British Journal of Radiology 74 (2001),991-1002 © 2001 The British Institute of Radiology
Vaccines in oncology: background and clinical potential
A C Armstrong, MRCP, MBChB, BSc (Hons) and
R E Hawkins, PhD, FRCP, MBBS
CRC Department of Medical Oncology, University of Manchester & Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK
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Abstract
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Cancer is one of the leading causes of death in Western society. Despite improvements in screening, diagnosis and treatment of cancer, many patients ultimately succumb to their disease. Advances in molecular biology and our increased understanding of how the immune system functions have led to an intense interest in the development of cancer vaccines.
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Immune response to tumours
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There is now clear evidence that the immune system is capable of recognizing and responding to tumour antigens, and that this immune response, at least in animal models, is sufficient to eliminate potentially lethal doses of tumour cells [1–3]. Although the humoral immune system may play a role in the generation of an anti-tumour immune response, several studies have demonstrated the critical importance of both cytoxic (CD8+) and helper (CD4+) T-cells in achieving tumour rejection [4, 5]. Most cancer vaccines therefore aim to induce a cellular antigen-specific T-cell response.
Role of T-cells in the anti-tumour immune response
The T-cell antigen receptor (TCR) recognizes antigen only when it is displayed on the surface of the target cell as peptide fragments by the class I and class II molecules of the major histocompatibilty complex (MHC) [6] (Figure 1
). Class I molecules are present on virtually all nucleated cells and predominantly present peptides derived from endogenous proteins. As new proteins are synthesized, a fraction is broken down into peptides and loaded onto class I molecules. Tumour cells therefore present peptides from tumour antigens in the context of class I MHC to CD8+ T-cells. Class II molecules, recognized by CD4+ T-cells, are present only on the surface of specialized antigen presenting cells (APCs), including dendritic cells, B-cells and macrophages. These are predominantly loaded with exogenous proteins taken up by these cells. Thus, protein released from tumour cells by secretion, shredding or tumour lysis are captured by APCs. These antigens are processed and peptide fragments are presented to CD4+ cells by class II MHC. CD4+ T-cells link the humoral and cellular arms of the immune response, through direct interaction with B-cells and by the secretion of cytokines to initiate and amplify the CD8+ T-cell response. Activated antigen-specific CD8+ cells ultimately become cytotoxic and are then able to lyse tumour cells [7]. APCs are also able to present processed peptide to CD8+ T-cells in association with MHC class I molecules.
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Figure 1. Tumour cells present antigens to T-cells as peptide fragments on the surface of major histocompatibility complex (MHC) molecules. (A) In the absence of co-stimulatory signals, tolerance may result. (B) Tumour antigens are also taken up by antigen presenting cells (APCs), which can present peptide fragments to both CD4+ and CD8+ T-cells. CD4+ T-cells secrete cytokines, which further amplify the CD8+ T-cell response. Activated CD8+ cells become cytotoxic and are then able to lyse tumour cells.
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The evidence suggests that T-cells are capable of recognizing and responding to tumours in experimental conditions, yet most tumours are able to evade detection by the immune system. It is now clear that when a T-cell encounters an antigen for the first time, the outcome may be tolerance and not activation [8]. It is the context in which the antigen is presented to the immune system that determines the outcome [9, 10]. An effective T-cell response is now known to be dependent upon co-stimulatory signals present at the time of antigen presentation. Inflammatory cytokines induce expression of co-stimulatory molecules (such as CD40) on APCs, which in turn promote T-cell activation. TCR engagement in the absence of co-stimulatory signals results in T-cell anergy, even if both signals are provided in a subsequent encounter with antigen. This requirement of T-cells for co-stimulation is thought to maintain tolerance to normal self antigens expressed on tissues that are unable to deliver the second signal.
Most tumour cells are poor APCs. They rarely express class II MHC molecules and frequently have complete or partial loss of class I expression [11]. Tumour cells are also incapable of expressing co-stimulatory molecules. In the absence of co-stimulation, tumour-specific T-cells are likely to be rendered anergic on encountering tumour antigens on the MHC molecules of the cancer cell.
