuroblastomaLenalidomideEarly Phase INCT04049864
TUMOR CELL VACCINES

The original tumor cell vaccine tends to fail to induce a strong immune response. In order to change this deficiency, molecular modification techniques have been employed to change the immune characteristics or genetic background of tumor cells to improve their immunogenicity and generate a stronger immune response. Tumor cell vaccine is a whole tumor cell vaccine containing a series of antigens prepared from surgically removed tumor tissues. The removed tumor tissues are minced to tumor cells which are usually inactivated by radiation in the laboratory so that they no longer have proliferative activity even after being imported into the human body. Tumor cell vaccines are basically divided into two types, namely autologous tumor cell vaccines and allogeneic tumor cell vaccines[7,8]. Autologous tumor cell vaccines are prepared by extracting tumor cells from the tumor tissues of patients receiving treatment. They have the advantages of carrying relatively complete known and unknown tumor antigens and not being restricted by major histocompatibility complex (MHC), thus avoiding the immune escape of tumor cells caused by the loss of certain antigens during the process of tumor progression. However, the vaccine made by inactivating tumor cells is extremely weak in immunogenicity and incapable of inducing sufficient anti-tumor immune effects. Allogeneic tumor cell vaccines are prepared using specific types of tumor cells from some other patients instead of the tumor cells from the patients receiving treatment themselves. These allogeneic tumor cell vaccines are more often used as off-the-shelf medicines. Some allogeneic tumor cell vaccines are prepared from mixed tumor cells extracted from tumor cells of several patients[8].

OncoVAX®

OncoVAX® is an autologous tumor cell vaccine developed using patients' autologous colorectal cancer cells and is used for adjuvant treatment of patients after colorectal cancer resection. The vaccine is a patient's autologous tumor cell vaccine that combines non-proliferative and non-tumorigenic autologous tumor cells with metabolic activity after irradiation and adjuvant of live attenuated TICE strain of bacillus Calmette-Guerin. The company Vaccinogen uses a patented method to extract and purify tumor cells from the resected colorectal cancer tissue, and then undergo radiation treatment, and then inoculate them to the patient to produce an effective and personalized immune response to the residual cancer cells that may still exist in the patient after the operation.

Vermorken et al[9] investigated the effect of OncoVAX® on 254 patients with stage II and III colon cancer in a randomized phase III clinical trial, and they published their results on the lancet. The patients were randomly divided into surgery group (control group, 126 cases) and surgery + vaccine group (treatment group, 128 cases). The median follow-up period was 5.3 years (8-107 mo). Among the tested patients, 65 patients relapsed, including 25 patients in the treatment group and 40 patients in the control group; the risk of recurrence of patients in the treatment group was reduced [risk ratio (RR) = 44%, 95% confidence interval (CI): 7%-66%, P = 0.023]. In the patient staging analysis, OncoVAX® had no significant effect on patients with stage III colon cancer, but it could significantly prolong the recurrence-free period of patients with stage II colon cancer (P = 0.011), and the overall risk of recurrence was reduced (RR = 61%, 95%CI: 18%-81%), the RFS of patients in the treatment group was significantly prolonged [the risk of recurrence or death was reduced (RR = 42%, 95%CI: 0%-68%, P = 0.032)].

5 clinical studies of OncoVAX®, including the study above, which established optimum dose and regimen, have been completed by 2014. 757 subjects with colorectal cancer, of which 720 had colon cancer, have been enrolled in OncoVAX® trials[10]. In addition, the results of the follow-up bioequivalent study (NCT00016133) involving 15 subjects with cGMP-level manufacturing standard concluded the immunogenicity of OncoVAX® was unaffected by the sterilization process[11]. OncoVAX® has reached a Special Protocol Assessment with the FDA and has been granted Fast Track status by the FDA. The phase IIIb clinical trial (NCT02448173) is under recruitment currently which is expected to be completed in July 2022.

Gemogenovatucel-T

Gemogenovatucel-T (FANG, Vigil™) is a whole autologous tumor cell vaccine developed by Gradalis Inc., which incorporates plasmid-encoded granulocyte-macrophage colony stimulating factor and a bifunctional small hairpin RNA interference vector targeting furin converting enzyme. Senzer et al[12] conducted a phase I clinical trial on patients with advanced tumors and demonstrated the long-term safety of the vaccine and the effect of inducing circulated and activated T cells against tumor cells during a 3-year follow-up.

Based on its safety, immunoeffectiveness, and suggested benefits previously verified, Nemunaitis et al[13] provided a follow-up study of a subset of 8 advanced hepatocellular carcinoma patients and demonstrated that no obvious toxicity was observed and a significant induction of systemic immune response. In the phase II clinical trial of patients with advanced ovarian cancer, the reaction with interferon-γ (IFN-γ) enzyme-linked immunospot assay (ELISPOT) before Gemogenovatucel-T vaccination serves as the baseline [negative rate: About 97% (30/31)]. In contrast, the IFN-γ ELISPOT reaction of the patient after vaccination was 100% (31/31) positive, and the circulating activated T cell population that induced by the autologous tumor cells was significantly expanded. In addition, the average RFS of the vaccinated group was 826 d with a median of 604 d, while the control group had an average RFS of 481 d with a median of 377 d (P = 0.033)[14].

