Вакцины против рака

Vaccines against cancer

S Chandra and al. Reference Module in Biomedical Research, 3rd edition 2014

Введение

Противоопухолевый иммунный надзор и противораковая иммунотерапия

Обоснование применения вакцин против рака

  • Cтратегии вакцинации

Превентивные противораковые вакцины

  • Рак шейки матки
  • Гепатоцеллюлярная карцинома

Лечебные противораковые вакцины

  • Опухоли головного мозга
  • Рак молочной железы
  • Колоректальный рак
  • Рак легких
  • Меланома
  • Рак поджелудочной железы
  • Рак простаты
  • Почечно-клеточная карцинома

Заключение

Литература


Introduction

The development of vaccines that can protect against cancer or even result in the eradication of established cancer is based on the ability of vaccines to induce a robust host immune response. The immune system is a complicated network of cells and molecules that integrate surveillance, recognition, and elimination of foreign pathogens in complex hosts. The system includes several novel features that help promote effective clearance of foreign pathogens and allows efficient functioning of organisms with multiple organs and other internal systems. These features include rapid evolution of cells to respond to an array of foreign molecules, memory functions to respond rapidly to subsequent insults with the same pathogens, and suppression to dampen uncontrolled immune activation and maintain immunologic homeostasis. The immune system can also be manipulated to develop highly specific memory responses through vaccination. This concept was firmly established by William Jenner in the late eighteenth century when he used vaccinia virus, presumably derived from the cowpox virus, to immunize healthy patients against smallpox. The process of immunizing against a foreign protein has been termed ‘vaccination’ based on Jenner’s studies with the vaccinia virus. The smallpox vaccine was highly successful and has resulted in the global eradication of smallpox from the planet. Despite this success, the molecular and cellular mechanisms involved in vaccination are still incompletely understood. The lessons from smallpox vaccination have now been applied to a wide variety of other infectious diseases, and there is emerging evidence that the same principles may be applied to cancer.

The concept that the immune system can recognize and eradicate tumor cells is not new. In the late 1890s William Coley, a New York surgeon, first reported the observation that some tumors regressed in his patients who developed concurrent infection, such as erysipelas (Coley, 1991). Coley spent much of his life trying to identify the molecular nature of infectious processes that mediated tumor regression, so-called ‘Coley’s toxins.’ His search for the molecular basis of tumor rejection, however, remained elusive. In the early 1900s, Paul Ehrlich was the first to hypothesize that the mechanism of tumor rejection was based on the activation of the immune system. In the 1950s, Macfarlane Burnet and Lewis Thomas established that tumor rejection was based on lymphocytes that recognized specific proteins expressed by tumor cells, termed tumor-associated antigens (TAAs). This work laid the foundation for modern tumor immunology and also explained rejection in the setting or organ transplantation. Their work resulted in a Nobel Prize and paved the way for the development of vaccines against cancer based on TAAs. Although the theoretical foundation for cancer vaccines was recognized, the clinical development of tumor vaccines was met with considerable disappointment through the end of the twentieth century.

Today, there is a much better understanding of how the immune system both promotes tumor immunosurveillance and can be activated against tumor cells. In addition, the important role of immune suppression in cancer patients is better defined and strategies that both activate immunity while inhibiting tumor-derived immune suppression are leading to more effective clinical approaches for patients with cancer. In the past decade several new immunotherapy agents have been approved for cancer therapy, including the first vaccine for the treatment of patients with advanced prostate cancer. The basis of tumor immunosurveillance has been well documented in murine models, and this has led to significant advances in tumor immunotherapy and vaccine development (Schreiber et al., 2011). This article will review the basis of cancer immunosurveillance, discuss the rationale and scientific basis for vaccination against cancer, and provide an update on the current status of vaccines in development for a wide variety of human cancers.

Cancer immune surveillance and tumor immunotherapy

The immune system has many functions and recent data has firmly established that it plays a role in cancer immune surveillance. This has considerable implications for the development of preventive vaccines and for tumor immunotherapy against established tumors. A cervical cancer vaccine that prevents the development of cervical cancer has been approved by the FDA and vaccination against hepatitis B virus (HBV) may also prevent the subsequent development of hepatocellular carcinoma. Thus, understanding immune surveillance has already resulted in clinically useful prophylactic vaccine strategies. Much of our understanding of cancer immune surveillance has derived from the elegant work of Robert Schreiber and his colleagues in murine models.

The concept of the immune system having dual roles in both suppressing tumor growth and promoting tumor progression was incorporated into a concept known as immunoediting (Schreiber et al., 2011). The role of the immune system in preventing tumor growth includes the protection of the host against viral infection and reducing virus-associated malignancies, preventing an infiammatory environment that can promote tumorigenesis, and eliminating transformed malignant cells that express ligands recognized by cells of the innate and adoptive immune system (Schreiber et al., 2011). Cancer immunoediting is composed of distinct phases that a cell may experience, although not necessarily always in a sequential fashion: ‘elimination,’ ‘equilibrium,’ and ‘escape.’ In the elimination phase, malignant cells are recognized and eliminated by the innate and adaptive immune system using mechanisms that are not yet fully understood. In some cases, the tumor cells may escape elimination and may lie in a dormant state and later fiourish as a recurrent or metastatic disease, a phase known as equilibrium. In the escape phase that usually follows next, the tumor cells evade immunosurveillance by complex mechanisms and there is progression of tumor growth. Immune evasion mechanisms include the promotion of antiapoptotic factors, loss of tumor antigen expression, secretion of local immunosuppressive factors in the tumor microenvironment (e.g., interleukin (IL)-10, transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF), indoleamine 2,3-dioxygenase), potentiation of immunosuppressive lymphocytes such as T regulatory cells (Tregs), presence of inhibitory tumor-associated macrophages and myeloid-derived suppressor cells, and the expression of inhibitory molecules that are involved in checkpoint blockade. These inhibitory molecules include the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor and programed cell death protein-1 (PD-1), which will be discussed further in the article.

Immunoediting suggests there is a dynamic interplay between the rapidly evolving malignant cell that is characterized by genetic heterogeneity, and the immune system that is characterized by the ability to induce highly specific and clonal responses against individual tumor cells. The coevolution of tumor cells and immune cells suggests that the tumor may shape the immune repertoire as much as the immune system may contain or modulate tumor cell evolution. Thus, early exposure of tumor cells to the immune system can result in the emergence of tumor cells capable of escaping immune control. The dynamic nature of these interactions also suggests that immunotherapy may be able to move tumor cells that have escaped immune detection back into equilibrium, or in some cases, into tumor elimination. Clinical evidence supports this concept in that many immunotherapy agents, such as interluekin-2 (IL-2) and the anti-CTLA-4 monoclonal antibody, ipilimumab, result in durable long-term remissions in some patients.

Another principle that has derived from the murine studies of immunosurveillance is the importance of adaptive immunity. The immune system includes an innate response, which senses danger signals from invading pathogens or abnormal cells. This induces an antigen nonspecific response and is mediated by natural killer (NK) cells. The innate response is often quite rapid and provides an early and rapid response to infected or transformed cells. In contrast, the adaptive immune response takes longer to develop, induces an antigen-specific response, and also maintains memory responses for future encounters with the same or similar pathogens and/or transformed cells. These responses are mediated by B and T cells. The B cells maintain humoral immunity through the production of antigen-specific antibody molecules that are secreted and bind to specific antigens, usually expressed on the cell surface of infected or transformed cells and target the cells for destruction by opsonization or recruitment of NK cells. T cells deliver cellular immunity and several subsets of T cells have been defined, but all respond in an antigen-specific manner. CD4+ T cells generally provide helper functions to activate CD8+ T cells, while some CD4+ T cells possess suppressive functions and have been termed regulatory T cells (Tregs). CD8+ T cells are effector cells that recognize antigen and release cytotoxic granules, such as perforin and granzyme B, that directly lyse infected or transformed cells. The induction and homeostatic control of the B and T-cell subsets is mediated by costimulatory molecules expressed on antigen-presenting and target cells and a range of proinfiammatory and suppressive cytokines and chemokines. Murine studies have highlighted the importance of T cells and the cytokine, interferon-gamma, in maintaining cancer immune surveillance.