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Tumour antigens
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The ideal tumour-specific antigen is one that is immunogenic, and expressed on tumour cells but not on normal cells. Identification of tumour-specific antigens has long been an important goal of researchers working in the field. Unfortunately, most tumour antigens are not sufficiently immunogenic to induce an effective immune response, and many tumour antigens are expressed to some degree on normal tissues. They are therefore "tumour associated" rather than truly tumour specific.
Tumour antigens have been studied since the 1970s, with melanoma tumour antigens initially identified by the reactivity of patients' sera with allogeneic and autologous melanoma cells [12]. As technology improved, monoclonal antibodies secreted from hybridoma cells were used [13], identifying antigens such as carcinoembryonic antigen (CEA), alpha-fetoprotein and HER-2/neu. In the last decade, with increasing knowledge of the critical role of the cellular immune response, techniques have been developed to identify tumour antigens that act as T-cell targets. Initially, tumour-specific CD8+ T-cell lines were required, and were used to define and clone tumour antigens including the melanoma antigens MAGE-1,-3 and tyrosinase [14–16]. Recently, another approach, SEREX (serological analysis of tumour antigens by recombinant cDNA expression cloning), has been described [17]. cDNA expression libraries are constructed from fresh tumour samples and screened using patients' serum. This method abrogates the need for established T-cell clones, and because it uses immune serum, identifies only clones to which there exists a high titre IgG antibody response and therefore a concomitant T-helper response. This method has identified two antigens, MART-1 and tyrosinase, both originally identified by cloning the cytotoxic T-lymphocyte (CTL) epitopes, as well as previously unknown genes, such as NY-ESO-1, a human oesophageal cancer-associated antigen.
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Antigens recognized by the immune system (Table 1)
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Oncofetal antigens
Oncofetal tumour antigens appear early in embryonic development, before immunocompetence develops, are not expressed on adult tissues, thus allowing self-reactive T-cells to escape deletion, and may therefore reappear on cancer cells. One such antigen, CEA, is thought to function as an adhesion molecule in the fetal colon [18]. It is expressed to a low level on adult colonic mucosa but is highly expressed by more than 95% of colorectal cancers and by a significant proportion of many other common cancers (including gastric, breast, lung and pancreatic cancers). Another well characterized group of oncofetal antigens are the so called cancer testis antigens. These antigens are expressed in fetal tissues, but in the adult their expression is restricted to immuopriviliged sites such as the testis and the eye, allowing them to evade recognition by the immune system. Consequently they are attractive candidates for cancer vaccine therapy. Cancer testis antigens include the mage gene family, with MAGE-1 being expressed by about 40% of melanoma cell lines and melanoma tumours tested [14], as well as by other tumour types such as breast cancer [19].
Tissue-specific differentiation antigens
The discovery that the majority of T-cells derived from patients with melanoma recognize melanocyte differentiation antigens expressed in normal melanocytes as well as melanomas [20] was of great interest to tumour immunologists, as it had previously been expected that such T-cells would have been either eliminated from the immune repertoire or rendered tolerant. Class I restricted epitopes from two of these antigens, MART-1/Melan-A and gp100, are recognized by T-cells from a large proportion of patients with melanoma [20–23], making them ideal targets for immunization.
Mutated gene products
Mutations in tumour suppressor genes such as p53, or oncogenes such as Ras, are central to the process of oncogenesis and as such make intriguing targets for anti-tumour immunity. Proteins expressed from mutated gene products can induce both cellular and humoral immune responses [24–26]. Unfortunately, the site of p53 mutations varies among tumours, resulting in a wide variety of antigenic epitopes derived from different mutated proteins. Vaccines aimed at specific mutations are somewhat impractical, but interest in using wild type p53 as a potential T-cell target is growing. Mutations in Ras are far less complex, those described to date involving only single amino acid substitutions, mostly at residues 12, 13 and 61.
Viral-associated tumour antigens
A number of viruses are known to play a role in the aetiology of human malignancies, including human papilloma virus (HPV) and cervical carcinoma, Epstein–Barr virus (EBV) and Burkitt's lymphoma, and hepatitis B virus (HBV) and hepatocellular carcinoma. Viral gene products are expressed by these tumours and elicit both T-cell and antibody responses. Cervical carcinoma, one of the commonest cancers worldwide, offers interesting prospects for vaccine therapy, with invasive disease being associated with a 96% prevalence of HPV infection [27]. The most promising targets for vaccine therapy are the viral genes E6 and E7.These genes have the capacity to transform cells, with sustained expression of these genes being required for maintenance of the transformed state [28].
