Antitumor Peptide-Based Vaccine: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Takumi Kumai.

The success of the is entry describes that the recent evidence that supports the rationale of peptide-basedmmune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor vaccineresponses in both mice and humans.

  • peptide vaccine
  • adjuvant
  • cancer

1. Introduction

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. 

2. Selecting Optimal Peptides for Cancer Peptide Vaccines

Based on anchor residues and other frequent amino acids, CD4 and CD8 T-cell epitopes can be predicted using a computer algorithm [7][1]. Several algorithms are available online to predict the epitopes from the whole amino acid sequence of TAAs (e.g., http://tools.iedb.org/mhci/, http://www.syfpeithi.de, accessed on 31 December 2021). Although the history of these predicting methods starts from the early 2000s [8][2], the quality of prediction has improved. Currently, NetMHCpan-4.1 and NetMHCIIpan-4.0 are considered as reliable methods by combining the data from MHC-binding affinity and mass spectrometry-eluted ligands to predict CD8 and CD4 epitopes, respectively [9][3]. Although these algorithms are useful for predicting the epitope sequences, Chaves et al. reported that there are huge disparities in the predicted scores among algorithms [10][4]. They found a high degree of false-negative and false-positive predictions in each algorithm by using a mouse influenza model. The potential of false-negative results using these algorithms has also been suggested in a melanoma model [11][5]. Nevertheless, these algorithms are efficient tools to estimate possible epitopes that could elicit antitumor T-cell responses when combined with biological assays, which confirms that the corresponding epitope peptides can actually induce T-cell responses [12,13][6][7].

