Many diverse vaccine platforms have now been evaluated in phase II and/or phase III clinical trials, including injection of peptides or proteins in adjuvant, injection of recombinant viruses or other recombinant microorganisms, delivery of killed tumor cells, or delivery of protein- or peptide-activated dendritic cells (DCs) to the patient (). Each of the 14 platforms in has strengths and weaknesses that can be influenced by the particular tumor-associated antigen (TAA) that is targeted, the disease and disease stage that is targeted, the clinical trial endpoint, and whether the vaccine is evaluated in combination with an immune stimulant, an inhibitor of immune suppression, or another mode of cancer therapy.
Spectrum of current vaccine platforms in phase II/III clinical studies*
DCs are the most potent antigen-presenting cells (APCs) (43
). Numerous phase II studies have now evaluated the use of peptide- or protein-pulsed, or viral vector–infected, DCs to treat patients with prostate cancer, colorectal cancer, melanoma, glioma, and other cancers ( and ) [eg, references (44
)]. The Sipuleucel-T vaccine (41
), which was recently approved by the US Food and Drug Administration (FDA) for the therapy of asymptomatic metastatic castrate-resistant prostate cancer (mCRPC), consists of APCs from peripheral blood mononuclear cells (PBMCs) that have been incubated with prostatic acid phosphatase (PAP, a prostate antigen) fused to granulocyte macrophage colony-stimulating factor (GM-CSF). This vaccine regimen consists of leukaphereses to purify PBMCs from the patient and processing in a central facility where the PAP fusion protein is added to the APCs; these cells are then reinfused to the patient for the purpose of conferring immunity; this process is repeated three times at biweekly intervals. One drawback of DC and/or APC platforms is that they require leukapheresis(es) and cell culture processing of PBMCs, and thus a limited number of vaccinations can be used.
Spectrum of current and potential therapeutic cancer vaccine targets*
Vaccines based on peptides from TAAs, which are usually administered in an adjuvant and/or with an immune modulator, are generally cost-effective and have the advantage that the investigator knows exactly which epitope to evaluate in terms of patients’ immune responses (1
). However, they also have a potential drawback because they target only one epitope or a few epitopes of the TAA. It is generally believed that for a cancer vaccine to be optimally efficacious, it must induce antigen-specific CD8+ cytolytic T cells (CTLs), which are responsible for tumor cell lysis, and antigen-specific CD4+ “helper” T cells, which provide cytokines to enhance CTL activity. Some polypeptide vaccines potentially contain both CD4 and CD8 epitopes; for example, Stimuvax contains both kinds of epitopes for mucin 1 (MUC-1), which is found as a cell surface proteoglycan associated with several tumor types (2
). Protein-based vaccines are more costly than peptide-based vaccines, but they usually also contain both CD4 and CD8 epitopes. Many peptide- and protein-based vaccines are used as part of a DC vaccine platform.
Anti-idiotype vaccines are directed against specific antibodies found on the surface of B-lymphoma cells (11
). They have the advantage of targeting a unique tumor-specific antigen. A disadvantage is that their generation and production are quite labor intensive in that, to date, each anti-idiotype vaccine has been patient specific. However, some researchers have shown that these patient-specific vaccines can be produced in less than a month [reviewed in (12
The most evaluated viral-based vectors are from the poxviridae family. They include vaccinia, modified vaccinia strain Ankara (MVA), and the avipoxviruses (fowlpox and canarypox; ALVAC). Poxviruses have the ability to accept large inserts of foreign DNA, and thus can accommodate multiple genes. Intracellular expression of the transgene(s) allows for processing of the tumor antigen by both the class I and class II major histocompatibility complex (MHC) pathways (17
). Because poxvirus replication and transcription are restricted to the cytoplasm, there is minimal risk to the patient (or host) of insertional mutagenesis. It has been shown in preclinical studies that when the transgene for a TAA is inserted in vaccinia or MVA, it becomes more immunogenic, most likely because of the Toll-like receptors (TLRs) and other properties of the virus that induce a local inflammatory response. This same property of the non-avian poxviruses, however, leads to virus neutralization by the host immune response and limits their use to one, or at most two, vaccination(s). Recombinant avipoxviruses can be used multiple times; they will induce antiviral immune responses, but they are not neutralizing because their “late” viral coat proteins are not produced in mammalian cells (18
Other viruses can also be used as vectors for TAAs. Alphaviruses such as Venezuelan Equine Encephalitis (VEE) virus are attractive vectors because, once they have infected the host, they replicate RNA in the cytoplasm and express high levels of a transgene (33
). Recombinant adenovirus vectors are easy to engineer and have shown utility as vaccines and gene therapy agents (34
), but clinical evaluation has been hindered by high levels of preexisting antiviral immunity. Newer variants of adenoviruses are being developed and evaluated that may potentially be less immunogenic.
Bacteria and yeasts have shown some promise as vaccine vectors in preclinical studies and may also serve as vectors for immunizing cancer patients. Heat-killed recombinant Saccharomyces cerevisiae
is inherently nonpathogenic, can be easily propagated and purified, and is very stable. Recombinant yeasts have been shown to activate maturation of human DCs and to present both class I and class II epitopes of transgenes (30
). Surprisingly, it appears that these vectors can be administered multiple times without eliciting host-neutralizing activity (31
). Attenuated recombinant Listeria monocytogenes
(Lm) bacteria have also been shown to target DCs, and, like viral and yeast vectors, they stimulate both innate and adaptive immune responses (32
Although DNA vaccine platforms have shown promise in preclinical studies (65
), early clinical trials have been disappointing. Their exact mode of action is not known at this time. However, new constructs and methods of administration may enhance their utility.
The use of whole tumor–cell vaccines has the advantage of presenting the patient's immune system with a range of both known and undefined TAAs as immunogens. However, this same property also potentially diminishes the relative level of expression of a particular TAA or group of TAAs and its presentation and processing by APCs. The use of a killed whole tumor–cell vaccine is usually accompanied by an immune stimulant such as GM-CSF, Bacillus Calmette–Guerin adjuvant (BCG), or CD40 ligand (CD40L).
Autologous tumor cell vaccines have a great advantage because they present the unique set of TAAs, such as particular point mutations or fusion gene products, from a given patient's own tumor (35
). Because this technology depends on the availability of tumor biopsies, it is feasible for only some tumor types and stages. In one variation of this technique, DCs and autologous tumor cells are fused together before immunization of the patient (37
). DC–tumor cell fusions combine the unique properties of whole tumor–cell vaccines with the enhanced antigen-presenting power of DCs.
Alternatively, allogeneic whole tumor–cell vaccines, which typically contain two or three established and characterized human tumor cell lines of a given tumor type, may be used to overcome many logistical limitations of autologous tumor–cell vaccines. The GVAX vaccine platforms (38
), which contain allogeneic pancreatic, prostate, or breast tumor cells, are a testament to the ability to provide such a vaccine for multicenter evaluation.