Idiotypic epitopes
B-cell malignancies are the result of clonal proliferation of cells each expressing surface immunoglobulin with the same unique variable regions. These variable regions contain determinants (epitopes) that can themselves be recognized as antigens or idiotypes. The idiotypic immunoglobulin of B-cell malignancies can therefore act as a tumour-specific antigen, making it a suitable target against which to direct specific immunotherapy. However, the antigen is patient-specific as well as disease-specific, and so any anti-idiotypic strategies must be tailored to individual patients [29].
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Cancer vaccine strategies (Table 2)
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Whole cell vaccines
Despite recent advances in the identification of an array of tumour antigens, it is still unclear which antigens are clinically relevant for the majority of tumours. For this reason, interest developed in the use of whole tumour cells as vaccines, based on the concept that tumour antigens will be more immunogenic than more ubiquitously expressed antigens.
Animal studies demonstrated that, in some murine models, mice could be partially protected from subsequent tumour challenge by a vaccination of tumour cells mixed with adjuvants such as Corynebacterium parvum [30]. Clinical trials followed. Berd et al [31] treated melanoma patients with low dose cyclophosphamide (used to potentiate the immune response) and an autologous, irradiated vaccine, with Bacillus Calmette Guerin (BCG) as an adjuvant. In 40 evaluable patients there were five responses: four complete and one partial. Other trials showed similar levels of efficacy.
With the increasing realization that immune responses against tumours are relevant, scientists began looking at non-specific ways to activate the immune system by investigating the effects of systemic administration of cytokines on tumour regression. Although there are some tumour regressions, with the response rate of malignant melanoma to interleukin-2 being 15–20% [32], the treatment is often accompanied by serious septic shock-like side effects. Work by Forni et al [33] demonstrated that peritumoral injection of low doses of cytokines could enhance the anti-tumour immune response without the side effects associated with systemic treatment. Improvements in molecular biological techniques have further advanced this area of research, allowing tumour cells to be transduced with genes encoding cytokines. This results in the production of high concentrations of cytokines in the vicinity of the tumour, altering the local immunological environment, enhancing antigen presentation by APCs, or enhancing the activation of tumour-specific lymphocytes. A number of cytokines have been used, with varying degrees of success. One murine study compared a number of different cytokines, using a number of poorly and moderately immunogenic tumour models, and demonstrated that of the cytokines used, tumours transduced with granulocyte macrophage colony stimulating factor (GM-CSF) produced the greatest degree of systemic immunity. Importantly, tumours genetically modified to express GM-CSF were able to cure pre-established tumours [4].
Results of a phase I trial using irradiated autologous renal cell carcinoma cells were published in 1997 [34]. 16 patients with metastatic renal cell carcinoma were randomized to receive vaccine cells with or without ex vivo human GM-CSF gene transfer. This study demonstrated that genetically modified vaccines can be administered safely, but also identified major limitations to the use of autologous whole cell vaccines, including the labour intensive techniques and the difficulties of expanding sufficient numbers of cells in vitro for the vaccine. The only clinical response was a partial response, seen in one of the patients receiving the GM-CSF gene-transduced vaccine.
Further studies have confirmed the safety of genetically modified, whole cell vaccines, with the most common side effect being self-limiting inflammatory skin changes at the site of vaccination. Some studies were able to demonstrate immunological effects of the vaccine [35, 36], mostly limited to delayed type hypersensitivity (DTH) reactions to the tumour cells, which in some cases correlated with a clinical response [37, 38].
One potential reason for the limited success of clinical trials that vaccinate patients with advanced disease was highlighted by a recent publication [39] which demonstrated that tumours can actively suppress the immune response in addition to developing passive mechanisms to evade the immune system. In the tumour model used, mice vaccinated with irradiated tumour cells, genetically engineered to secrete GM-CSF and given simultaneously with a tumour challenge, are protected from that tumour challenge. This protection was found to be mediated by T-cells. Mice given the cancer vaccine a week after tumour challenge were no longer protected, although the anti-tumour activity of T-cells isolated from these mice could be restored on in vitro stimulation. Further in vitro assays revealed that potent immunosuppressive factors, TGF-beta and IL-10, were secreted by the tumour cells inhibiting T-cell function. That similar mechanisms may be involved in the immunosuppressive effects of large tumour burdens in man is suggested by the finding that IL-10 levels were raised in 40 of 99 patients with a range of solid tumours [40].
