Peptide Immunotherapy in Vaccine Development

From Epitope to Adjuvant

Hyun Yang; Dong Seok Kim1    Research and Development Center, Peptron, Inc., Daejeon, South Korea
1 Corresponding author: email address: dskim@peptron.co.kr

1 Introduction

Synthetic peptide vaccines are usually composed of 20–30 amino acids containing the specific epitope of an antigen related to infectious and/or chronic diseases including cancers. Peptide vaccines theoretically have several advantages over other types of vaccines such as conventional vaccines and newly developed DNA or cellular vaccines (Ingolotti, Kawalekar, Shedlock, Muthumani, & Weiner, 2010). Easy synthesis with low cost, increased stability, and relative safety are generally demonstrated in numerous preclinical and clinical studies. In addition, peptide vaccines have no limitation in target diseases from virus infection to Alzheimer disease and even allergy (Fig. 1A) (Larche, 2007; Mocellin, Pilati, & Nitti, 2009; Nava-Parada, Forni, Knutson, Pease, & Celis, 2007; Park et al., 2014). Peptide vaccines can be designed with self- or nonself-antigen to properly balance the immune responses, which is not possible for conventional vaccines (Purcell, McCluskey, & Rossjohn, 2007). However, it was recently reported that no peptide vaccine is approved by FDA, although more than 500 peptides had progressed to clinical trials (Li, Joshi, Singhania, Ramsey, & Murthy, 2014). According to ClinicalTrials.gov, a public database which is a service of the U.S. National Institute of Health, there are 73 clinical trials in phase I, 65 clinical trials in phase II, and 4 clinical trials in phase III in the search result of peptide vaccine in March 2015 (Fig. 1B). The series of failures in peptide vaccines in clinical trials suggest several issues critical for the successful development of peptide vaccines. These include (1) limitation of single peptide epitopes as vaccine candidates, (2) an immune evasion, (3) the failure to elicit the controlled and prolonged immune response, (4) a lack of efficacy, and (5) the inappropriate design of clinical trials. In this review, we discuss the roles of peptides in vaccine formulation focusing on the innovative approach overcoming those limitations in the recent clinical studies or the researches close to clinical development.

2 Cancer Vaccine

The rational of cancer vaccine development is that tumor cells can be eradicated by induction of cytotoxic T lymphocyte (CTL) response against tumor-associated antigen (TAA) (Fig. 2) (Inoda et al., 2011; Melief & van der Burg, 2008). TAAs are generally processed in antigen-presenting cells (APCs) and presented to T cells in a human leukocyte antigen (HLA)-restricted pathway (Hirano et al., 2006; Parmiani et al., 2002). TAA-specific CTL can be activated and attack cancer cells recognized by TAA expression (Parmiani et al., 2002). Many peptide cancer vaccines are designed to stimulate T cells but most of them failed to show clinical benefits in clinical trials even though some of the vaccines successfully activated APC and TAA-specific T cells. The lack of vaccine efficacy was thought to result from HLA restriction, diversity of cancer phenotype, and immune evasion (Chentoufi et al., 2010; Khong & Restifo, 2002). To overcome these limitations, multiple peptides are employed in the development of cancer vaccine formulation rather than a single peptide.

IMA901 (Immatics) is a peptide cancer vaccine composed of multiple tumor-associated peptides (TUMAPs) using GM-CSF as adjuvant (Walter, Weinschenk, Reinhardt, & Singh-Jasuja, 2013; Walter et al., 2012). TUMAPs consist of 10 different peptide epitopes (Fig. 3), which are found to be overexpressed in the majority of renal cell carcinoma (RCC) (Bedke & Stenzl, 2013; Rausch, Kruck, Stenzl, & Bedke, 2014).

In a phase II clinical trial of IMA901, a randomized trial with 68 HLA-A*02-positive RCC patients, the group 1 patients (n=35) received IMA901 while the group 2 patients (n=33) received IMA901 with the pretreatment of cyclophosphamide (300 mg/m, n = 35) or IMA901 preceded by a single immune modulatory dose of i.v. cyclophosphamide (group 2 [n = 33]; 300 mg/m2) (Pal, Hu, & Figlin, 2013; Walter et al., 2012). The patient groups then received up to 17 injections of IMA901 plus GM-CSF over a period of up to 9 months (Walter et al., 2012). Among those patients that elicited an immune response to IMA901, cyclophosphamide pretreatment was associated with a significantly prolonged survival (Rausch et al., 2014; Walter et al., 2012). However, cyclophosphamide pretreatment had no impact on survival in the subset of patients who lacked an immune response. IMA901 is currently in a phase III clinical trial and has been granted orphan drug designation in the United States and Europe for the treatment RCC in HLA-A*02-positive patients.

On the other hand, GV1001 (KAEL-GemVax) is a cancer vaccine composed of a single synthetic peptide containing multiple epitopes in a 16-amino acid-long peptide. The peptide is derived from the human telomerase reverse transcriptase (Brunsvig et al., 2006; Park et al., 2014). Because GV1001 could bind to multiple HLA class I and HLA class II molecules (Kyte, 2009), it may therefore elicit combined CD4/CD8 T cell response, considered important to initiate tumor eradication and also long-term memory (Raval, Sharabi, Walker, Drake, & Sharma, 2014). In a phase II study with advanced pancreatic cancer patients, GV1001 showed total immune responses (63%) and a greater median survival (216 days; 146–323) in immune responders than in nonresponders (88 days; 53–190) (Bernhardt et al., 2006; Middleton et al., 2014). However, in a three-group, open-label, randomized phase III trial with locally advanced or metastatic pancreatic cancer patients, GV1001 fails to improve overall survival. Interestingly, cytokine analysis for the prediction of biomarker revealed that in the subset of patients with high eotaxin (CLL11) level GV1001 improved the median overall survival (high eotaxin = 14.8 vs. low eotaxin = 7.9) (Neoptolemos, 2014). Although the efficacy of GV1001 depending on eotaxin levels should be examined in a large phase III clinical trial, GV1001 recently received new drug approval in Korea for the pancreatic cancer patients with high level of eotaxin.

3 Allergy Vaccine

In normal physiological condition, body's immune system operates in steady-state condition to maintain immune homeostasis (Liu et al., 2007). However, abnormal failure of this homeostasis results in immune disorders such as autoimmune diseases and allergies (Burton & Oettgen, 2011). As we more understand the immunopathological events in immune-related diseases through the series of clinical studies, many innovative immunotherapies have been designed including vaccines.

Cat-Pad (Circassia) is a cat allergy vaccine composed of seven synthetic peptide immunogen-regulatory epitopes originated from the major cat allergen Fel d 1 (Worm, Patel, & Creticos, 2013). Because native allergen or long peptides can induce allergenic responses, Cat-Pad employed seven short peptides (13–17 amino acids) derived from binding analysis to common HLA-DR molecules (Table 1) which enable the peptides to bind to broad range of HLA molecules (Worm et al., 2013). In the randomized, double-blind, placebo-controlled study (phase IIb), the vaccine was well tolerated and demonstrated clinical benefits in both Total Rhinoconjunctivitis Symptom Scores (TRSS) and Total Nasal Symptom Scores (TNSS) that persisted 2 years after treatment (Aydogan et al., 2013; Patel et al., 2013). The randomized, double-blind, placebo-controlled,...