Rocconi et al[15] has carried out a study (ClinicalTrials.gov, NCT02346747), in which 91 eligible patients with stage III or IV high-grade serous, endometrioid, or clear cell ovarian cancer were randomly assigned to receive Gemogenovatucel-T (n = 47) or placebo (n = 44). Recurrence-free survival was 11.5 mo (95%CI: 7.5-not reached) for patients assigned to Gemogenovatucel-T vs 8.4 mo (7.9-15.5) for patients assigned to placebo [hazard ratio (HR) 0.69, 90%CI: 0.44-1.07; one-sided P = 0.078]. According to the results, no grade 3 or 4 toxic events was reported among the Gemogenovatucel-T arm. Serious adverse events were reported in 4 patients in the placebo arm and 3 patients in the Gemogenovatucel-T arm. No treatment-related deaths occurred in either group[15].

Rocconi et al[16] posted the data of the double-blind, placebo-controlled trial in phase IIb. Patients were in complete response with Stage III/IV high grade serious, endometroid or clear cell ovarian cancer. Results demonstrated clinical benefit in homologous recombination proficient (HRP) ovarian cancer. RFS was improved with Vigil (n = 25) in HRP patients compared to placebo (n = 20) (HR = 0.386; 90%CI: 0.199- 0.750; P = 0.007), results were verified by Rhabdomyosarcoma 2-Associated Transcript (RMST) (P = 0.017). Similarly, OS benefit was observed in Vigil group compared to placebo (HR = 0.342; 90%CI: 0.141-0.832; P = 0.019). Results with OS were also verified with RMST (P = 0.008)[16].

DENDRITIC CELL VACCINES

Dendritic cell (DC) is widely recognized as the most powerful full-time antigen-presenting cell since its antigen-presenting ability is hundreds of times higher compared with other antigen presenting cells. The development of DC vaccines is still at an early stage, but a large amount of valuable experimental data has been obtained showing that DC exerts a powerful function in antigen presentation and initiating anti-tumor immunity. DC-based immunotherapy has been used to generate tumor cytotoxic T cells, which is an effective means to fight tumor cells[17-20]. So far, the United States FDA has only approved one DC vaccine sipuleucel-T for the treatment of metastatic CRPC; Switzerland and Brazil approved two DC vaccines- DCVax®-Brain for the treatment of brain tumors and HybriCell for the treatment of kidney cancer and melanoma[6].

Stapuldencel-T

Stapuldencel-T (DCVAC/PCa) is a vaccine which a Czech biotech company (Sotio a.s.) uses autologous leukocytes obtained from prostate cancer patients during the leukapheresis process as raw material to grow immature DCs in vitro. The high hydrostatic pressure kills the immunogenic tumor cells which sensitize the immature DCs and make them mature. The loaded mature DCs are then be inoculated into prostate cancer patients. Podrazil et al[21] conducted a phase I/II clinical trial (EudraCT 2009-017295-24) of combining DCVAC/PCa and docetaxel to treat 25 patients with metastatic CRPC, the median OS (mOS) of the subjects was 19 mo, which is obviously longer than the mOS of 11.8 and 13 mo predicted by Halabi nomogram and MSKCC nomogram, respectively. There were no DCVAC/PCa-related adverse reactions. Long-term vaccination with DCVAC/PCa can induce and maintain the growth of prostate-specific antigen (PSA)-specific T cells. Fucikova et al[22] conducted a phase I/II trial (EudraCT 2009-017259-91) involving 27 patients with rising PSA levels. The median PSADT (PSA doubling time) in all treated patients increased from 5.67 mo prior to immunotherapy to 18.85 mo after 12 doses (P < 0.0018). Moreover, specific PSA-reacting T lymphocytes were increased significantly already after the 4th dose.

Sotio has accomplished 5 earlier trials of DCVAC/PCa in prostate cancer at varying stages namely SP001 (NCT02105675), SP002 (NCT02107391), SP003 (NCT02107404), SP004 (NCT02107430), SP010 (NCT02137746). Based on previous trials, it launched an extensive global multi-center phase III clinical trial studying DCVAC/PCa in prostate cancer (SP005:NCT02111577) to determine whether DCVAC/PCa added onto standard of care (SOC) therapy can improve survival rate. The VIABLE study (actiVe ImmunotherApy using DC-Based treatment for late stage prostatE cancer) enrolled 1182 prostate cancer patients across 21 European countries and the United States. As of January 21, 2021, results of VIABLE study were submitted to United States trial registry but have not yet been announced. However, SOTIO terminates the phase I/II SP015 trial (NCT03514836; EudraCT2015-004314-15) in prostate cancer in Czech Republic owing to insufficient patient accrual.