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Antigen-specific vaccines
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Peptide vaccines
T-cells recognize antigens as peptide epitopes on the surface on MHC molecules. Antigenic peptides can be mixed with an immunological adjuvant and administered, with the aim of loading empty MHC molecules in vivo. Almost all peptide-based vaccines to date have used MHC class I restricted peptides.
Once murine studies had provided proof of principle [41, 42], peptide vaccines began to be tested in the clinic. Marchand et al [43] conducted a phase I trial, in which 12 HLA-A1 patients with stage III or IV melanoma, and whose tumours expressed MAGE-3, were vaccinated with 3 monthly injections of a synthetic MAGE-3.A1 peptide. Although no evidence of a cytotoxic T-cell response could be detected in any of the patients, three patients had partial tumour regressions with the spontaneous regression rate for melanoma being less than 0.5% [44].
Rosenberg et al [45] immunized melanoma patients with a synthetic A2-restricted peptide, derived from gp100 and modified by a single amino acid substitution to increase its binding to A2. 10 of 11 patients who received the peptide in incomplete Freud's adjuvant developed peptide-reactive and, in some cases, tumour-reactive T-cells, but there were no objective clinical responses in these patients. 19 further patients were vaccinated with the peptide given in conjunction with systemic IL-2. Only three patients had demonstrable peptide-reactive T-cell responses, but there was an objective clinical response in eight patients including one complete response. The response rate to IL-2 alone, based on comparison with historical controls, is expected to be about 17% [30]. A multicentre, randomized phase III trial of this peptide vaccine is planned and should yield interesting results.
The efficacy of peptide vaccines might be expected to have certain limitations. Use of peptides as vaccines requires knowledge of the MHC haplotype of each patient, as well as the corresponding class I binding motifs of the tumour antigen. The latter are relatively well known for some tumour antigens for common MHC haplotypes, but class II motifs remain less well defined. It may be that lack of antigen-specific T-cell help results in a suboptimal immune response. Toes et al [46] reported that vaccination of mice with the immunodominant epitope of an adenoviral-induced murine tumour in incomplete Freud's adjuvant led to T-cell tolerance and an inability to reject the tumours, whereas immunization of mice with irradiated tumour cells expressing the complete adenoviral antigen induced protective immunity. This protection disappeared when the mice were injected with the peptide 3 days before tumour challenge.
Another concern with the use of minimal epitope vaccines is that there will be immune selection of tumours with subtle genetic variations that no longer express the peptide epitope. Immunohistochemical analysis of repeat biopsies from patients who had initially responded to a melanoma peptide, but then relapsed in the presence of peptide-specific CTLs, showed gradual loss of antigen expression in association with disease progression [47]. Induction of a polyclonal immune response capable of recognizing multiple antigenic determinants, by using vaccines containing one or more whole antigens, may prevent tumour escape.
Protein vaccines
Idiotypic antigenic determinants expressed by B-cell malignancies offer a useful model for developing the optimal cancer vaccine. Animal studies have shown that active immunization with idiotypic protein, produced by fusing tumour cells with hybridomas, can induce protective immunity against tumour challenge [48–50]. Studies in non-human primates demonstrated that optimal immunization required conjugation of the protein to a strongly immunogenic carrier protein, such as keyhole limpet haemocyanin, as well as emulsification in an adjuvant [50]. This vaccine formed the basis of a clinical trial in which 41 patients with B-cell lymphoma were vaccinated against their tumour idiotype. 20 patients generated an idiotype-specific immune response as evidenced by an anti-idiotypic antibody response and/or a cellular proliferative response. Analysis of 32 patients that were vaccinated during first remission showed an improved clinical outcome for those patients who mounted an idiotypic immune response [51].