The immune system recognizes both self and nonself-antigens that are presented on specific cells known as antigenpresenting cells (APCs). These specialized cells include dendritic cells (DCs), macrophages, and activated B cells and are responsible for presenting the proteins or peptides derived from bacteria or viruses, and normal cells that have transformed into malignant cells. Normal cells transform into malignant cells by undergoing genetic alterations and expressing TAAs, which include normal proteins expressed at higher levels, mutated or misfolded proteins, expression of derepressed embryonic proteins and viral proteins, or altered expression patterns. In order to trigger an immune response, altered proteins are processed into smaller peptides that are taken up and presented in association with major histocompatibility complex (MHC) molecules by APCs to effector T cells which recognize specific antigen epitopes bound to MHC (Soares et al., 2012). There are two types of MHC molecules, types I and II, which are transmembrane glycoproteins on the surface of cells which present intracellularly processed peptides to naive T cells and lead to their activation and clonal proliferation (Ribas et al., 2003). After APCs process and express the tumor antigens in association with MHC class I or class II, the cells migrate to lymph nodes and result in the activation of circulating CD8+ and CD4+ T lymphocytes, respectively. CD4+ T cells help activate APCs and maintain a CD8+ T-cell response, the principal effector cells of the adaptive immune response (Ribas et al., 2003). CD4+ T cells recognize MHC class II restricted peptides on APCs and activate the cells by mediating the binding of CD40 ligand on the T cell to the CD40 receptor on the APC. CD8+ T cells recognize MHC class I restricted peptides on APCs via the T-cell receptor (TCR) and result in clonal expansion of activated antigen-specific cytotoxic T cells that circulate and mediate apoptosis of cells expressing the same antigenic peptides. Another type of immune cells known as NK cells are the first line of innate defense by the immune system. Although they do not have antigenic peptide specificity, NK cells are important in cytotoxic-mediated cell death by recognizing allogeneic or mismatched MHC-restricted cells that can be seen in transplanted tissue and pregnancy. NK cells also recognize cells expressing low levels of MHC, often seen in malignant or infected cells (Ribas et al., 2003).

The full activation of T cells depends on the delivery of at least two different signals. The first signal is provided to the TCR that recognizes cognate antigen in the form of MHC– peptide complexes presented by APCs. The second signal is a T-cell costimulatory molecule that provides signaling within the T cell to proliferate, generate proinfiammatory cytokines, and differentiate into effector cells. The best described T-cell costimulatory molecule is B7-1 that is expressed on APCs and is required for T-cell activation. B7-1 binds to CD28 on the T cell and promotes T-cell priming. Following activation, the CTLA-4 is mobilized to the T-cell surface and binds B7-1 with higher affinity than CD28. CTLA-4 is considered a coinhibitory molecule as binding results in T-cell proliferative arrest, cessation of cytokine production, and dampening of T-cell responses. This system of costimulatory and coinhibitory molecules works as a rheostat to maintain T-cell homeostasis and to prevent uncontrolled T-cell proliferation and autoimmunity. This system seems to be particularly important for tumor immunity as recently an antibody that blocks CTLA-4 signaling, ipilimumab, has shown a significant improvement in the overall survival for patients with metastatic melanoma, a cancer that is known to be immunogenic. In addition, most tumor cells do not express costimulatory molecules, which may limit T-cell activity within the tumor microenvironment, while many tumor cells do express coinhibitory molecules that can inhibit activated T cells. In contrast to tumors, professional APCs, including DCs, express T-cell costimulatory molecules and may be better able to induce effector T-cell responses and this is the basis of the current Sipuleucel-T vaccine approved for patients with advanced prostate cancer.

In addition to the T-cell coinhibitory molecules, the immune system has developed cellular regulatory mechanisms to prevent excessive immune activation and autoreactivity to self-antigens. As mentioned above, one of these mechanisms includes a specific population of CD4+ T cells (Tregs) that express FoxP3 and high levels of CD25. Tregs can result in the suppression of the immune system by constitutively expressing receptors such as CTLA-4, by directly dampening APC or CD8+ T cells, and through the production of immunosuppressive cytokines, such as IL-10 and TGF-beta (Ribas et al., 2003). Furthermore, the production of additional factors such as VEGF, and indoleamine-pyrrole 2,3-dioxygenase may also be involved in immune suppression (Mocellin et al., 2001). IL-2 is essential to the survival of activated T cells and a lack of this cytokine can lead to cell death (Lenardo et al., 1999). The frequency of Tregs have found to be increased upto fourand fivefold in cancer cells; however, the levels decreased in patients with melanoma and renal cell carcinoma (RCC) who responded to high-dose IL-2 therapy (Cesana et al., 2006). Furthermore, a subset of DCs, instead of activating T cells, can also paradoxically result in the proliferation of Tregs that suppress the activity of the effector T cells (Curiel, 2007; Dong et al., 2002; Munn and Mellor, 2007; Rescigno, 2010; Sakaguchi et al., 2008; Thomas and Massague, 2005). Suppressor CD8+ T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory NK cells have also been shown to be associated with inhibition of antitumor immunity (Gajewski, 2007; Lindenberg et al., 2011). The importance of these suppressive mechanisms have been highlighted in preclinical studies that demonstrated improved responses to vaccines when these suppressor mechanisms are inhibited.

Rationale for vaccines against cancer

Current therapeutic modalities for cancer including surgery, chemotherapy, and radiation are associated with local and systemic side effects attributed to the therapy’s lack of specificity for cancer cells. These modalities often do not detect and cannot kill the micrometastases or residual disease that can lead to disease progression (Aly, 2012). Vaccines, a type of active immunization that involves the induction of an endogenous immune response, have been extensively studied and developed in the prophylactic, adjuvant, and metastatic settings in solid tumors to harness the immune system to recognize and kill tumor cells. The identification of TAAs provided specificity of the vaccine to target tumor cells with minimal impact on normal tissues. Several strategies for delivering the antigens have been employed, including peptides, proteins, recombinant viruses, and loading of the antigen onto DCs. These vaccines have been tested alone and with other immune potentiating and/or inhibiting agents to activate innate and adaptive immunity in numerous vaccine clinical trials (Ruzevick et al., 2012).

Melanoma and RCC are considered to be two of the most immunogenic solid tumors and have been studied extensively in vaccine development. Evidence to support their immunogenic properties include (1) the absence of a primary melanoma in 5% of patients with metastatic melanoma suggest that the primary melanoma underwent immune-mediated regression, (2) the frequent finding of lymphocytes within the tumor microenvironment, (3) reports of occasional spontaneous regression of metastatic tumors, and (4) regression of metastatic tumors in response to IL-2 and anti-CTLA-4 therapy, both potentiators of the immune system (Rietschel and Chapman, 2006). Other types of cancer may also be susceptible to vaccination.

Vaccine strategies

There are currently two major types of cancer vaccines, prophylactic and therapeutic vaccines. There has been some success with the development and efficacy of prophylactic virus-associated vaccines, specifically in human papillomavirus (HPV)-associated cervical cancer and HBV-associated hepatocellular carcinoma. However, to date, there has only been one therapeutic vaccine that has been approved for metastatic disease, Sipuleucel-T (Provenge ) that is approved for prostate cancer.