Rocapuldencel-T

Rocapuldencel-T (AGS-003) is a mature monocyte-derived DC vaccine developed by Argos Therapeutics, Inc. using patients’ own amplified tumor RNA plus synthetic CD40L RNA for electroporation, which induces the activation and expansion of new T cells (including persistent memory cells and killer cells) based on Arcelis technology platform, specifically attacking the unique antigens of each patient’s tumor. Amin et al[23] carried out a phase II clinical trial that combined AGS-003 and sunitinib in 21 patients with advanced renal cell carcinoma (RCC). The results showed that 13 patients (62%) were effective in this therapy (9 patients responded and 4 patients were in stable condition), but none of the patients achieved complete remission. The median progression-free survival (PFS) of all patients was 11.2 mo (95%CI: 6.0-19.4), and the mOS was 30.2 mo (95%CI: 9.4-57.1); 7 patients (33%) survived at least 4.5 years, 5 cases (24%) survived for more than 5 years, including 2 cases in the continuous response period without disease progression at the completion of the report; the patients tolerated AGS-003 well, and only mild adverse reactions occurred at the vaccination site.

The ADAPT trial recruited 462 patients that were randomized 2:1, 307 to the combination group and 155 to the SOC group between 2013 and 2016. mOS in the combination group was 27.7 mo (95%CI: 23.0-35.9) and 32.4 mo (95%CI: 22.5-not reached) in the SOC group HR of 1.10 (95%CI: 0.83-1.40). PFS was 6.0 mo and 7.83 mo for the combination and SOC groups, respectively [HR = 1.15 (95%CI: 0.92-1.44)]. The ORR was 42.7% (95%CI: 37.1-48.4) for the combination group and 39.4% (95%CI: 31.6-47.5) for the SOC group. Median follow up was 29 mo (0.4-47.7 mo). On account of the lack of clinical efficacy, the ADAPT trial was terminated on February 17, 2017. Immune responses were detected in 70% of patients treated with Rocapuldencel-T, and the magnitude of the immune response positively correlated with OS. Figlin et al[24] has conducted the phase III trial to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic RCC. The results indicated that the combination therapy did not improve the patient's OS. Nevertheless, the phase III trial identified two potential survival-predictive biomarkers namely interleukin (IL)-12 produced by the DC vaccine and higher numbers of T regulatory cells present in the peripheral blood of advanced RCC patients.

DCVax®–L

DCVax® was developed and is being commercialized by Northwest Biotherapeutics, Inc. (MD, United States), serving as a platform technology that uses activated autologous DCs to reinvigorate and educate the immune system to attack cancers. DCVax®-L) is designed to cover all solid tumor cancers in which the tumors can be surgically removed. Theoretically, DCVax®-L induces the differentiation and maturation of peripheral blood mononuclear cells into DCs, which are activated and loaded with biomarkers (specific antigens) obtained from the patient's own tumor tissue. Antigens can be derived from autologous tumor lysates as in DCVax®-L for glioblastoma multiforme (GBM) or specific recombinant antigenic epitopes[25,26]. The loading of biomarkers into the DCs “educates” them about what the immune system needs to attack. The activated, educated DCs are then isolated with very high purity and comprise the DCVax®-L personalized vaccine[26].

A 348-patient double blind, randomized, placebo-controlled phase III clinical trial (NCT00045968) with DCVax®-L for newly diagnosed GBM is being implemented, whose enrollment completed in 2015. The primary endpoint of the trial is PFS, and secondary endpoints include OS and other measures. The trial is under way at 51 sites (medical centers) across the United States. Liau et al[27] posted its first results on survival indicating that addition of DCVax®-L to standard therapy is feasible and safe in glioblastoma patients and may extend survival. mOS was 23.1 mo from surgery without DCVax®-L. As of this analysis involving 331 patients in 2018, 223 patients are ≥ 30 mo past their surgery date; 67 of these (30.0%) have lived ≥ 30 mo and have a Kaplan-Meier-derived mOS of 46.5 mo. 182 patients are ≥ 36 mo past surgery; 44 of these (24.2%) have lived ≥ 36 mo and have a KM-derived mOS of 88.2 mo[27].

PEPTIDE VACCINES

Peptide vaccines that initially targeted tumor enriched antigens can be classified into two distinct categories: Tumor-associated antigens (TAA) and tumor-specific neoantigens antigens[28,29]. Tumor neoantigen is a specific peptide epitope of tumor cells that can be recognized by T cells due to gene mutations in tumor cells, which can activate T cells and exert anti-tumor immune responses. Currently, Peptide vaccines are mainly used in patients with advanced tumors, and clinical trials have been carried out for patients with CRPC, lung cancer, gastrointestinal tumors, cholangiocarcinoma, pancreatic cancer and GBM. Most of the peptide vaccine research is currently in phase I and phase II clinical trials.