To induce an immune response against weakly immunogenic antigens, adjuvants are needed to provide a non-specific signal to activate the immune system (Table 3). Many adjuvants are not licensed for use in humans because of deleterious side effects; other methods of enhancing the immunogenicity of vaccines are therefore required. Fusion of the tumour idiotype to cytokines such as GM-CSF creates a vaccine that is, in mice, capable of inducing protective anti-idiotypic immunity without the need for carrier proteins or immunological adjuvants [48, 52]. A more recent clinical trial immunized patients with B-cell lymphoma with Id-KLH mixed with soluble GM-CSF. 8 of 11 patients with previously detectable minimal residual disease subsequently developed molecular remissions. Tumour specific CD4+ and CD8+ cells were found in 19 of 20 patients, with antibodies also detected, but these did not appear to be necessary for a clinical response [53].
DNA vaccines
Idiotypic protein vaccines need to be made individually for each patient, usually by generating hybridomas that secrete tumour immunoglobulin, a technically demanding and costly process. However, the surprising discovery that injection of naked DNA into muscle could induce potent immune responses [54] has led to an interest in the development of DNA cancer vaccines.
For idiotypic vaccines the variable heavy and light chain sequences can be identified from biopsy material and assembled as a single chain variable fragment (scFv), with the two chains separated by a linker peptide to allow the scFv to fold properly [55]. DNA vaccines encoding the scFv alone were able to induce only weak immune responses, necessitating the use of methods to enhance the vaccine's immunogenicity. Immunization of DNA encoding a fusion protein of the idiotype, a foreign constant region and GM-CSF yielded better results and was comparable in efficacy with the same protein vaccine but was more practical [56]. Fusion of the idiotypic DNA to fragment C of tetanus toxoid also appears to improve the vaccine and induces both antibody and CD4+ responses, as well as protecting from tumour challenge [57]. Following a feasibility study in patients with advanced lymphoma [58], a phase I/II trial of this vaccine approach is now underway. A further advantage of the use of the fragment C fusion is that it allows a useful immunological read-out for the trial.
Recombinant viral vaccines
Efficient and reliable gene transfer can also be achieved using viral-based systems in which recombinant viruses containing therapeutic gene(s) of interest within their chimeric genome are exploited for their natural ability to infect eukaryotic cells. A variety of recombinant viral vectors have been evaluated in murine models, with the commonest vectors currently in direct clinical use being recombinant vaccinia and other pox viruses. Retroviruses, which result in stable integration of the therapeutic gene within the cellular genome, are often used for ex vivo modification of tumour cells.
One advantage in the use of viral vectors may lie in their intrinsic ability to initiate immune responses. Some viruses, such as vaccinia, are able to directly infect APCs in vivo, allowing for efficient presentation of antigens in the context of class I and II pathways. Vaccinia, a live virus, also causes cellular damage as a result of viral replication. The resulting inflammatory response and cytokine production attracts and activates APCs, thus enhancing the immune response. Replication-incompetent viruses, such as modified adenoviral vectors, may cause less cellular damage, but expression of viral (and therefore foreign) genes themselves may act as an immunological adjuvant. However, this ability of some viral vectors to activate the immune system may also be one of the major barriers to their widespread use. Exposure to viruses such as vaccinia or adenovirus, either as the result of previous immunization or cross-reactive viruses in the course of natural infection, results in neutralizing antibodies that reduce the "take" of future vaccines. This problem may be avoided by the use of non-immunogenic, replication-incompetent viruses such as gutless adenoviruses or modified vaccinia virus (MVA). Such vectors should be safer for widespread clinical use, but may require the incorporation of adjuvants into the vaccine design.
Phase I studies using vaccinia virus have already been completed. The first European study used a recombinant vaccinia virus encoding the E6 and E7 proteins from HPV 16 and 18. Eight patients, each with late stage cervical cancer, were vaccinated with a single dose of the virus. Three patients developed an HPV-specific antibody response, with an HPV-specific CTL response detectable in the one patient who also had a clinical response [59]. Whilst this may have been due to a spontaneous remission rather than effect of the vaccine, the vaccine-induced CTL response occurred despite the presence of pre-existing anti-vaccinia antibodies. Other pox vectors in clinical use include avipoxviruses, which are able to infect but not replicate in mammalian cells. One such vector, ALVAC-CEA, a canary pox vector expressing CEA, was able to elicit CEA-specific CTLs in seven of nine A2 positive patients, although no clinical response was seen in this group of patients with advanced disease [60].