There are several different methods of vaccine development. One strategy is to use whole proteins or peptide fragments of known TAA. Many peptide-based vaccines are not very immunogenic, that is, they are self-molecules and often do not elicit an immunologic response when administered alone. Therefore, they are often given along with a nonspecific immunologic adjuvant (e.g., incomplete Freund’s adjuvant), a cytokine (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF), IL-2, IL-12) or a toll-like receptor agonist (e.g., imiquimod). Cytokines, such as GM-CSF, can enhance the immune response by stimulating and activating CD4+ and CD8+ T cells, and has shown adjuvant activity in murine tumor models (Jaffee, 1999). Peptide vaccines were added to cytokines such as GM-CSF and elicited increased DC activation and antigen presentation. Peptide vaccines can also be developed from autologous or allogeneic tumor cells. Patients receiving peptide vaccines need to have an identical HLA haplotype as the synthetic peptide(s), and it is unknown whether class I, class II or both sets of peptides are needed to elicit an optimal immune response (Kaufman, 2012).

In contrast to peptide vaccines, whole cell vaccines include the entire irradiated whole tumor cell and therefore, multiple tumor antigens can be processed by APCs and the method does not require a priori antigen identification. Whole cell vaccines can be autologous, derived from an individual patient; or allogeneic, derived from other patients. Autologous whole cell vaccines require a significant tumor burden to be resected from which the vaccine is prepared. This is advantageous because a patient’s own tumor contains immunogenic antigens unique to that patient but the process is hampered by the need for large quantities of tumor and the time necessary to process the tissue and develop a clinically acceptable vaccine. In contrast, allogeneic whole cell vaccines can be manufactured in advance and preparation does not depend on the disease burden of the patient but may not necessarily contain antigens specific to a given patient’s tumor. Furthermore, whole cell vaccines can be ‘pulsed’ with peptides, antigens, RNA, or DNA to enhance antigen specificity (Kaufman, 2012).

DCs are an efficient APC and are often loaded with TAAs and have been used in numerous vaccine trials. The use of autologous DC requires ex vivo preparation, which can be cumbersome. Nonetheless, the removal of DC from patients with tumors may be beneficial by eliminating the suppressive effects of the cancer and allow sophisticated manipulation of the cells to optimize T-cell activation. This optimization process includes the controlled differentiation of the DC, loading of TAAs to generate specific T cells and the inclusion of immune adjuvants, such as GM-CSF. Whole proteins, peptides, DNA, and RNA have been used for ‘loading’ DC as vaccines. This approach has been widely evaluated in preclinical models and has led to approval of the first human cancer vaccine for prostate cancer (see Section on Prostate Cancer).

Recombinant vaccines are based on bacterial or viral vectors, which may be engineered to coexpress TAAs and/or immune potentiating cytokines. They are used to directly vaccinate the host or as oncolytic vectors to directly kill tumor cells and generate a host antitumor immune response. Among the most widely studied vectors are the bacteria, Bacille Calmette-Guerin (BCG), Listeria monocytogenes, and Salmonella species, and viruses, such as adenovirus, poxvirus, and herpes virus (Soares et al., 2012). L. monocytogenes, for example, is easy to grow and to engineer antigen expression, and it targets both MHC class I and II pathways (Singh et al., 2005). Poxviruses are DNA viruses with vaccinia virus being the prototypic poxvirus (Kaufman, 2012). However, vaccinia virus results in a robust antibody response that precludes it from being used in booster vaccinations. This has led to the development of nonreplicating poxviruses such as fowlpox virus and the modified vaccinia Ankara (MVA) virus. Modified herpes viruses have significant oncolytic potential and have been used with GM-CSF expression as treatment for melanoma with some success. In general, recombinant vaccines can be easily manufactured and have had a good safety profile. To understand the effectiveness of these agents, randomized, prospective clinical trials are in progress.

Current status of preventive cancer vaccines

Cervical Cancer

Currently, there are two preventive or prophylactic vaccines that are FDA approved for specific HPV viral strains. Gardasil and Cervarix protects against the two types of HPV strains, 16 and 18 that cause approximately 500 000 cases of cervical cancer per year. Although HPV has been associated with other types of cancer, including head and neck cancers, cervical cancer is 100% associated with HPV infection. Gardasil is based on HPV antigens or ‘virus-like particles’ that are not infectious, and are associated with four HPV types 6, 11, 16, and 18, which are combined to manufacture the quadrivalent vaccine. Cervarix is a bivalent vaccine and based on HPV antigens or ‘virus-like particles’ of types 16 and 18 and is approved for females to prevent cervical cancer. As more time passes from the approval date and the use of these prophylactic vaccines increases, the efficacy of reducing the incidence of cervical cancer will be better understood.

Hepatocellular carcinoma

Nearly 80% of hepatocellular cancers can be attributed to chronic hepatitis B and C virus infections that accounts for more than 600 000 deaths per year worldwide (Lok, 2011; Parkin et al., 2005). The hepatitis B vaccine has been available in the United States since 1981. In 1991, strategies were developed to reduce HBV transmission in the United States that included prenatal testing of pregnant women to identify at risk newborns who would require immunoprophylaxis, routine vaccination of infants and adolescents, and the vaccination of high risk adult groups (“http://www.cdc.gov/vaccines/pubs/ pinkbook/downloads/hepb.pdf”). Hepatitis B surface antigen (HBsAg) is an antigen found on the surface of the virus and can be identified by serologic assays in the serum of individuals 30–60 days after exposure. After an acute HBV infection or following HBV vaccination, antibody to HBsAg (anti-HBs) can be detected and indicates immunity to HBV.

Initially, the hepatitis B vaccine was a plasma-derived vaccine that was produced from the HBsAg particle purified from the plasma of people with chronic HBV infections. Although the vaccine was proven to be safe and efficacious, it was removed from the US market in 1992 because of fears of transmission of HBV and other blood borne pathogens such as the human immunodeficiency virus (HIV) (“http:// www.cdc.gov/vaccines/pubs/pinkbook/downloads/hepb.pdf”). A recombinant HBV was approved in the United States in 1986, with a second similar recombinant vaccine approved in 1989. The recombinant vaccine is produced by the insertion of a plasmid containing the gene for HBsAg into the yeast, Saccharomyces cerevisiae, which then produces the HBsAg. The recombinant vaccine is made of 95% HBsAg protein, and about 5% of yeast-derived proteins. The lack of complete viral particle expression by the recombinant vaccine precludes a risk of infection. The two current approved recombinant HBV vaccines include Recombivax HB and Engerix-B , both of which are available in adult and pediatric formulations. Although there is an age-related decline in immunogenicity, booster immunizations are not routinely recommended as even low antibody levels protect against clinically significant HBV infection.

The prevention of overt hepatitis B infection likely prevents the subsequent development of hepatocellular carcinoma although epidemiological data is limited. The HBV vaccine would not be considered useful in patients with established hepatocellular carcinoma or in those patients without HBV infection. The paradigm that infectious disease vaccination may prevent cancer development, however, is worth exploring as this may be applicable in other cancers where there is a known viral precursor state.

Current status of therapeutic cancer vaccines

Therapeutic vaccines have been studied in numerous tumor types. Thus far, the only approved therapeutic vaccine is in prostate cancer. We will briefiy review some of the historic and current approaches in the development of therapeutic vaccines in cancer.