Seviprotimut-L

Seviprotimut-L (POL-103A) is currently in orphan drug status and developed by Polynoma Lewis Lung Carcinoma (LLC), which is a combination of shed antigens produced by three proprietary melanoma cell lines. Polynoma LLC announced the start of Melanoma Antigen Vaccine Immunotherapy Study (MAVIS), the company’s phase III trial of POL-103A vaccine for melanoma in June 2012. MAVIS (NCT01546571), a global, multi-center, double-blind, placebo-controlled study, is expected to recruit 1224 participants with resected stage IIb, IIc or III melanoma and a high risk of recurrence. The trial is expected to be initially completed on January 1, 2025[30].

Tedopi® (OSE-2101, EP-2101, IDM-2101)

Tedopi® is a synthetic peptide vaccine developed by the French company OSE Immunotherapeutics, which is a specific treatment for HLA-A2+ patients, a key receptor for the cytotoxic T-immune response, through its proprietary combination of 9 optimized neo-epitopes plus one epitope giving universal helper T cell response targeting T cell activation. Currently, Tedopi® is being investigated in two major cancer indications: Non-small cell lung cancer (NSCLC) with an ongoing phase III trial and pancreatic cancer with an ongoing phase II trial[31].

In February 2016, OSE Immunotherapeutics launched the phase III clinical trial (NCT02654587) named Atalante 1 that compared OSE-2101 as a second and third-line drug with docetaxel or pemetrexed for HLA A2+ IIIB or IV NSCLC patients after immune checkpoint inhibitor (CPI)s [programmed death 1 (PD1)/programmed death-ligand 1] failure. The trial included 99 HLA-A2-positive patients with stage IIIB or metastatic stage IV. They were randomly divided into Tedopi® vaccine treatment group or chemotherapy group (pemetrexed or docetaxel) at a ratio of 2:1. The trial is expected to be completed in December 2021 and was initially completed in February 2020. According to the positive step-1 phase III results announced at the European Society for Medical Oncology Virtual Congress 2020, among the 63 patients in the Tedopi® group, 29 patients survived at least 12 mo and the 12-mo survival rate was 46% higher than expected 25%. In the chemotherapy control group, 13 of the 36 patients survived at least 12 mo, which is equivalent to a 12-mo survival rate of 36%[32].

In previous phase II clinical trials of IDM-2101, this vaccine also achieved promising data.

IDM-2101 (previously EP-2101) was administered for a total of 63 patients positive for HLA-A2 every 3 wk for the first 15 wk, then every 2 mo through year 1, then quarterly through year 2, for a total of 13 doses. Results showed that one-year survival in the treated patients was 60%, and median survival was 17.3 mo[33-35].

NUCLEIC ACID VACCINES

Nucleic acids have been well acknowledged as potent adjuvants[36,37]. Nucleic acid vaccines include plasmid DNA vaccines, RNA vaccines and viral vector vaccines. Both RNA and DNA have been utilized as adjuvants, meanwhile they take the responsibility to code for TAA[38]. RNA is transcribed in vitro (IVT) by a DNA template encoding the antigen and bacteriophage RNA polymerase; RNA vaccines can release a large number of tumor-derived specific antigens and induce humoral and cellular immune responses, provide costimulatory signals, and are well tolerated without carcinogenic potential[39,40].

VGX-3100

VGX-3100 is a DNA vaccine developed by INOVIO Pharmaceuticals, Inc. in the United States. The vaccine contains two DNA plasmids targeting E6 and E7 oncogenes associated with HPV-16 as well as HPV-18, which are responsible for transforming HPV-infected cells into precancerous lesions or cancer cells. Therefore, the vaccine is designed to increase the T cell immune response to eliminate infections caused by HPV-16 and HPV-18 and to destroy precancerous cells or lesions, without the associated risk of losing the patient’s reproductive function[41,42].

Trimble et al[43] conducted a randomized, double-blind, placebo-controlled phase IIb clinical trial in patients with high-grade cervical squamous intraepithelial lesions (HSIL) related to HPV types 16 and 18, and 125 patients were divided into the VGX-3100 group; 42 patients were assigned to the placebo group. Results showed that 55 out of 114 patients in the VGX-3100 group (48.2%) and 12 out of 40 patients in the placebo group (30.0%) had histopathological regression [percentage difference between the two groups was 18.2% (95%CI: 1.3%-34.4%), P = 0.034)]. Patients in the treatment group were well tolerated, and the most common adverse reaction was erythema at the vaccination site, and no serious adverse events were reported.