2.1. Selecting Tumor Antigens as a Source of Vaccines

Although the origin of the tumor is self-tissue, cancer and hematologic malignancies can be targets of peptide vaccines. As tumors utilize signaling pathways in an unregulated manner, these signaling proteins, including TAAs, are overexpressed in tumors compared to normal tissues. Since most of self-antigen-reactive T-cells are deleted in the thymus by negative selection to prevent autoimmune diseases, low-affinity self-antigen-reactive T-cells that can only react to tumor cells with high TAAs expression exist in cancer patients [14][8]. Existing in healthy donors without any clinical symptoms, these T-cells that escape negative selection might react only with tumors that express a high amount of antigens but not with normal tissues, which express relatively low amounts of TAAs, including the cancer–testis antigens and cancer stem-like antigens [15,16][9][10]. Recently, mutation-derived peptides (neoantigens) have been immunologically regarded as non-self-antigens (tumor-specific antigens (TSAs)) [17][11].
Tumors express an abundance of cell signaling proteins such as the epidermal growth factor (EGFR), which is expressed in healthy tissues to a relatively low extent [18][12]. As T-cells are not deleted when a self-antigen is expressed at a low concentration [19][13], these TAAs-reactive T-cells may recognize tumors, but not healthy tissues. Previously, wusing algorithm-predicted epitope peptides generated EGFR-specific HTLs from healthy donors using algorithm-predicted epitope peptides [14][8]. We confirmed tThe reactivity and cytotoxicity of EGFR-specific HTLs against tumor cell lines and the presence of EGFR-specific HTLs in head and neck cancer patients be confirmed, suggesting that self-antigen-reactive T-cells exist and can recognize tumors. Notably, none of the donors and patients recruited in the study had autoimmune diseases related to the EGFR. Using the EGFR as a TAA model, the frequency of EGFR-specific CTLs was significantly correlated with the EGFR expression in head and neck cancer, strengthening the idea of targeting self-antigens as a TAA [20][14]. Therefore, even if target proteins are expressed in healthy tissues to some extent, the aberrant expression of these proteins in cancer can induce antitumor T-cells that only react to tumors.
Among TAAs, the expression of cancer-testis antigens such as MAGE and NY-ESO-1 is restricted in tumors and testes, but not in adult somatic tissues, indicating that this type of antigen is a favorable target for tumor immunotherapy [21][15]. Because CTL responses against cancer–testis antigens naturally occur in melanoma patients [22][16], the immune system can spontaneously recognize cancer–testis antigens as an immunogen. Cancer stem cells (CSCs) frequently express cancer–testis antigens. CSCs play a role in tumor initiation and chemotherapy resistance within a heterogeneous cancer population [23][17]. Targeting CSCs by cancer–testis antigen-based immunotherapy has shown superior antitumor effects than targeting survivin, a well-described noncancer testis TAA in a mouse model [16][10].
The most evident answer for unregulated tumor proliferation is the gain-of-function mutation of the signaling pathway [24][18]. Mutations in the tumor suppressor genes also contribute to tumor development. For example, mutated p53 loses the ability to sense DNA damage and fails to induce tumor apoptosis and senescence [25][19]. Approximately, three quarters of cancers express mutated p53 with amino acid substitutions, most of which are concentrated in the DNA-binding domain [26][20]. These mutations in cancer have paved the way for identifying the novel types of tumor antigens called neoantigens. Containing amino acid sequences derived from mutations, neoantigens are immunologically considered non-self-antigens that can activate high-affinity T-cells. The cytotoxic effect of CTLs induced by mutant p53 peptides is superior to that of wild-type p53 peptides [27][21]. Although high immunogenicity is an advantage of neoantigens against conventional TAAs, neoantigens have several issues that need to be addressed in clinical practice. The detection and confirmation of immunogenicity of non-shared neoantigens is time- and cost-consuming (tailor-made vaccines). Moreover, neoantigen-based peptides lose their antitumor effects, when a second mutation occurs in the neoantigen sequence. Because neoantigens are derived from frequently mutated tumors, targeting neoantigens has a high risk of antigen loss due to secondary mutations. Since antigen loss is common in tumor immunotherapy [28][22], it would be useful to select epitopes from non-mutated shared TAAs to switch tumor antigens to another. Because of their immunogenicity to induce antitumor T-cells [13][7], conventional TAAs can be used as clinical peptide vaccines with high versatility and replaceability when compared to neoantigens.
In classical cancer immunotherapy, CTLs are focused on as the “killer” T-cells against tumors, and HTLs are considered as the “helper” T-cells that support the cytotoxic function of CTLs. Although CTLs are potent in killing tumors, HTLs can directly exert antitumor effects through the production of cytokines such as IFN-γ, TNF-α, granzyme-B, and perforin [29,30,31][23][24][25]. Moreover, several reports have shown that HTLs are more important than CTLs in cancer immunotherapy by the direct tumor killing and education of CTLs or natural killer (NK) cells [32,33,34,35][26][27][28][29]. Because the support of HTLs to prime CTLs is only applied to high-avidity CTLs [36][30], high-avidity CTLs can be selectively activated with HTL epitope-combined CTL vaccines, whereas low-avidity CTLs compromise high-avidity CTLs with CTL vaccines alone. Collectively, it would be better to combine HTLs with the CTL epitope to augment antitumor responses with the vaccine. Since HTL and CTL epitopes should be presented by the same type of DCs to fully activate CTLs [36][30], CTL-included or CTL-linked HTL epitopes, rather than a mix of CTL and HTL epitopes, is appropriate to be presented by the same APCs and achieve the proper help of activated HTLs to CTLs through immune synapse [37][31]. Although it is possible that tumor-irrelevant HTLs might provide enough support to activate antitumor CTLs [38][32], it is rational to target tumor-reactive HTLs to obtain a benefit from the direct tumor cytotoxicity of these HTLs [39][33].