Brain tumors

High-grade gliomas are associated with a high morbidity and mortality. It was previously thought that the brain was an immunologically privileged site; however, recent data suggests that lymphocytes, and APCs including macrophages and DCs are able to cross the blood–brain barrier and migrate to the tumor site (Brabb et al., 2000; Calzascia et al., 2005; Hussain and Heimberger, 2005; Quattrocchi et al., 1999; Serot et al., 1997; Yang et al., 2010). The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation that encodes a constitutively active tyrosine kinase resulting in enhanced tumorigenicity and resistance to chemoradiation and is widely expressed in malignant gliomas (Sampson et al., 2008). In a phase I trial, DCs were pulsed with PEPvIII, a protein that is part of EGFRvIII conjugated to the keyhole limpet hemocyanin (KLH) and administered to 16 patients with high-grade gliomas. All patients showed an ex vivo immune response, with 2 of 3 patients with grade III gliomas alive without evidence of tumor progression at 66.2 and 123.7 months after vaccination. Subset analysis in patients with Glioblastoma Multiforme, the median time to progression was 46.9 weeks, and a median survival of 110.8 weeks (Sampson et al., 2008). A phase II trial known as the ACTIVATE trial used DCs loaded with PEPvIII that revealed increased ex vivo titers of antiEGFRvIII and anti-KLH antibodies and an increase in CD8ю, interferon (IFN)-gamma expressing, EGFRvIII-specific T cells. These patients had a median time to progression of 64.5 weeks and median survival of 126.1 weeks. In the ACTIVATE II trial, temozolomide given with the EGFRvIII vaccine, known as CDX-110, resulted in similar anti-EGFRvIII immune activity.

Breast cancer

In breast cancer, several tumor-associated antigens have been identified, including mammoglobin-A, a secretory protein overexpressed in human breast cancers and the HER2-neu protein that is a member of the epidermal growth factor (EGF) receptor family and is normally expressed during fetal development, but overexpressed in 30% of breast cancers (Holmes et al., 2008). Mammaglobin-A (Mam-A) is a human breast cancer associated antigen that has been studied as a potential therapeutic target for vaccine development. When T cells from Mam-A vaccinated mice were transferred into immunodeficient NOD/SCID harboring transplanted human breast cancers, tumor regression was observed (Narayanan et al., 2004). Based on these preclinical findings, a phase I clinical trial was conducted in which Mam-A cDNA vaccination was injected in seven patients with metastatic breast cancer. At 6 months following the first vaccine, in comparison to the control patients, the vaccinated patients’ fiow cytometric studies revealed an increase in CD4+ICOShi T cells and a decrease in the inhibitory T regulatory cells. Furthermore, the CD4+ICOShi T cells switched from producing IL-10 to interferon-gamma and lysed cancer cells expressing the Mam-A protein (Tiriveedhi et al., 2012).

A phase I/II trial evaluated the safety and immunogenicity of combined trastuzumab, a HER2-neu monoclonal antibody inhibitor, and a HER2-neu vaccine in metastatic breast cancer patients overexpressing HER2-neu. Twenty-two patients received trastuzumab and were vaccinated with a HER2-neu peptide vaccine. The authors noted that the patients tolerated the combination therapy with no increased cardiac toxicity above what can be seen with trastuzumab therapy. Furthermore, they noted that besides the pretreatment immunity to HER2-neu that many of the patients already had, vaccination boosted HER2-specific immunity as measured by baseline and posttreatment cellular immune responses. However, at a median follow up of 36 months, the median overall survival endpoint had not been met (Disis et al., 2009).

Numerous immunogenic peptides from the HER2-neu protein have been tested in clinical trials, including a peptide from the extracellular domain, E75; transmembrane domain, GP2; and the intracellular domain, AE37. The AE37 peptide is an HLA class-II binding peptide that stimulates CD4+ T-helper cells; whereas the GP2 and E75 peptides are HLA class I peptides that stimulate CD8+ peptide-specific T lymphocytes (Benavides et al., 2011). As reviewed by Benavides et al. (2011), there have been phase I/II dose escalation studies evaluating the safety and immunogenicity of HER2-neu peptides with and without the cytokine GM-CSF. All three peptides produced an immunologic response as measured ex vivo dimer assay or T-cell proliferation assay, and in vivo by measuring delayed-type hypersensitivity (DTH). DTH is thought to be a reliable method of monitoring immune response to cancer vaccines and tumor antigenspecific DTH responses have been shown to correlate with increased antigen-specific T-cell responses and are a refiection of systemic immunization (Disis et al., 2000). The authors of the trial noted that the patients who required dose reductions, especially for local reactions, experienced increased immune responses.

Colorectal cancer

Colorectal cancer (CRC) is the second most common cancer and third leading cause of death worldwide (Jemal et al., 2006). Preclinical studies have shown tumor-specific and TAAs, such as carcinoembryonic antigen (CEA), mucin-1 (MUC-1), and 5T4 are expressed in CRCs and have been used in a variety of vaccine approaches for treatment of advanced CRC. Among the most widely studied have been recombinant poxvirus vectors engineered to encode human CEA, MUC-1, and 5T4, which have entered into clinical trials. These antigens are all membrane glycoproteins that are overexpressed in 90% of GI malignancies.

An attenuated strain of vaccinia virus, known as MVA, that had been previously shown to have a tolerable safety profile in humans, was used to express the tumor antigen 5T4 (the vaccine was designated TroVax). In a phase I/II clinical trial, 17 patients with metastatic CRC received TroVax. In this trial, 16 of 17 patients had a 5T4-specific T-cell response and 14 of 17 patients had detectable anti-5T4 antibody levels following vaccination (Harrop et al., 2006). Five of the patients who had a 5T4-specific immune response had disease stabilization ranging from 3 to 18 months. There have been several clinical trials utilizing vaccinia and fowlpox viruses encoding human CEA given with or without GM-CSF. These studies also revealed that many patients developed CEA-specific immune responses but clinical responses were generally limited to disease stabilization or short-term responses. A recombinant canarypox virus (ALVAC) expressing CEA and the B7-1 T-cell costimulatory molecule was tested in combination with standard cytotoxic chemotherapy in a multiinstitutional phase II clinical trial (Kaufman et al., 2008). In this study 118 patients with metastatic CRC were randomized to vaccination followed by chemotherapy (5-fiuorouracil, leucovorin, and irinotecan), concurrent vaccination and chemotherapy, or chemotherapy followed by vaccination. Overall, 42 of 118 (40.4%) patients had an objective clinical response but there was no significant difference between the treatment arms. The study did, however, confirm the safety of vaccinating patients treated with chemotherapy.

In another approach, autologous DCs were loaded with six peptides derived from three colorectal TAAs. The antigens included CEA, MAGE-2, a melanoma antigen that can be over expressed in GI malignancies, and HER2-neu, a receptor in breast malignancies that is also present in 20–50% of colon cancers (Agus et al., 2000; Brossart et al., 1998; Hasegawa et al., 1998; Mitchell, 1998; Thompson et al., 1991). In a phase I/II trial, out of 21 enrolled patients with previously treated metastatic disease, 13 patients had adequate numbers of DCs that were apheresed, pulsed with the tumor antigens, and cultured with a bacterial membrane fraction from Klebsiella pneumoniae and interferon-gamma, and then infused back into the patients (Kavanagh et al., 2007). A CD8+ T-cell response was seen against all three tumor antigens; however all patients had progression of disease. In another phase II trial, 20 patients with advanced CRC were vaccinated with autologous DCs pulsed with allogeneic MAGE tumor antigen from a melanoma cell line (Burgdorf et al., 2008). About 79% of the patients expressed at least one or more of the MAGE antigens, and the authors hypothesized that the patients who expressed MAGE antigens would respond to the vaccine. No clinical response was seen, although four patients had stable disease, of which one patient did not express any MAGE antigens.

Although CRCs with a predominant T-cell infiltration have been associated with an improved prognosis compared to tumors without T-cell infiltration, recent work has highlighted the importance of infiammation in promoting CRC progression. This has been associated with a loss of Tregs and inability to contain the proinfiammatory induction of tumorigenesis. Thus, the immune system may need to be suppressed in order to reestablish innate antitumor immunity in the GI tract. This is contradictory to the standard approach elsewhere but might explain the disappointing therapeutic results seen in CRC. Further research is needed to see if antigen-specific vaccination in combination with antiinfiammatory strategies would enhance vaccination against CRC.