The company launched the VGX-3100 critical phase III trial (REVEAL 1: NCT03185013) in June 2017 and completed the initial goal of recruiting 198 participants in June 2019. On March 1, 2021, INOVIO announced that the REVEAL 1 study has reached the primary and secondary clinical endpoints, thus being the first DNA medicine to achieve efficacy endpoints in a phase III trial. The REVEAL 1 study enrolled 201 patients with HPV-16/18-related HSIL. Among the 193 patients with evaluable efficacy, 23.7% (31/131) of the these in the treatment group reached the common primary endpoint of achieving histopathological regression of HSIL combined with virologic clearance of HPV-16 and/or HPV-18 at week 36, while the placebo group was 11.3% (7/62) and results were statistically significant (P = 0.022; 95%CI: 0.4-22.5). The study reached all secondary endpoints as well.

ProstAtak® (AdV-tk+valacyclovir, CAN-2409)

ProstAtak® is an adenovirus vector tumor vaccine developed by Advantagene, Inc. in the United States to prevent and treat recurrence of prostate cancer. It utilizes a gene transfer method to directly deliver a vaccine containing the herpes simplex virus thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by an anti-herpetic prodrug valacyclovir into the prostate tumor via trans-rectal ultrasound guided injection, and then the patient continuously takes valacyclovir for 14 d. Theoretically, the initial local cytotoxicity is mediated by nucleoside analogues produced by valacyclovir phosphorylation, which activates the immune system by stimulating T-cell proliferation and IL-2 production therefore generates a systemic anti-tumor immune response. Advantagene Biotech launched a randomized, completely blind, placebo-controlled phase III clinical trial of ProstAtak® (PrTK03; NCT01436968) combined with radiotherapy in 711 patients with moderate to high-risk localized prostate cancer in September 2011. The subjects were randomly divided into treatment group and control group at a ratio of 2:1. The trial is expected to be initially completed in September 2023. Additionally, the company's phase II clinical trial of ProstAtak® (ULYSSES; NCT02768363) for patients with localized prostate cancer was also launched in May 2016. The trial has recruited 187 participants and its primary completion time was estimated to be March 2021.

FixVac (BNT111)

It has been well-acknowledged that mRNA has the potential to be promoted as an important character in therapeutic regimens since over 20 years ago. Since the successful development and current massive use of mRNA vaccines for coronavirus disease 2019 (COVID-19) immunization, more mRNA-based tumor immunotherapies have been under-developed. Some typical mRNA-based tumor vaccines and COVID-19 vaccines are listed in Tables 2 and 3. FixVac (BNT111) is an intravenously administered liposomal RNA (RNA-LPX) vaccine developed by Biopharmaceutical New Technologies (BioNTech), which comprises RNA-LPX encoding 4 TAAs—NY-ESO-1, melanoma-associated antigen A3, tyrosinase, and trans-membrane phosphatase with tensin homology[44]. These 4 antigens are non-mutated antigens quite common in melanoma and highly immunogenic but are barely expressed in normal tissues. The mRNA is enveloped by lipid nanoparticles to increase its stability, improve its transfection efficiency and avoid degradation[44,45]. With regard to the FixVac platform, its product candidates feature the proprietary immunogenic mRNA backbone optimized for encoding specific shared antigens; and RNA-lipoplex, or RNA-LPX, the delivery formulation, meant to enhance mRNA’s stability and translation, targeting DCs in lymphoid compartments body-wide and to stimulate potent immune responses[44,46]. BNT111 is an off-the-shelf mRNA vaccine product from the FixVac platform and not individualized for particular patients, but its proprietary RNA-LPX formulation with the general utility of these 4 non-mutant shared tumor antigens turned out to be effective.