Dendritic cell vaccines
For an effective T-cell mediated immune response, T-cells require antigens to be presented to them to sensitize naive T-cells and to re-stimulate primed T-cells. Antigen presentation is therefore a crucial step in the initiation of an effective immune response, with vaccine-based immunity largely depending on the effectiveness of the APC that initially processes and presents the antigen. The most efficient APC is the dendritic cell (DC) (Figure 2). Only these cells, with the possible exception of B-cells, are capable of presenting antigen to naive T-cells [61]. To initiate T-cell immunity, peptides from infected cells located anywhere in the body must be recognized by circulating T-cells. Infected cells or tumours have few MHC molecules on their surface and usually lack co-stimulatory molecules. The increasing awareness that it is DCs that enable the immune system to tackle these difficulties has led to an interest in the development of DC vaccines.
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Figure 2. Methods of loading dendritic cells (DCs) with tumour antigens. (A) DCs loaded with class I restricted peptides are only able to prime CD8+ T-cells. Lack of antigen-specific T-cell help may result in a suboptimal immune response. (B) DCs loaded with whole antigens are able to prime both CD8+ and CD4+ T-cells. (C) DCs can also be transduced with genes encoding tumour antigens, allowing the activation of both CD8+ and CD4+ T-cells. Tumour antigen expression within the DCs provides the cells with a renewable source of antigen.
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Initially described by Langerhans in 1868, research was hampered until recently by difficulties in isolating DCs, and by a paucity of cell surface markers able to identify the cells. These difficulties are being overcome, and it is now possible to generate large numbers of DCs from mobilized CD34+ haematopoeitic stem cells [59, 60] or from peripheral blood monocytes [64], and to define them phenotypically by a panel of surface markers. There is still no single marker that is specific for DCs.
DCs are found in most tissues where they exist in an immature state, unable to stimulate T-cells but possessing an exceptional ability to capture and process antigens. These captured antigens can be presented efficiently by both class I and class II MHC molecules. Antigen capture acts as a signal for the cell to mature and mobilize to the regional lymph nodes. There the cells undergo extensive transformation, and antigen capturing abilities decrease and T-cell stimulatory functions increase. The unique capacity of these "mature" DCs to activate T-cells is probably related to the presence of an exceptionally high number of MHC, co-stimulatory and adhesion molecules [65–67].
DCs generated ex vivo and loaded with tumour antigen prior to re-infusion are now entering clinical trials. In one study [68], which was recently updated [69], patients with B-cell lymphoma were vaccinated with idiotype-pulsed DCs. A cellular immune response was documented in 8 of 10 patients vaccinated after relapse, and in 8 of 16 patients vaccinated in first remission, with two of these patients achieving vaccine-induced molecular remissions. Another group immunized metastatic melanoma patients with DCs loaded with a cocktail of specific tumour peptides or tumour lysates, together with KLH as a helper antigen. Objective clinical responses were seen in 5 of 16 patients, with two complete and three partial responses. All patients had an immune response to the vaccine as evidenced by a DTH reaction to KLH, in addition to a positive DTH to peptide-pulsed DCs evident in 11 patients [70]. Another interesting study was published more recently. Patients with metastatic renal cell carcinoma were vaccinated with a hybrid cell vaccine consisting of autologous tumour cells fused to DCs, with allogeneic rather than autologous DCs used to recruit alloreactive helper T-cells. An impressive 7 of 17 patients had an objective clinical response, including four complete remissions [71].
DCs can also be genetically modified with genes encoding tumour antigens (and/or cytokines). Tumour antigen expression within the DCs should provide the cells with a renewable source of antigen for presentation, and consequently more sustained antigen expression. Non-viral methods of DNA transfer, which include electroporation, lipid-mediated transfection and calcium phosphate precipitation, are often unreliable and inefficient. Recombinant viruses, including adeno viruses and retroviruses, can be used to transduce DCs, with transduction efficiencies of up to 95% [72, 73], but this may also result in expression of viral genes. DCs are potent APCs; viral genes expressed by the transduced DC may prime anti-viral immunity including CTLs, which may rapidly destroy the DCs in subsequent rounds of immunization. This may not be a problem, as several murine models have shown that pre-existing immunity does not prevent successful immunization with adenoviral-infected DCs [74–76]. However, there are new vectors ("gutless adenovirus") that do express viral gene products.