Lung cancer

Nonsmall cell lung cancer (NSCLC) is thought to be a nonimmunogenic tumor; however, spontaneous tumor-specific T cells have been seen suggesting the presence of immunosurveillance (Nakamura et al., 2009; Tsuji et al., 2009). There have been various vaccine targets investigated in NSCLC, both in the locally advanced/metastatic and adjuvant settings. In the metastatic setting, the proteins and growth factors including MUC-1, TG4010, EGF, and TGF-beta 2 have been studied as potential immunotherapy targets. As mentioned previously, MUC-1 is a glycoprotein normally expressed on epithelial cells, with an aberrantly glycosylated form seen in NSCL that may be immunogenic. L-blp25 is a synthetic peptide vaccine against MUC-1 that has been administered with low-dose cyclophosphamide as an immunologic adjuvant and had minimal toxicity in a phase I trial, and was found to elicit a T-cell response and improved survival in a phase II trial (North and Butts, 2005; Palmer et al., 2001). TG4010 is a recombinant MVA viral vector that expresses MUC-1. In a phase II trial, patients with metastatic NSCLC were randomized to receive TG4010 plus cisplatin and vinorelbine versus TG4010 alone until disease progression at which time TG4010 was given with chemotherapy. In the arm where patients received TG4010 plus chemotherapy, a partial response was seen in 13 out of 37 evaluable patients, while in the TG4010 alone arm, 2 patients experienced stable disease for more than 6 months, with 1 complete response and 1 partial response out of 14 evaluable patients when subsequent chemotherapy was given (Ramlau et al., 2008a). Another phase II study which was published in abstract form that studied the vaccine plus chemotherapy versus chemotherapy alone with 70 patients in each arm showed an increased response in the experimental arm, 30 of 70 (43%) versus 18 of 70 (26%) (Ramlau et al., 2008b). A subpopulation of patients with increased activated NK cells at baseline showed a statistically significant increase in median survival (17.1 vs 11.3 months), which suggested that activated NK cells might be a potential biomarker predictive of a clinical response with this vaccine.

A different vaccine targeting the epidermal growth factor receptor ligand conjugated to a carrier protein was tested with low-dose cyclophosphamide as an adjuvant agent in a phase II trial (Neninger Vinageras et al., 2008). Eighty patients with NSCLC previously treated with chemotherapy were randomized to vaccine versus best supportive care. In this study there was minimal toxicity attributed to the vaccine. Although there was no overall survival benefit, there was a statistically significant improvement in survival among patients less than 60 years of age, in those who showed a strong immune response, and among those who had decreased EGF levels. Another interesting vaccine approach makes use of TGF-beta, a cytokine that is known to have immunosuppressive activity by suppressing NK and DCs. Belagenpumatucel-1 is an allogeneic whole cell vaccine derived from four different NSCLC cell lines (2 adenocarcinoma, 1 squamous, and 1 large cell) and is combined with an antisense gene modification against TGF-beta-2 to maintain immunity in the tumor microenvironment (De Pas et al., 2012). A phase II dose escalation trial revealed that the response rate was dose dependent, although not statistically significant, with limited toxicities (Nemunaitis et al., 2006). Another vaccine composed of autologous tumor cells expressing GM-CSF to enhance neutrophil and monocyte activity has been shown to have activity in early phase studies, with prolonged remissions seen in bronchoalveolar carcinoma (Nemunaitis et al., 2004; Salgia et al., 2003).

Melanoma-associated antigen-3 (MAGE-A3) has been studied in the adjuvant setting in NSCLC. MAGE-A3 is a tumorspecific antigen that is expressed in tumors such as melanoma, bladder, NSCLC, head and neck, squamous, esophageal, and hepatocellular carcinomas. The antigen is expressed in 35–50% of NSCLC, more commonly in squamous cell carcinoma, and is associated with a poor prognosis (Thomas and Hassan, 2012). A phase II trial with a MAGE-A3 protein-based vaccine was given alone or in combination with the adjuvant ASO2B which contains a monophosphoryl lipid A and a saponin tree extract to stage I or II NSCLC patients as an adjuvant. In this trial, increased anti-MAGE-A3 antibody production was seen in the combination treatment arm (Atanackovic et al., 2004). Furthermore, booster vaccinations with MAGE-A3 resulted in increased antibody responses and induction of CD4+ and CD8+ T-cell responses against MAGE-A3 epitopes in patients treated with the vaccine (Atanackovic et al., 2008). In a phase II double-blind, placebo-controlled study, patients with resected stage IB or II NSCLC expressing MAGE-A3 were randomly assigned to receive the vaccine or placebo. There was a trend toward improved disease-free interval, disease-free survival, and overall survival in patients who received the vaccine. Of interest was that patients with a pretherapeutic gene signature consisting of immune-related genes was predictive of a benefit with the vaccine and a decreased relative risk of cancer (Vansteenkiste et al., 2008). An ongoing randomized double-blind, placebo-controlled phase III trial (MAGRIT) is studying the efficacy of the MAGE-A3 vaccine in resected stage IB, II, or IIIA NSCLC expressing MAGE-A3 in the adjuvant postchemotherapy or immediate postsurgery setting. The primary endpoint of this trial is disease-free survival, and a secondary endpoint includes the validation of the gene signature predictive of benefit from MAGE-A3 vaccine (Tyagi and Mirakhur, 2009). Results are anticipated in the near future.

Melanoma

Melanoma has a rising worldwide incidence and a 5-year survival of stages I and II after wide local excision of about 80–90%, which decreases to 50% for stage III and 10% for stage IV (“American Cancer Society: Facts and Figures, 2012. Available at http://www.cancer.org/acs/groups/content/@ epidemiologysurveilance/documents/acspc031941.pdf”; Balch et al., 2009; Garbe et al., 2011). Melanoma has proven to be highly susceptible to treatment with immunotherapy and targeted therapy, most notably with BRAF inhibitors in those patients whose tumors harbor a mutation in BRAF (Chapman et al., 2011). The use of high-dose IL-2 for the treatment of metastatic melanoma results in an objective response in 17% of patients while the anti-CTLA-4 monoclonal antibody, ipilimumab, induces objective responses in 11–15% of patients. Remarkably, the objective responses observed with both IL-2 and ipilimumab may be quite durable suggesting the potential of immunotherapy for melanoma. To date, vaccine therapy has been studied extensively in melanoma with numerous trials showing promising results, largely with oncolytic viruses in advanced disease and protein/peptide vaccines in the adjuvant setting. There are several defined TAAs that have been identified in melanoma as putative targets for vaccine development. Some of these antigens represent normal melanocyte differentiation proteins that are overexpressed during malignant transformation, such as gp100, Melan-A/ MART-1, tyrosinase, tyrosinase-related protein-1 (trp-1), and tyrosinase-related protein-2 (trp-2) (Boni et al., 2008; Coulie et al., 1994; Kawakami et al., 1998; Lindsey et al., 2006; Wang et al., 1998). In contrast, some antigens have been identified as cancer-testis antigens that are uniquely expressed by melanoma cells and only found on normal testis tissue (typically thought to be an immune privileged site), such as NY-ESO-1.

