Send Orders for Reprints to [email protected] 38 Recent Patents on Inflammation & Allergy Drug Discovery 2015, 9, 38-45 Peptide Vaccines for Cancer Therapy Daniela Cerezo, María J. Peña, Michael Mijares, Gricelis Martínez, Isaac Blanca and Juan B. De Sanctis* FOCIS Center of Excellence, Instituto de Inmunología, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela Received: October 13, 2014; Accepted: January 21, 2015; Revised: January 24, 2015 Abstract: For around four decades, vaccines of different kinds have been developed to treat different types of cancer. However, promising results encountered in the early phase contrasted with the results recorded in clinical studies. Recent discoveries in the vaccine field, adjuvants and delivery systems, and antigen presentation have lead to new patented approaches. The current review is focused on gen- eral description of peptide vaccines involving cancer antigen presentation, specific immune response, cell death dependent pathways, and target therapy for modified or mutated oncogenes. A rapid evolving research in the area may evolve in fruitful outcomes in the near future. Keywords: Adjuvants, antigen presentation, cancer, immune response, peptide, vaccines. INTRODUCTION antigens generated through nonstandard transcriptional and translational mechanisms may also be presented by MHC-I The key issue in inducing immune response is antigen [2-5]. presentation [1]. Antigen presentation is a complex process that involves intracellular compartments with a sequence of Antigen presentation by tumor cells is different from nor- events from degradation of a complex pathogen, or cell up to mal cells and therefore analysis of tumor antigens and cryptic binding to major histocompatibility complex proteins (MHC) tumor antigens differs enormously between them [2-5]. Ex- class I (MHC-I) or class II (MHC-II). Antigen presentation perimental data have revealed that tumor antigens are ex- generates a specific response, cytotoxic, MHC-I, antibody, T pressed differently (enhanced amount of antigen, novel neo helper response and, MHC-II [1]. The protective specific epitopes, etc.) as compared to normal cells [2-5]. In some tu- anti-tumoral immune response involves cytotoxic T cells and mors, the use of docking models, based on the data generated consequently MHC-I presentation [2-5]. However, immune from different MHC-I and relevant tumor-specific antigens response against tumor involves also the other T cell sub- (TSA) or tumor-associated antigens (TAAs), has revealed a populations [3-5]. probability cluster [2-5]. This cluster refers to binding and possible in vivo response [5]. Despite this fact, novel and The peptides presented by MHC-I vary from 8 to 11 highly immunogenic epitopes, capable of inducing an effec- amino acids in length and are generated from the proteaso- tive anti-tumor response, are not easily encountered [2-5]. In mal degradation of cytosolic protein antigens that are taken addition, adjuvants and delivery systems used in vaccines may up by the endoplasmic reticulum (ER) and consequently modulate antigen presentation by antigen presenting cells re- loaded onto MHC-I molecules [1-5]. Once the peptide binds sulting in a decrease in effective anti-tumor response or an to MHC-I, in the ER, it stabilizes the complex which is then increase in tolerogenic response. Thus, therapeutic cancer vac- transported to the cell membrane [1-5]. In the membrane, the cines have been proposed as a result of analyzing the wide peptide can be scrutinized by circulating CD8 cells, a proc- variety of genetic mutations and abnormal protein expressions ess usually named “immune surveillance” [2-5]. Since encountered in different tumors [2-5]. Its major drawback in- MHCs are highly polymorphic, the binding of the antigen volves the limited expression of the antigen and the highly and its presentation is not universal [2-5]. There are certain probability of mutation depending on the stage and type of “public” MHC-I proteins which are predominantly expressed tumor [2-5]. In addition, tumor microenvironments induce in different ethnic groups and thus serve as the target mole- tolerogenic responses and ideally, but it is not always encoun- cules for therapeutic vaccines [2-5]. Nonetheless, cryptic tered; adjuvants, peptides and immune enhancers should be able to surpass the tolerogenic response [4, 5]. *Address correspondence to this author at the Instituto de Inmunología, The aim of the present review is to give a brief picture of Facultad de Medicina, Universidad Central de Venezuela, Apartado 50109, Caracas 1050-A, Venezuela; Tel: +58-212-6934767; peptide vaccines in cancer therapy and the new patents that Fax: +58-212-6932815; Email: [email protected] have been submitted in the recent years. 