2.2. The Factors That Modulate Peptide Immunogenicity

The immunogenicity of tumor antigens depends on a complex series of events, including the isotype variants of antigens, antigen processing/presentation, and the post-translational modification of peptides [40][34]. Despite the inclusion of HTLs with CTL epitopes, as mentioned above, the length of the peptide itself is an important factor in determining the immune response. The addition of a few amino acids to the N-terminal of the CTL epitope increases its ability to be cross-presented by professional APCs [41][35]. Because longer peptides require further processing by professional APCs such as DCs, elongated peptides are selectively presented by professional APCs. In contrast, minimal epitopes do not require antigen processing and can be presented by non-professional APCs, which induces T-cell anergy [42][36]. Because protein-based vaccines and long-peptide vaccines can elicit antipeptide antibodies that have a potential risk of inducing anaphylaxis [43][37], long peptides should be designed without B-cell epitopes. Although antibodies that can capture antigens facilitates cross-presentation through the Fcγ receptor on DCs [44][38], the vaccine efficacy and safety should be carefully examined. Self-assembling amino acid sequences are unique amphiphilic peptides, which can form large complexes (20–200 nm), such as nanofibers by hydrophobic clustering and intermolecular hydrogen bond formation [45,46][39][40]. This complex can be selectively processed through professional APCs followed by the increased antigen-specific T-cell activation without risking the inclusion of B-cell epitopes [47][41]. The size of self-assembly nanoparticles can be controlled to 20 nm, irrespective of the peptide composition [48][42]. The insolubility of the complex can be improved by the insertion of suitable spacer amino acids [49][43]. The palmitoylation of peptides and their combination with cell-penetrating peptides will further increase the delivery of peptides into APCs through lipid bilayers and electrostatic/hydrophobic interactions, respectively [50,51,52][44][45][46]. Extracellular chaperon proteins such as heat shock protein 70 support the phagocytosis of exogenous antigens by penetrating APCs, followed by antigen processing and presentation [53][47].
Post-translational modifications are the result of coordinated enzymatic actions and are important in the regulation of cellular metabolism and gene expression. In cancer cells, the phosphorylation of proteins is involved in enhanced signal transduction, which affects the proliferative and metastatic potential of cancer cells. Histone acetylation has also been implicated in the upregulation of tumor-associated proteins, such as p53, c-myc, and survivin. Notably, TCRs can distinguish post-translationally modified peptides, including phosphorylated, acetylated, citrullination, or glycosylated peptides from their relevant wild-type peptides [54,55,56][48][49][50]. In addition, T-cells that recognize these post-translationally modified epitopes escape from negative selection in the thymus [57][51]. Thus, targeting the post-translational modification of epitopes would be a strategy to selectively target tumors, which aberrantly express post-translationally modified proteins, with a peptide vaccine. Because histone deacetylase inhibitors (HDACis) induce the acetylation of proteins, HDACis could augment the antitumor responses of acetylated p53-reactive T-cells [56][50]. Accordingly, it would be effective to combine HDACis with a peptide vaccine targeting acetylated TAAs.
Since TCRs can distinguish slight changes in epitopes such as post-translational modifications, TCRs accept the substitution of several amino acids within the epitope peptide. This concept has been widely accepted in mouse melanoma models. Mouse T-cells that respond to the human gp100-derived peptide (KVPRNQDWL) can recognize and kill B16 cells that express mouse gp100 (EGSRNQDWL) [58][52]. Because human gp100 could induce better antitumor T cells against mouse melanoma than mouse gp100, the substitution of amino acids to increase MHC binding might improve the T-cell responses to peptide vaccines. In addition, human T-cells that react to EGFR-derived peptides can react with homologous peptides derived from human epidermal growth factor receptor 2 (HER-2), HER-3, or c-Met [14][8], suggesting that peptide vaccines can be applied to tumors which express analogous epitopes to the targeted TAAs. Nevertheless, the reactivity to wild-type, modified, or analogous epitopes should be confirmed in the biological assay.