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Analysis of the anti-tumour immune response
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The ultimate aim of a cancer vaccine is to induce a sustained clinical response, which can be maintained if necessary with booster vaccinations. To be able to improve current vaccines and to optimize the immunization schedule, relevant immunological assays are needed.
However, although attention is on the induction of an anti-tumour cytotoxic T-cell response, it is still not established which immune effectors are needed for the optimal anti-tumour response. Indeed, it is likely that the most important immune effectors will vary with the tumour (antigen) used, and therefore trials should, at least for the foreseeable future, examine many different parameters, including both arms of the immune response.
One major problem facing immunologists is that none of the current methods used to monitor specific cellular responses are as reliable as the ELISA (enzyme linked immunosorbant assay) at examining the humoral immune response. Measurement of effector T-cells often requires one or more rounds of in vitro restimulation, which potentially reduces the relevance of any positive results to what is actually happening in vivo. Some assays, such as ELISPOT (enzyme linked immuno-spot) and tetravalent HLAs, require predictions about likely peptide epitopes, and furthermore restricts the analysis to patients for whom the class I peptide binding motifs are known. Other methods to measure T-cell populations include proliferation assays, intracellular flow cytometry staining or specific cytokine release, although the relative importance of any positive result to clinical outcome remains unclear. Currently, DTH testing appears to be the assay that, in a number of trials, correlates most strongly with patient response [31, 34, 77].
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Autoimmunity and cancer vaccines
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Clinical trials to date have demonstrated the safety of vaccine therapy for cancer, with the side effects induced so far being minimal. One potential problem with vaccinating against antigens expressed on normal tissues is the induction of autoimmunity—about 20% of melanoma patients that respond to systemic IL-2 develop vitiligo [78]. Autoimmune disease involving organs other than the skin is potentially more serious. Whilst patients participating in the clinical trials that have taken place so far have not shown any other evidence of autoimmune phenomena, it does remain a possibility. In one model using mice transgenic for a tumour antigen, anti-tumour treatment of peptide-pulsed DCs was accompanied by fatal autoimmune disease [79]. The vaccine regimen was more intensive than regimens used in the majority of trials (four immunizations within 12 days) but this did allow the researchers to cure established tumours rather than prevent the growth of a tumour following vaccination, which is the basis for most murine trials.
Other studies suggest that there may be a therapeutic window in which CTLs are able to reject tumours but unable to induce autoimmune disease. Vaccination of mice with murine p53 epitopes prevents the growth of tumours that overexpress the protein, without any demonstrable damage to normal tissue [80, 81]. In another transgenic model, CTLs with high avidity for the transgene product were shown to be tolerant to the transgenic tumour antigen, whereas CTLs with a lower avidity for the tumour antigen were not tolerized and were able to provide protection against tumour challenge whilst being insufficient to induce autoimmunity [82].
It may be that one of the consequences of inducing effective anti-tumour immunity is the concurrent induction of autoimmune disease. Where this is limited to organs or tissues for which replacement therapy is available, such as the pancreas or thyroid, or organs that are not necessary, such as the prostate, it is likely to be acceptable to patients who might otherwise face the prospect of dying from their cancer. In contrast, autoimmune diseases against the cardiovascular or nervous system may limit the use of cancer vaccines using antigens that are expressed on vital organs, unless the autoimmune disease can be controlled by immunosuppressive drugs that do not abrogate the anti-tumour immunity.
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Conclusions
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It is clear that the immune system is capable of recognizing tumour antigens. The challenge for immunologists is to amplify these immune responses into effective clinical responses without unacceptable autoimmunity. Recent advances in immunology have led to an increased understanding of the mechanisms involved in antigen presentation and T-cell activation. We are now able to design cancer vaccines based on rational immunological principles. Successful pre-clinical models are being translated into clinical trials. Given that clinical responses may be rare until patients with low volume disease are vaccinated, interpretation of these trials will require the development of reliable and relevant immunological assays. Once vaccine protocols have been optimized it is hoped that, for some malignancies at least, cancer vaccines will form part of the standard treatment options available to oncologists.
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Acknowledgments
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We are grateful to the Kay Kendall Leukaemia Fund, who support a Clinical Research Fellowship to Anne Armstrong.
Received for publication February 19, 2001.
Accepted for publication August 13, 2001.
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Abstract
Immune response to tumours