In a phase II clinical trial, 26 patients with advanced melanoma were vaccinated with a mixture of four gp100 and tyrosinase peptides that were HLA-A2 restricted, along with a tetanus helper peptide to generate CD4+ T cells, and low-dose IL-2 either in an emulsion GM-CSF and Montanide adjuvant, or pulsed on autologous DCs (Slingluff et al., 2003). The former group demonstrated an increased T-cell response to melanoma peptides in 42% of peripheral blood samples (vs 11% in dendritic peptide-pulsed arm) and 80% of immunized sentinel nodes (vs 13% in dendritic peptide-pulsed arm), with a statistically significant increased overall immune response in the GM-CSF vaccine arm. A tetanus T-cell response was seen in peripheral blood. An objective clinical response was seen in two patients in the GM-CSF arm, two patients had stable disease, whereas in the DC arm, one patient had an objective clinical response, and one patient had stable disease. A subsequent phase II trial was designed to evaluate whether the addition of GM-CSF to a peptide vaccine would enhance tumor immunity. One hundred and twenty one patients with stage IIB, III, or IV melanoma were randomized to receive a vaccine with 12 gp100, Melan-1/MART-1, and tyrosinase MHC class I restricted melanoma peptides with a tetanus peptide, all administered in incomplete Freund’s adjuvant, with or without GM-CSF (Slingluff et al., 2009). T-cell responses were significantly higher in the peptide alone arm versus the peptide vaccine with GM-CSF arm (73 vs 34%). Overall, the data suggested that GM-CSF may not be an effective adjunct for peptide vaccines in melanoma (Kaufman, 2012). Another phase II trial randomized 121 patients into one of three arms: peptide vaccine alone that consisted of HLA-A2 restricted peptides including gp100, MART-1, and tyrosinase versus peptide vaccine plus GM-CSF versus peptide vaccine plus interferonalpha. When T-cell responses were measured against the three peptides, an immune response to at least one peptide was observed in 26 of 75 patients; however, no correlation with GM-CSF or interferon-alpha was observed. The study investigators noted that there was a correlation between improved overall survival and immune responders versus the nonresponders (21.3 vs 10.8 months) (Kirkwood et al., 2009).

Three phase II trials that enrolled 132 HLA-A2 positive patients with advanced melanoma evaluated the combination of gp100 peptide with different doses of IL-2. At a median follow up of 60 months, the objective response rate was 16.5% overall, with an overall complete response rate of 9% and partial response rate of 7% which suggested that there was no benefit of the combination treatment (Atkins et al., 1999). A phase III trial evaluated high-dose IL-2 as an adjunct to peptide vaccination in which patients with unresectable stage III or IV melanoma were randomized to receive IL-2 alone versus gp100 peptide vaccine followed by IL-2 (Schwartzentruber et al., 2011). The combination arm had an improvement in objective clinical response rate (16 vs 6%) and a longer progression-free survival (2.2 vs 1.6 months) compared to IL-2 alone. Furthermore, the median overall survival was increased in the combination group (17.8 vs 11.1 months) suggesting that the combination of vaccine and IL-2 may be an effective treatment modality in melanoma.

MAGE-A3 is a cancer-testis antigen that is overexpressed in 65% of melanoma, and has been shown to be associated with poor survival (Kaufman, 2012). In a trial evaluating 10 patients who expressed MAGE-A3 and were infused with autologous, genetically modified lymphocytes expressing MAGE-A3, antiMAGE-A3 T lymphocytes were shown in three of the patients with evidence of T-cell migration to the tumor site that elicited an infiammatory response (Fontana et al., 2009). In a phase I/II trial of recombinant MAGE-A3 protein vaccine administered to 26 patients, there was 1 partial and 4 mixed responses (Kruit et al., 2005). Based on the objective clinical responses noted and the relative tolerability of the vaccine, a phase III randomized trial, known as the DERMA trial is in progress, in which 1300 patients expressing MAGE-A3 antigen with stage III melanoma and macroscopic lymph node involvement after complete lymph node dissection were randomized to receive MAGE-A3 protein vaccine or placebo. The trial has been closed to accrual and results are anticipated shortly.

Allovectin-7 is a recombinant plasmid that contains the DNA encoding HLA-B7 and is directly injected into the tumor. It is thought to elicit an antitumor response by activating adaptive immune responses generated by fragments of the HLA-B7 that are processed and presented as foreign by the tumor cells or local APCs that take up plasmid-transduced tumor cells. In a phase II trial, allovectin-7 was administered directly into the tumor of patients with unresectable stage III or IV melanoma (Bedikian et al., 2010). Of the 133 patients enrolled, 15 patients had an objective response with a median duration of response of 13.8 months, and 2 patients had a complete pathologic response. A large prospective randomized phase III trial comparing Allovectin-7 to chemotherapy (dacarbazine or temozolomide) has been completed and results are expected soon.

A novel approach to melanoma vaccination has utilized an oncolytic virus, a type of virus that infects and kills a target cell directly (Nanni et al., 2013). A vaccine based on an attenuated herpes virus encoding human GM-CSF has been generated and named Talimogene laherparepvec (T-VEC). This vector is used to directly infect tumor cells resulting in lytic destruction and initiation of local and systemic antitumor immunity enhanced by the local expression of GM-CSF. T-VEC was tested in a phase I trial in which patients with melanoma, head and neck, breast, and CRC were given intratumoral injections of the vaccine in escalating doses in 13 patients and a multidose regimen in 17 patients. Three patients had stable disease and 6 patients had objective responses with tumor necrosis in 14 of the posttreatment biopsy specimens (Hu et al., 2006). In a phase II trial in which 50 patients were enrolled with unresectable stage IIIC or IV melanoma were vaccinated with T-VEC and showed a 28% objective response rate, including 8 complete and 5 partial responses, and 10 patients had stable disease for at least 3 months. The overall 2-year survival was 52% (Senzer et al., 2009). Patients in this trial also demonstrated the induction of MART-1-specific CD8+ T cells within the injected tumor microenvironment and an associated decrease in Tregs and myeloid-derived suppressor cells suggesting the induction of systemic antimelanoma immunity (Kaufman et al., 2010). Based on these results, a phase III trial, the OPTIM trial was initiated evaluating T-VEC vaccine alone compared to recombinant GM-CSF with a primary endpoint of durable objective response and a secondary endpoint of overall survival. The study has completed enrollment and the primary endpoint was met demonstrating a 16% durable response rate for T-VEC compared to 2% for GM-CSF (Andtbacka et al., in press). The overall survival data is expected shortly. A followup clinical study combining T-VEC with ipilimumab is already in progress.

An allogeneic, irradiated, whole tumor cell vaccine known as CancerVax was made of three allogeneic melanoma cell lines. In a phase II trial, 263 patients with resected stage IV melanoma were evaluated in which 150 patients were vaccinated with CancerVax and 113 patients were observed (Hsueh et al., 2002). The 5-year survival was 39% in vaccinated patients versus 19% in the observation arm. Furthermore, a DTH response to the vaccine was noted that correlated with overall survival. In a subsequent phase III trial, 1160 patients with resected stage III and 496 patients with resected stage IV disease were randomized to receive CancerVax or placebo, both given with BCG that was used as an adjuvant. Although the trial was terminated prematurely by an Independent Data and Safety Monitoring Board based on the low probability of showing a difference between the treatment arms, the 5 year overall survival for the stage IV group was 42.3%, and for the stage III group, 63.4%. The patients treated with CancerVax formed an antigen–antibody complex against a tumor-associated 90-kd glycoprotein (TA90) that is found on melanoma cells, which was found to be correlated with clinical response (Tsiolias et al., 2001). In another phase II trial, 51 patients with TA90 complexes and 168 patients with no TA90 complex detected were all vaccinated. All patients who had the TA90 complex prior to vaccination remained positive and 79 patients (47%) of the seronegative patients converted after vaccination. The seroconvertors had a higher 2-year disease-free survival (59 vs 32%) and overall survival (78 vs 63%) compared to the seronegative patients. Although the endpoints of the phase III trial were not met, BCG may have elicited the unexpectedly high 5-year survival seen in both arms. Studies using BCG as a single agent in resected stage IV melanoma are underway. Another type of vaccine is known as M-vax, which is a type of autologous whole cell melanoma vaccine. It is prepared from irradiated whole tumor cells and then modified with a hapten, dinitrophenyl (DNP), which conjugates to proteins on autologous tumor cells and is thought to increase their antigenicity (Berd, 2002). In a phase II trial, M-Vax was administered to 97 patients with metastatic melanoma following cyclophosphamide with 2 complete responses, 4 partial responses, and 5 mixed responses (Berd et al., 2001). The median survival in responders versus nonresponders was 21.4 versus 8.7 months. A DTH response to the DNP-modified and unmodified melanoma autologous melanoma cells was seen in 87 versus 42% and correlated with prolonged survival.