Table 2 Typical mRNA-based tumor vaccines.
VaccinemRNA-encoded antigenFormulation typeDiseaseNCT IDPhasesStatusSponsor/collaboratorResults
mRNA-2416OX40LLNPRelapsed/Refractory Solid Tumor Malignancies or Lymphoma Ovarian CancerNCT03323398Phase I/IIRecruitingModernaTX, Inc.Any dose of intratumoral injection is tolerable when mRNA-2416 is administered alone. Results indicate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity after mRNA-2416 injection
mRNA-2572OX40L, IL-23, IL-36γLNPDose Escalation: Relapsed/Refractory Solid Tumor Malignancies or Lymphoma Dose Expansion: Triple Negative Breast Cancer, Head and Neck Squamous Cell Carcinoma, Non-Hodgkin Lymphoma, and Urothelial CancerNCT03739931Phase IRecruitingModernaTX, Inc., AstraZenecaAny dose of intratumoral injection is tolerable when mRNA-2572 is administered alone or in combination with PD-L1 inhibitor. IFN-γ, TNF-α, and PD-L1 levels increased
mRNA-4157 KEYNOTE-603Neo-AgLNPSolid TumorsNCT03313778Phase IRecruitingModernaTX, Inc., Merck Sharp & Dohme Corp.All tested doses is tolerated, and clinical responses were observed when mRNA-4157 is combined with Pembrolizumab
KEYNOTE-942Neo-AgLNPMelanomaNCT03897881Phase IIRecruitingModernaTX, Inc., Merck Sharp & Dohme Corp.Not available
mRNA-5671/Merck V941KRAS mutations: G12D, G12V, G13D, G12CLNPNSCLC, Pancreatic cancer, Colorectal cancerNCT03948763Phase IRecruitingMerck Sharp & Dohme Corp.Not available
FixVac (BNT111); Lipo-MERITNY-ESO-1, MAGEC3, tyrosinase, TPTELipo-MERIT, LNPMelanomaNCT02410733Phase IActive, not recruitingBioNTech SEBNT111 alone or in combination with PD1, mediates durable objective responses in CPI-experienced patients with unresectable melanoma. Durable clinical responses in both monotherapy and combination with CPI are accompanied by the induction of strong CD4+ and CD8+ T cell immunity. BNT111 vaccination was safe and well tolerated with no dose limiting toxicity
RO7198457 (BNT122)Neo-AgLipo-MERIT, LNPMelanoma, NSCLC, Bladder Cancer, CRC, Breast Cancer etc.NCT03289962Phase IRecruitingBioNTech, GenentechThe combination of RO7198457 and atezolizumab is generally well tolerated. RO7198457 combined with atezolizumab can induce pro-inflammatory cytokine release and peripheral T cell response in most patients
Neo-AgLipo-MERIT, LNPAdvanced MelanomaNCT03815058Phase IIRecruitingGenentech, Inc., BioNTech SENot available
Neo-AgLipo-MERIT, LNPStage II and III CRC (surgically resected)NCT04486378Phase IIRecruitingBioNTech SENot available
Neo-AgLipo-MERIT, LNPPancreatic Cancer (surgically resected)NCT04161755Phase IRecruitingMemorial Sloan Kettering Cancer Center, Genentech, Inc.Not available
Neo-AgLipo-MERIT, LNPNSCLCNCT04267237Phase IIWithdrawnHoffmann-La RocheNot available
SAR441000 (BNT131)IL-12sc, IL-15sushi, IFNα and GM-CSFVarious formulationsadvanced melanomaNCT03871348Phase IRecruitingSanofi, BioNTech RNA Pharmaceuticals GmbHNot available
RiboMab (BNT141)mRNA encoding secreted IgG antibodies that target multiple epithelial solid tumorsVarious liver-targeting LNP formulationsCLDN18.2-positive Solid TumorsNCT04683939Phase I/IINot yet recruitingBioNTech SENot available
IVAC MUTANOME, RBL001/RBL002Neo-Ag/TAAnaked mRNAAdvanced MelanomaNCT02035956Phase ICompletedBioNTech RNA Pharmaceuticals GmbH, BioNTech SE
CV8102TLR7/8/RIG-1 agonist based on noncoding single stranded RNARNActive, (Protamine)Melanoma (Skin), Squamous Cell Carcinoma of the Skin Carcinoma, Squamous Cell of Head and Neck Carcinoma, Adenoid CysticNCT03291002Phase IRecruitingCureVac AG, Syneos HealthNot available
Peptide vaccine and mRNAIMA970A plus CV8102 and CyclophosphamideHepatocellular carcinomaNCT03203005Phase I/IICompletedNational Cancer Institute, Naples, immatics Biotechnologies GmbH, CureVac AG, European Commission-FP7-Health-2013- Innovation-1Not available
BI-1361849 (CV9202)NY-ESO-1, MAGE-C2, MAGE-C1, survivin, 5 T4, MUC1RNActive, ProtamineMetastatic NSCLCNCT03164772Phase I/IIActive, not recruitingLudwig Institute for Cancer Research, Cancer Research Institute, New York City; Boehringer Ingelheim, MedImmune LLC, CureVac AG, PharmaJet, Inc.CV9202 was well-tolerated, and antigen specific immune responses were detected in majority of patients (84%)
CV9201MAGE-C1, MAGE-C2, NY-SEO-1, survivin,5 T4RNActive, ProtamineStage IIIB/IV NSCLCNCT00923312Phase I/IICompletedCureVac AGCV9201 was well-tolerated and results indicated immune responses after vaccination. Median PFS and OS were 5 and 10.8 mo, respectively
CV9103PSA, PSCA, PSMA, STEAP1RNActive, ProtamineProstate cancerNCT00831467Phase I/IICompletedCureVac AGCV9103 is well tolerated and immunogenic