2212-2710/15 $100.00+.00 © 2015 Bentham Science Publishers Cancer & Peptide Vaccines Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 39 TUMOR ANTIGENS culated epitopes could bind multiple HLA A3 alleles in the superfamily, suggesting that these peptides could overcome Many groups of researchers have tried to understand if some differences in HLA expression in patient to patient the usually hampered immune response against a tumor is comparisons [3]. Algorithmic models also fail to provide the due to the lack of recognition of the abnormal cells or im- only specific interaction since antigen binding may be re- mune tolerance. In order to address this issue, an overview of corded to other MHC molecules with different affinity [3]. the different approaches used is presented. One may envision that algorithmic models may represent The first lesson that the researchers have learned is that partially what occurs in vivo, and possibly the direct assess- tumor antigen expression is heterogeneous [3]. There are ment of cytotoxic cells in the tumor would give more spe- tumor specific and associated antigens [2-5]. Moreover, sev- cific results [3, 5]. eral levels of expressions of these antigens may be encoun- Studies with HPLC and mass spectroscopy of the MHC-I tered back as: 1) lack of antigen; 2) low amount of antigen; peptide complex are able to validate the predictive models 3) high amount of antigen; and 4) homogenous and/or het- and generate new possible targets [3, 5, 8-10]. Immunopro- erogeneous antigens (mixed or combined antigens). Conse- teomic analysis represents an enormous advantage due to the quently, it is not a simple task to find the ideal antigen to fact that epitopes that are naturally presented on tumor cells which the immune response should be directed. surface correspond to the clinically important targets for The first approach in cancer vaccines was to homogenize immunotherapy and vaccine design [3, 5, 8-10]. Moreover, tumor cells in order to assess specific antigens [2-5]; how- cancer neoepitopes should be addressed consciously [9]. ever, this approach and the use of vaccine with and without These identification techniques permit subtract antigens pre- adjuvants and immune enhancers resulted in a lack of spe- sented in normal tissue leading to only relevant molecules cific responses and a high amount of unwanted secondary for cell activation. Several models, including an in silico effects. The proteomic analysis and comparisons of normal model predicting peptide epitopes and vaccines have been and tumor cells were, in most cases, difficult to accomplish. published [8-11]. An alternative approach to tumor homogenates was the The important issue is to ascertain the real epitopes to use of cDNA libraries of tumor cells and subsequently trans- which the vaccine should be designed, the construct, adju- fect them into normal, antigen presenting cells [3-5]. By this vant, immune enhancer and the delivery which would lead to approach, translated antigens are processed and presented as the ultimate goal, an effective immune response against the epitopes loaded in MHC-I molecules. This technique is use- tumor. ful for MAGE-1, melanoma antigen, presented by HLA-A1, tyrosinase presented by HLA-A2, and other antigens [3-5]. CANCER PEPTIDE VACCINES Nevertheless, the processing of the tumor antigen does not Several reviews have addressed the issue of different necessarily resemble real in vivo antigen presentation since vaccines assays, clinical trials and their outcomes [3-5, 12- transcription of the antigen may be modulated differently in 15, http://www.clinicaltrials.gov]. The current review gives tumor cells as compared with normal cells [3-5]. There may only a general overview of the most important up to date be over or under expression of the antigen plus the posttran- approaches which are summarized in Tables 1 and 2. scriptional modifications may differ among tumor versus As aforementioned, most of the peptide vaccines were normal cells [3]. Skipper and co-workers [6] showed the developed with prediction motif methodology. Using this difference in CD8 response to tyrosinase tumor antigen in technique, the most studied models involved melanoma and vivo and the aforementioned technique. Fortunately, a renal carcinoma. The first clinical trial implicated the protein change in amino acid, an asparagine to aspartic acid, did not MAGE 1 (melanoma associated antigen). The results of im- affect HLA-A2 binding and generated a robust T cytotoxic munoproteomic assessments involved multiple epitopes [2-5, response. With several other antigens, the response was ei- 8]. The first interesting report dealt with the effectiveness of ther deem or nonexistent [3]. Proteolytic activity, involved in a 12 versus a 4 MHC-I peptide-based vaccine, a Phase II trial antigen presentation, may also be responsible for this differ- with stage IIB to IV melanoma patients [16]. Even though, ence [3-5]. no significant clinical results were recorded; the production Another method to identify tumor antigens is motif pre- of IFN was increased in cytotoxic cells and consequently, diction using pMHC-I binding algorithms [3-5]. The model the vaccine was able to generate a cytotoxic response to the involves sequences of peptides that bind MHC-I that can be inoculated antigens [16].