Vaccines are biological preparations that elicit an immune response and provide active acquired immunity against a particular infectious or malignant disease. Vaccine immunization is traditionally thought of as a means of preventing disease, and vaccines contain or encode antigens that prime the immune system to respond to a target pathogen or antigen. Examples of conventional vaccine platforms include:
Toxoid
Utilizes the toxin created by the pathogen instead of the actual pathogen and is used to protect against diphtheria and tetanus. Vaccines can also be used therapeutically. Advances in design and development have renewed interest in therapeutic vaccination as a precision medicine strategy.1 Therapeutic vaccines differ from preventive or prophylactic vaccines, such as measles and influenza, which protect against future disease, in that they prime a patient’s immune system to combat an existing disease.11
Therapeutic vaccination for cancer takes advantage of the fact that cancer cells possess distinguishing proteins, or antigens, which differ from normal cells. Although immune surveillance can recognize and eliminate abnormal cells, tumors can develop mechanisms to evade immune detection. For this reason, there is a current focus on vaccines not as a means of preventing cancer but treating it. Initially, research efforts concentrated on developing vaccines against shared proteins commonly expressed in certain cancers. However, the failure of this strategy in large clinical trials in the mid-2010s has shifted the focus toward personalized approaches.12
Personalized cancer vaccines are tailored specifically to individual patients. They work by:
Inducing antigen-specific CD4+ and/or CD8+ T-cell responses against tumor-derived antigens;
Promoting immune recognition and elimination of tumor cells presenting those antigens, with the potential to generate immunologic memory.
Cancer cells can generate mutated proteins that the immune system recognizes as foreign, prompting an immune response. Individualized vaccine approaches commonly focus on identifying tumor-specific neoantigens. Tumor tissue obtained at biopsy or surgery can be genetically analyzed to identify tumor-specific neoantigens and other candidate antigens.11 Vaccines can then be designed to target selected antigens. Vaccine-induced T cells can recognize and destroy tumor cells presenting these antigens, with the potential to generate immunologic memory.14
Although enormous progress has been made in recent years with cancer vaccines, considerable hurdles remain. For example, cell-based vaccines are very labor-intensive, and the process of isolating and culturing patient-specific immune cells requires substantial resources and expertise, resulting in high production costs. Additionally, tumors can develop immune evasion mechanisms and create immunosuppressive microenvironments, which include barriers to immune infiltration by anti-cancer immune cells, selective recruitment of immunosuppressive cells, induction of T cell death, production of immunosuppressive enzymes and metabolites, and hypoxic conditions in tumors, all of which can hinder vaccine-induced anti-cancer immune responses.15 Moreover, because of high intratumoral and intertumoral heterogeneity, a vaccine targeting antigens from one tumor sample may not cover all tumor clones or metastatic sites.16
Vaccine development, from basic research to approval, typically takes about 5 to 10 years.17 Although a large number of vaccine studies are conducted at the preclinical stage, less than 10% of vaccines are approved. Four broad cancer vaccine platform types are summarized (Table 1).18 A major driver of recent vaccine development is the significant progress made with messenger RNA (mRNA) development.19,20 The relatively short time required to design and manufacture mRNA vaccines encoding selected antigens is a major advantage. mRNA platforms also offer flexibility for encoding multiple antigens and for rapid manufacturing.21 Moreover, mRNA platforms can support rapid and scalable manufacturing through in vitro transcription. mRNA cancer vaccines include both shared-antigen and individualized approaches and remain under active clinical investigation.