CV9104PSA, PSCA, PSMA, STEAP1, PAP, MUC1RNActive, ProtamineProstate cancerNCT01817738Phase I/IITerminatedCureVac AGTerminated due to insufficient activities
Table 3 Typical mRNA-based coronavirus disease 2019 vaccines have entered phase III or IV clinical trials.
VaccineNCT IDTitlePhaseStatusEstimated number of participantsSponsor/collaborator
BNT162b2NCT04816669Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Lyophilized Formulation of BNT162b2 Against COVID-19 in Healthy AdultsPhase IIIRecruiting550BioNTech SE, Pfizer
NCT04713553A Phase 3 Study to Evaluate the Safety, Tolerability, and Immunogenicity of Multiple Production Lots and Dose Levels of BNT162b2 Against COVID-19 in Healthy ParticipantsPhase III Recruiting1530BioNTech SE, Pfizer
NCT04754594Study to Evaluate the Safety, Tolerability, and Immunogenicity of SARS-CoV-2 RNA Vaccine Candidate (BNT162b2) Against COVID-19 in Healthy Pregnant Women 18 Years of Age and OlderPhase II/IIIRecruiting4000BioNTech SE, Pfizer
NCT04775069Antibody Response to COVID-19 Vaccines in Liver Disease PatientsPhase IVNot yet recruiting900Humanity & Health Medical Group Limited
mRNA-1273NCT04860297A Study to Evaluate Safety and Immunogenicity of mRNA-1273 Vaccine to Prevent COVID-19 in Adult Organ Transplant Recipients and in Healthy Adult ParticipantsPhase III Recruiting240ModernaTX, Inc.
NCT04796896A Study to Evaluate Safety and Effectiveness of mRNA-1273 Vaccine in Healthy Children Between 6 Months of Age and Less Than 12 Years of AgePhase II/IIIRecruiting6750ModernaTX, Inc.
NCT04470427A Study to Evaluate Efficacy, Safety, and Immunogenicity of mRNA-1273 Vaccine in Adults Aged 18 Years and Older to Prevent COVID-19Phase III Active, not recruiting30420ModernaTX, Inc., Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases (NIAID)
NCT04649151A Study to Evaluate the Safety, Reactogenicity, and Effectiveness of mRNA-1273 Vaccine in Adolescents 12 to <18 Years Old to Prevent COVID-19Phase II/IIIActive, not recruiting3000ModernaTX, Inc., Biomedical Advanced Research and Development Authority
CV-NCOV-011NCT04848467A Trial Studying the SARS-CoV-2 mRNA Vaccine CVnCoV to Learn About the Immune Response, the Safety, and the Degree of Typical Vaccination Reactions When CVnCoV is Given at the Same Time as a Flu Vaccine Compared to When the Vaccines Are Separately Given in Adults 60 Years of Age and Older (CV-NCOV-011)Phase III Not yet recruiting1000Bayer, CureVac AG
CVnCoVNCT04860258A Study to Evaluate Safety, Reactogenicity and Immunogenicity of the SARS-CoV-2 mRNA Vaccine CVnCoV in Adults With Co-morbidities for COVID-19Phase III Not yet recruiting1200CureVac AG
NCT04838847A Study to Evaluate the Immunogenicity and Safety of the SARS-CoV-2 mRNA Vaccine CVnCoV in Elderly Adults Compared to Younger Adults for COVID-19Phase III Not yet recruiting180CureVac AG
NCT04652102A Study to Determine the Safety and Efficacy of SARS-CoV-2 mRNA Vaccine CVnCoV in Adults for COVID-19Phase II/IIIRecruiting36500CureVac AG
NCT04674189A Study to Evaluate the Safety and Immunogenicity of Vaccine CVnCoV in Healthy Adults in Germany for COVID-19Phase III Recruiting2520CureVac AG
SARS-CoV-2 mRNA VaccineNCT04847102A Phase III Clinical Study of a SARS-CoV-2 Messenger Ribonucleic Acid (mRNA) Vaccine Candidate Against COVID-19 in Population Aged 18 Years and AbovePhase III Not yet recruiting28000Walvax Biotechnology Co., Ltd., Abogen Biosciences Co. Ltd., Yuxi Walvax Biotechnology Co., Ltd.,
CoVPN 3006NCT04811664A Study of SARS CoV-2 Infection and Potential Transmission in University Students Immunized With Moderna COVID-19 Vaccine (CoVPN 3006)Phase III Recruiting37500National Institute of Allergy and Infectious Diseases (NIAID)
KYRIOSNCT04869358Exploring the Immune Response to SARS-CoV-2/COVID-19 Vaccines in Patients With Relapsing Multiple Sclerosis (RMS) Treated With Ofatumumab (KYRIOS)Phase IVNot yet recruiting40
ENFORCENCT04760132National Cohort Study of Effectiveness and Safety of SARS-CoV-2/COVID-19 Vaccines (ENFORCE) (ENFORCE)Phase IVRecruiting10000Jens D Lundgren, MD, Ministry of the Interior and Health, Denmark; Rigshospitalet, Denmark
AMA-VACCNCT04792567Exploring the Immune Response to SARS-CoV-2 modRNA Vaccines in Patients With Secondary Progressive Multiple Sclerosis (AMA-VACC) (AMA-VACC)Phase IVRecruiting60
COVAXIDNCT04780659COVID-19 Vaccination of Immunodeficient Persons (COVAXID) (COVAXID)Phase IVRecruiting540Karolinska University Hospital, Karolinska Institutet
DemiVacNCT04852861Safety and Immunogenicity of Demi-dose of Two Covid-19 mRNA Vaccines in Healthy Population (DemiVac)Phase IVNot yet recruiting200Sciensano, Mensura EDPB, Institute of Tropical Medicine, Belgium; Erasme University Hospital