Pancreatic cancer

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related deaths in the United States (“American Cancer Society, Cancer Facts and Figures, 2012. Atlanta: American Cancer Society, 2012”). Initially, pancreatic ductal adenocarcinoma was thought to be a poorly immunogenic tumor; however, recent data has shown that resected tumor specimens have increased levels of CD4+ and CD8+ T cells, as well as DCs which was associated with longer overall survival (Fukunaga et al., 2004). Furthermore, several antigens have been identified in pancreatic cancer cells suggesting this may be a tumor amenable to vaccine immunotherapy.

Mesothelin is a TAA that is overexpressed in most pancreatic adenocarcinomas, mesotheliomas, NSCL, and ovarian cancers (Argani et al., 2001; Le et al., 2012). A study using immunized lymphocytes from patients with pancreatic cancer who were treated with GVAX, a GM-CSF secreting allogenic whole cell vaccine, demonstrated an increase in post vaccine T cells specific for mesothelin that was associated with an increased disease-free survival (Thomas et al., 2004). In a separate study, a live attenuated Listeria monocytogenes recombinant bacterial vaccine that expressed mesothelin was administered to patients with metastatic pancreatic cancer and at least 37% lived longer than 15 months (Le et al., 2012). Annexin, another TAA that is expressed in pancreatic adenocarcinoma, was measured in the serum preand posttreatment of GVAX in 60 patients and the patients who had an increased disease-free survival had a posttreatment induction of annexin antibodies (Zheng et al., 2011). A double-blind, placebo-controlled trial in which a gastrin-based vaccine was given to 154 patients with advanced pancreatic cancer, there was a twofold increase in the median overall survival in the treatment group (151 vs 82 days) (Gilliam et al., 2012). An antigastrin immune response was seen in 73.8% of the patients and was associated with an increased overall median survival. Telomerase is active in 85% of pancreatic ductal adenocarcinoma cells, and when studied in phase I and II trials, showed an increased survival in immune responders (Bernhardt et al., 2006; Vonderheide et al., 1999). PANVAC-V is a poxvirus-based vaccine that uses a prime-boost approach with vaccinia and fowlpox viruses encoding CEA, MUC-1, and three T-cell costimulatory molecules (B7-1, ICAM-1, and LFA-3). When PANVAC-V was combined with GM-CSF in a phase I trial of patients with advanced pancreatic cancer, there was an increased median overall survival of 6.3 months (Kaufman et al., 2007). A MUC-1 or CEA-specific T-cell response was seen in 62.5% of the patients and correlated with a survival advantage over the nonresponders (15.1 vs 3.9 months). However, when compared to gemcitabine in a phase III trial, overall survival was not improved (Arlen et al., 2007). An autologous DC vaccine pulsed with MUC-1 peptides was tested as an adjuvant in a small early phase trial in which 12 patients with completely resected pancreatic ductal adenocarcinomas or biliary cancers were vaccinated. Although the sample size was small, 33% of the patients were alive at 4 years, despite a lack of rise of antibodies to MUC-1 (Lepisto et al., 2008).

An allogeneic whole cell vaccine known as GVAX which contains GM-CSF was tested in a phase I dose escalation study where 14 patients with stage II or III resected pancreatic ductal adenocarcinoma received the vaccine and then standard adjuvant chemoradiation for 6 months followed by additional vaccinations. Of the 14 patients, 3 showed a DTH response to autologous tumor cells and were alive at 12 years from diagnosis (Jaffee et al., 2001). A phase II GVAX trial was conducted in which 60 patients with resected pancreatic cancer received vaccine followed by standard chemoradiation. If patients then had no evidence of disease, they went on to receive additional vaccinations. These treated patients had a median disease-free survival and overall survival of 17.3 and 24.8 months, respectively. Another phase II trial studied GVAX with low-dose cyclophosphamide in 50 patients with metastatic pancreatic ductal adenocarcinoma who had failed gemcitabine treatment and had a median survival 2.3 versus 4.7 months in the combined treatment arm (Laheru et al., 2008). A type of whole cell allogeneic vaccine is the HyperAcute vaccine which is composed of irradiated cells that were genetically modified to add alpha(1,3)-galactosyl residues (as human cells lack a key enzyme in the pathway) on their cell surface which leads to complement activation and destruction of the aGal labeled tumor cells that results in an enhanced antitumor immune response. In a phase II trial with HyperAcute vaccine in a cohort of 20 patients with resected pancreatic ductal adenocarcinoma, 18 patients had 90% overall survival of 1 year (Hardacre et al., 2010).

Prostate cancer

Prostate cancer, the second leading cause of death from cancer in men, had until recently only one approved therapy for metastatic disease, the chemotherapeutic agent, docetaxel. In 2010, the vaccine Sipuleucel-T (Provenge ) was approved by the FDA for use in asymptomatic metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells including APCs that are leukopheresed from patients. The cells are then activated ex vivo with a recombinant fusion protein which consists of a prostate antigen known as prostatic acid phosphatase, which is fused to the cytokine GM-CSF (Kantoff et al., 2010a). Given the results of a previous smaller randomized trial, which showed a trend toward increased survival with Sipuleucel-T, a larger randomized double-blind, placebo-controlled phase III trial consisting of 512 patients with metastatic castration-resistant prostate cancer was conducted. The patients were enrolled from 2003 to 2007 and randomly assigned into one of two arms: Sipuleucel-T or placebo. The patients could have any Gleason pathologic/ histologic risk score, a PSA level of greater than 5 ng mL 1, serum testosterone of less than 50 ng dL 1, and minimally symptomatic disease. Adverse events were noted more frequently in the Sipuleucel-T group and included chills, pyrexia, fatigue, nausea, and headache. The patients in the Sipuleucel-T arm had a relative reduction of 22% in the risk of death, which represented a 4.1-month improvement in median survival (25.8 months in the Sipuleucel-T arm versus 21.7 months in the placebo arm) (Kantoff et al., 2010a).

Furthermore, the rate of 3-year survival was higher in the Sipuleucel-T group (31.7 vs 23%), which was consistent from previous studies (Small et al., 2006). However, the time to objective disease progression was not significant between the two groups that, according to the authors of the study, could be possibly attributed to a delayed onset of antitumor responses after active immunotherapy. The improved survival was seen across all subgroups that are known to be adverse prognostic factors in prostate cancer, including elevated PSA, LDH, alkaline phosphatase, number of bone metastases, advanced Gleason score, poor performance status, and presence of pain. Furthermore, this trial allowed for crossover for patients in the placebo group in an open-label salvage protocol with optional APC8015F, a product manufactured similar to Sipuleucel-T with cryopreserved cells that were collected at the time the placebo was prepared. Despite the crossover study design, a survival effect was observed which led to the approval of Sipuleucel-T as the first therapeutic vaccine for use in asymptomatic advanced prostate cancer.