Table 1Cancer vaccine types
| Vaccine | Description |
|---|
| Cell-based | Generated normally from either complete cells or cell fragments, resulting in a wide range of tumor antigens, which induce a broad immune response. Examples include dendritic cells (DCs), which can be immunogenic but may be expensive and complex to produce. |
| Viral vector | Uses a modified version of a virus as a vector that leads to a strong immune response involving both B and T cells. Engineered oncolytic viruses act as vectors capable of presenting high quantities of tumor antigens, resulting in long-term memory, but are also complex to produce. |
| Peptide-based | Comprised of synthetic or biosynthetic peptides representing known or predicted tumor-antigen epitopes, these vaccines aim to elicit antigen-specific T-cell responses. Their immunogenicity may be limited by the small size of peptide epitopes and by major histocompatibility complex (MHC) polymorphisms. |
| Nucleic acid-based (deoxyribonucleic acid (DNA) or messenger RNA (mRNA)) | Capable of encoding full-length tumor antigens, which allows APCs to present multiple antigens simultaneously, eliciting strong MHC I-mediated CD8+ T cell responses, resulting in both humoral and cellular immunity. To initiate transcription, DNA vaccines must enter the cell nucleus, whereas mRNA vaccines only require entry to the cytoplasm to allow antigen translation and expression. DNA vaccines carry the potential risk of inserting mutations into the genome, a risk not associated with mRNA vaccines. |
Although cancer vaccines have been researched for over 30 years, few have achieved major clinical success. Sipuleucel-T (Provenge®), an autologous cellular immunotherapy for metastatic castration-resistant prostate cancer, is the sole cancer vaccine approved for clinical use in the United States.22,23
Other FDA-approved cancer immunotherapies are sometimes discussed alongside therapeutic cancer vaccines, but their mechanisms and regulatory classifications differ:
Bacillus Calmette-Guérin (BCG) is a live attenuated Mycobacterium bovis preparation used intravesically to treat certain bladder cancers;
Nadofaragene firadenovec (Adstiladrin®) is a non-replicating adenoviral vector-based gene therapy approved for high-risk BCG-unresponsive non-muscle-invasive bladder cancer;
T-VEC (Imlygic®) is an oncolytic viral therapy used to treat certain unresectable melanoma lesions.
This landscape has changed in recent years due to some of the aforementioned advances. Improvements in target identification, formulation, manufacturing and development, combination therapy regimens, and patient selection are showing promise. A 2022 landscape analysis identified approximately 360 active clinical trials of cancer vaccines.23 For example, one study reported results from a clinical trial using the VB10.16 vaccine. VB10.16 is a therapeutic vaccine composed of three parts: the first encodes the E6/E7 fusion protein of human papillomavirus (HPV16 E6/7), which plays a key role in developing certain types of cancer; the second comprises a dimerization entity; and the third encodes a protein that specifically binds to antigen-presenting cells. The authors reported that this vaccine was well tolerated and showed promising evidence of efficacy and strong HPV16-specific T-cell responses in patients with high-grade cervical intraepithelial neoplasia.24
Another study reported on TG4050, an individualized viral vector vaccine comprising a modified Vaccinia virus Ankara viral vector encoding tumor-specific neoantigens developed using advanced genetic engineering and artificial intelligence technologies. The authors reported that this personalized vaccine was safe, well-tolerated, and induced T cell responses in cold tumors from patients with head and neck carcinoma.25
Early clinical trials of mRNA therapeutics include studies of paracrine vascular endothelial growth factor, mRNA for heart failure, and CRISPR-Cas9 mRNA for a congenital liver-specific storage disease.26 Developing vaccines against cancer is more challenging than against infectious diseases due to the weak immune response and immunosuppressive effects within the tumor microenvironment.27 However, progress is being made, and several studies are reporting positive results.
A randomized phase IIb study reported that the individualized neoantigen therapy mRNA-4157 (V940), when combined with pembrolizumab, improved recurrence-free survival compared with pembrolizumab alone in patients with resected high-risk melanoma.28 Exploratory subgroup analyses suggested that the recurrence-free survival benefit was similar in tumor mutational burden-high and non-high groups. The individualized therapy encoded up to 34 patient-specific neoantigens selected from tumor sequencing data.
Another recently reported phase I clinical trial from Memorial Sloan Kettering Cancer Center used mRNA vaccines directed against the patient’s tumor neo-antigens.29 Tumors were surgically removed from patients, and autogene cevumeran was developed to encode up to 20 patient-specific neoantigens. After surgery, treatment was administered sequentially: atezolizumab, autogene cevumeran, and then mFOLFIRINOX; 16 patients received atezolizumab and autogene cevumeran, and 15 of these 16 subsequently received mFOLFIRINOX. Eight of 16 vaccinated patients generated high-magnitude neoantigen-specific T-cell responses. At a median follow-up of 18 months, these vaccine responders had a longer median recurrence-free survival (not reached) than non-responders (13.4 months; P = 0.003). Given the small, non-randomized phase I study, these findings were hypothesis-generating rather than definitive evidence of clinical efficacy. A follow-up phase II trial (NCT05968326) has opened to build upon this approach to determine its effectiveness.
Preclinical work on STX-001, a locally administered lipid nanoparticle-formulated self-replicating mRNA encoding IL-12, reported systemic immune responses and antitumor activity in solid-tumor models.30 In preclinical models, STX-001 induced immunogenic tumor cell death, promoted T-cell and NK-cell recruitment to the tumor microenvironment, and enhanced antitumor responses when combined with PD-1/PD-L1 checkpoint inhibitors. These findings support further clinical evaluation but do not establish clinical efficacy.