Sahin et al[47] has conducted the clinical trial named Lipo-MERIT (NCT02410733), which is a multicenter, open-label, dose-escalation phase 1 trial to evaluate the safety and tolerability of vaccinated patients with stage IIIB-C and stage IV melanoma. According to the interim analysis as of July 29, 2019 of 89 patients who was intravenously administered BNT111 ranging from 7.2 μg to 400 μg, BNT111 alone or in combination with blockade of the CPI PD1, mediates durable objective responses in CPI-experienced patients with unresectable melanoma. Durable clinical responses in both monotherapy and combinatory therapy were accompanied by the induction of strong CD4+ and CD8+ T cell immunity. BNT111 vaccination was safe and well tolerated with no dose limiting toxicity. Most common adverse events were mild to moderate, transient flu-like symptoms, such as pyrexia and chills. Mostly they are early-onset, transient and manageable with antipyretics, and could be resolved within 24 h.

Based on the promising results of Lipo-MERIT, BioNTech launched the randomized, multi-site, phase II trial (NCT04526899) designed to evaluate the efficacy, tolerability, and safety of BNT111 combined with cemiplimab (Libtayo®) in anti-PD1-refractory/ relapsed patients with unresectable Stage III or IV melanoma. The trial was scheduled to recruit 120 participants and estimated to start in May 2021[48]. In addition, iNeST is another typical platform in BioNTech and represents the pioneer in developing fully individualized cancer immunotherapies, which utilizes optimized mRNA encoding neoantigens identified on particular patients and features proprietary size- and charge-based RNA-LPX targeting DCs formulation[44]. There are four ongoing clinical trials based on its product candidate RO7198457 (BNT122), two of which has entered phase 2.

CONCLUSION

The pursuit of tumor vaccines has been for more than a century. In the field of immunotherapy, the past decade has witnessed tremendous progress in the usage of immune checkpoint blockades and the adoptive cell therapy, although still many patients fail to benefit from the immune therapies alone. Such effectiveness of novel immune therapies has greatly motivated people to revisit the concept of tumor vaccines. At present, one of the main restricting factors of tumor vaccines is the weak immunogenicity of the tumor antigens, which poses tumor immune tolerance or immune escape. Moreover, since the tumors in patients are highly heterogeneous, the development of tumor vaccines is undergoing a transition from universality to individualization, so that the treatment is more tailored to individual patient. Different types of vaccines have their own distinct advantages and disadvantages. Tumor cell vaccine contains the full spectrum of tumor antigens and it is simple to prepare. However, it requires a large amount of autologous tumor tissues or allogeneic tumor cell lines, and their immunogenicity is usually weak. DC vaccine can stimulate a wide range of immune responses and can be loaded with antigens in diverse ways, but DC cell culture in vitro is challenging, and the vaccine preparation process may generate immature DCs which may induce immune tolerance. Peptide vaccine has strong specificity and high safety, and is not restricted by MHC haplotype and easy to modify, but it tends to provoke a weak immune response and is prone to tumor antigen modulation. With regard to the nucleic acid vaccine, it is easy to produce, economical and safe, and can elicit a wide range of immune responses, but it requires to be used in a large amount so that it can be taken up by cells in sufficient amount to stimulate effective immunity. It is also worth noting that storage, stability and delivery techniques of nucleic acid vaccine are also issues to be overcome.

The past 20 years have witnessed the application of mRNA technology in multiple indications and its transition from theory to vaccine products and clinical treatments. Before the global health pandemic COVID-19, mRNA technology had already been regarded as the most advanced in the area of cancer immunotherapy but its full potential remains latent. The efforts made to the recent fast approval of two mRNA-based COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), definitely promotes the mRNA vaccine development in every aspect, such as its modification strategy to stabilize and to control its immunogenicity, cell delivery strategy and transportation and maintenance strategy. Undoubtedly, this will be a huge push to apply mRNA technology in additional infectious disease prevention and in the area of cancer treatment. We envision mRNA technology is poised to be the next generation cancer immunotherapy in the near future.

In summary, we are experiencing an outbreak of different types of tumor vaccines, and we are making every effort to transform the idea of therapeutic tumor vaccines into a standard clinical application. Many pending questions remain to be addressed. However, with the advancement of new technologies and deepened understanding of tumor immunology, the joint efforts of scientific researchers from all over the world will certainly make the development of therapeutic tumor vaccines a good prospect.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): A

Grade B (Very good): 0

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Korbelik M S-Editor: Fan JR L-Editor: Filipodia P-Editor: Li JH

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