Another approach that has been extensively studied in prostate cancer is the use of recombinant poxviruses. Clinical studies with vaccinia and fowlpox viruses encoding prostatespecific antigen (PSA) with or without T-cell costimulatory molecules have been demonstrated to be safe and immunogenic (Eder et al., 2000; Gulley et al., 2002; Sanda et al., 1999). However, neutralizing antibodies were noted to develop which limited the continuous treatment with vaccinia-PSA (rV-PSA). In a prime-boost strategy using vaccinia-PSA followed by booster vaccinations with recombinant fowlpox-PSA (rF-PSA) demonstrated a longer progression-free survival (Kaufman et al., 2004). Preclinical work revealed that the addition of immune stimulatory molecules to the poxviral vectors resulted in the induction of T cells with higher avidity for antigen and the triad of B7-1, ICAM-1, and LFA-3 were incorporated into the vectors, which were termed PROSTVAC-VF (Hodge et al., 2006; Hodge et al., 1999). In a phase II randomized, double-blinded, placebo-controlled trial, 125 patients were randomized to either receive PROSTVAC-VF versus placebo to study the vaccine’s effect on progression-free and overall survival (Kantoff et al., 2010b). The progression-free survival was similar in the two groups, and the median overall survival was 25.1 months for the PROSTVAC arm and 16.6 months for the control arm, with a hazard ratio of 0.56. There were no detectable antibody responses to PSA. There was a phase II trial conducted by the National Cancer Institute in which 13 of 28 patients had twofold increases in PSA-specific immune responses, and 4 of the 5 responders survived greater than 40 months, while low or nonresponders had a median overall survival of 20 months (Gulley et al., 2010). Additional work has been done evaluating these vaccines with chemotherapy and radiation therapy with promising initial results. A prospective, randomized phase III clinical trial is needed to validate the therapeutic effects of this vaccine in prostate cancer.

Renal cell carcinoma

RCC is the most common cancer of the kidney with an increasing incidence in the United States (Howlader et al., 2011; Itsumi and Tatsugami, 2010). RCC, like melanoma, is an immunogenic cancer and has been shown to respond to interferon-alpha and IL-2, with the latter resulting in durable responses and survival benefit (McDermott and Atkins, 2008). Several antigens have been defined in RCC and could be used in vaccine development. EphA2 is a tyrosine kinase receptor that is expressed in renal epithelial cells and plays a role in cell adhesion, and the mutated form has been shown to be associated with better prognosis in RCC. However, at present, it has not been studied as a vaccine target in clinical trials (Tandon et al., 2011; Tatsumi et al., 2003).

In order to avoid defining specific antigens, heat shock protein 96 peptide complexes were derived from autologous RCC tissue for vaccination. In an open-label randomized trial, 728 RCC patients who had undergone a nephrectomy received either an autologous heat shock protein 96 peptide vaccine (vitespen) or were assigned to an observation arm. At a median follow up of 21 months, there were fewer recurrences in the vaccine group, although not statistically significant, and there was no difference in recurrence-free survival in the two groups (Wood et al., 2008). Another autologous whole tumor vaccine was studied in a phase III trial in which 558 RCC patients with high-risk features and who had undergone nephrectomy were randomized to receive the autologous renal tumor cell vaccine versus observation. There was a significant improvement in tumor progression rate that favored the vaccine group (HR 1.58 at 60 months, and HR 1.59 at 70 months) (Jocham et al., 2004). The progression-free survival rates at 60 and 70 months was 77.4 and 72% for the vaccine and control groups, respectively.

Another target antigen that has been studied is 5T4, which is a cell surface glycoprotein that is expressed on placenta, gastrointestinal cancers, and also RCC, including clear cell and papillary histologies (Griffiths et al., 2005). As studied in CRCs, MVA-5T4, a vaccine that is based on the MVA vector engineered to express 5T4 has been studied in phase II and III trials in RCC. In a separate single arm, open-label phase II studies of patients with primary clear cell or papillary renal carcinomas treated with MVA-5T4 followed by low-dose or high-dose IL-2, significant objective responses were observed and these correlated with 5T4-specific immune responses (Amato et al., 2008; Kaufman et al., 2009). However, these results have not always been replicated (Hawkins et al., 2009). A large, multiinstitutional phase III clinical trial, in which 733 patients with locally advanced or metastatic RCC who had received first line treatment with sunitinib, interferon-alpha or IL-2, were randomized to receive MVA-5T4 or placebo. Overall, there was no clinical benefit noted, except in an unplanned subset analysis which revealed an overall survival benefit in those patients who had favorable prognostic features and who had received previous IL-2 therapy (Amato et al., 2010). These data suggest that careful selection of appropriate patients might result in better outcomes.

Conclusions

Vaccines against cancer have been a goal for over a century and provide a highly specific and safe strategy for targeting malignant cells for elimination. The theoretical principles guiding vaccine development, including antigen identification, vector construction, and preclinical proof-of-concept have all been achieved yielding a vast array of different vaccines for use against a range of different cancers. A better understanding of cancer immunosurveillance and the role of immunoediting in shaping the host antitumor immune response have had profound implications for tumor immunotherapy. In the past decade, several major advances in tumor immunology, vaccine development, and clinical trial results have led to the approval of the first preventive and therapeutic vaccine for cervical and prostate cancer, respectively. The importance of generating antigen-specific and memory T-cell responses is now widely accepted as the goal of vaccine development in cancer. In addition, a number of hurdles have been identified that may prevent effective vaccination in patients with cancer (Fox et al., 2011). The approval of ipilimumab, an anti-CTLA-4 monoclonal antibody, for melanoma has also helped generate interest in immunotherapy and highlighted some of the current limitations in clinical trial design and patient assessment.

Among the many hurdles to successful vaccine development, the heterogeneity and rapid evolution of tumor cells may be the most profound to overcome. Recent data suggests that interand intratumor heterogeneity may be a major confounding factor in the failure of a monovalent vaccine approach (Fidler, 1978). Genomic data from four patients with RCC obtained from primary and multiple metastatic sites preand posttreatment have shown that about two-thirds of the mutations detected in a single biopsy were not detectable in all of the sampled regions of the patient’s tumor (Gerlinger et al., 2012). Although multiple genes may be mutated in a given tumor, new studies of whole tumor cell genomics have suggested that less than 15 mutations were likely responsible for the growth and maintenance of the tumor (Wood et al., 2007). Thus, the use of autologous tumor cell vaccines or direct injections of oncolytic vectors into tumors harboring the specific mutations may be better to overcome antigen loss as a means of tumor escape. Other challenges include the generation of cellular and molecular factors that mediate immune suppression, such as the generation of Tregs and myeloid-derived suppressor cells in the tumor microenvironment and the release of suppressive cytokines, such as IL-2, TGF-beta, and VEGF. Overcoming local immune suppression is being actively studied and may allow vaccines to become more effective at mediating tumor regression. Combination of vaccines with chemotherapy, radiation therapy, surgical resection, and immunotherapy will be a major focus in the field for years to come.

Studies of ipilimumab have suggested that clinical responses may be significantly delayed to the prolonged kinetics of immune-mediated tumor rejection. In fact, in two randomized phase III clinical trials of ipilimumab there was no impact of progression-free survival observed but a significant improvement in overall survival was seen supporting the concept that initial response rate and progression-free survival may be misleading endpoints for immunotherapy clinical trials. Thus, current methods of evaluation in clinical trials may need to be revised to fully assess the potential benefit of vaccines and a new set of immune-related response criteria have been proposed (Wolchok et al., 2009). Other hurdles include the lack of research funding for this field, the lack of relevant murine models, and the complex regulatory environment that is not optimal for rapid combination of novel agents under development by different institutions and organizations. Despite the hurdles, cancer vaccines hold tremendous promise for both the prevention and treatment of human cancer. Further research into optimizing vaccine potency, identification of predictive biomarkers, improved preclinical testing methods, and improvements in clinical trial design will likely make vaccines against cancer a reality in the future.

See also: Antigen Presentation; CD4 and CD8 Molecules: Molecular Biology, Expression, and Function; Development of Human T Lymphocytes; Effector CD4+ T Lymphocytes; Evolution of the Immune System; Herpes Simplex Virus; HLA, the Human Major Histocompatibility Complex; Immunological Tolerance; Lymphocytes That Participate in Innate Immune Responses; Receptors in Antiviral Immunity; Structure and Function of Immunoglobulins; T-Cell Activation; The T-Cell Antigen Receptor; Toll-Like Receptor Function and Signaling; Viral Vaccines; White Blood Cells and Lymphoid Tissue.

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