3. Clinical Evidence of Cancer Peptide Vaccines

Several phase I and phase II clinical trials of cancer peptide vaccines have been conducted since the first discovery of MAGE-A1 [112][53]. Unfortunately, most phase III studies using peptide vaccines do not show improved survival rates. For example, phases I and II studies initially showed that HER2-derived peptide vaccines, E75 (nelipepimut-S), AE37, and GP2 are safe and appear to show clinical efficacy in breast cancer patients [113,114,115][54][55][56]. However, the phase III clinical trial does not demonstrate improved disease-free survival with nelipeptimut-S and GM-CSF [116][57]. According to a review by Rosenberg et al. in 2004 [63][58], the overall response rate of peptide vaccines in clinical trials was 2.9% (n = 11/381), which is far from satisfactory. The efficacy of peptide vaccines partly depends on the types of tumors enrolled in clinical trials. Melanoma contains several immunogenic antigens, leading this tumor to be an ideal immunotherapy target, which has been proven in ICI trials. In melanoma patients, peptide vaccines have shown immune responses along with prolonged survival in some clinical trials [117,118][59][60]. A phase III study combining glycoprotein 100 (gp100) peptide vaccine with IL-2 in advanced melanoma showed an improvement in the overall survival, progression-free survival, and median survival rate. The toxicity of the peptide vaccine was consistent with a single IL-2 therapy [119][61]. However, the phase III trial of a peptide vaccine targeting multiple antigens (gp100, MART-1, and tyrosinase) and GM-CSF against resected high-risk melanoma patients did not improve the relapse-free survival and overall survival, indicating that the immunogenicity of the tumor type is not the only factor for predicting peptide vaccines responses. Because T-cells expanded ex vivo by peptides could effectively cure cancer in the clinical setting [120][62], it is plausible that the imitation of the ex vivo environment may improve the activation of T-cells in vivo. As described in the previous sections, the switching of conventional adjuvants such as IFA or GM-CSF to modern adjuvants (e.g., poly-IC) is the key to improving the efficacy of clinical peptide vaccines [39][33]. The safety of poly-ICLC with peptide vaccines has been demonstrated in several trials. Hilf et al. carried out a phase I trial using patient-tailored vaccines, APVAC1 (shared glioblastoma-associated peptides) and APVAC2 (de novo synthesized patient-specific glioblastoma-associated tumor-mutated peptides) with poly-ICLC against glioblastoma patients and showed significant T-cell activation [121][63]. Recent early phase trials have suggested the high immunogenicity of peptide vaccines combined with poly-ICLC [122[64][65],123], and several clinical trials are ongoing. The improvement of standard therapy with the addition of immunotherapy is an attractive topic. Several trials have demonstrated the synergistic effect of chemotherapy with a peptide vaccine. In a phase II trial of IMA901 (nine HLA class I-binding TAA peptides with an HLA class II-binding TAA peptide) plus GM-CSF with cyclophosphamide against relapsed or refractory renal cell carcinoma, favorable overall survival was associated with peptide-reactive T-cell responses [124][66]. In contrast, a phase III study of IMA901 with GM-CSF and sunitinib did not prolong the overall survival in renal cell carcinoma patients [125][67], indicating that the reduction of immunosuppressive regulatory T-cells by cyclophosphamide may support the activity of peptide-reactive T-cells [124][66]. A phase I trial combining a vascular EGFR-2 peptide (elpamotide) with gemcitabine was conducted to target patients with advanced pancreatic cancer [126][68]. The combined therapy was related to the prolonged survival (8.7 months) compared to the gemcitabine monotherapy group (5.7 months). However, a randomized phase II/III clinical trial using a combination of elpamotide and gemcitabine was not effective in patients with advanced pancreatic cancer [127][69]. Moreover, a phase III study using gemcitabine with GV1001 peptide vaccine did not improve the overall survival in patients with locally advanced or metastatic pancreatic cancer [128][70], suggesting that cyclophosphamide, but not gemcitabine, would have a synergy with the peptide vaccine. Clinical studies using peptide vaccines have shown only a few serious adverse events (AEs). The most prevalent AEs include injection site reactions, which are reversible and manageable. Grade 3 hematological AEs are sometimes observed but are mainly due to the progression of cancer [121,129][63][71]. Kjeldsen et al. have demonstrated the long-term safety of the indoleamine 2,3-dioxygenase-derived peptide vaccine [130][72]. They administered the peptide for up to five years, and it was well tolerated without inducing severe AEs. Therefore, peptide-based vaccines are considered safe and well-tolerated therapie

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