British Medical Bulletin

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (27) Request Permissions Disclaimer Google Scholar Articles by Dermime, S. Articles by Stern, P. L Search for Related Content PubMed PubMed Citation Articles by Dermime, S. Articles by Stern, P. L Related Collections Immunology Oncology Drugs Social Bookmarking          What's this?

British Medical Bulletin 62:149-162 (2002)
© 2002 The British Council

Cancer vaccines and immunotherapy

Said Dermime, Anne Armstrong, Robert E Hawkins and Peter L Stern

CRC Departments of Medical Oncology and Immunology, University of Manchester and Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK

	Abstract

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
It is now clear that many human tumour antigens can be recognised by the immune system. These tumour antigens can be classified into several groups including cancer-testis, differentiation, tissue specific, over-expressed, and viral-associated antigens. In many cases, there is a known molecular basis of carcinogenesis which provides the explanation for the differentiated expression of these antigens in tumours compared with normal cells. Improved understanding of the biology of the immune response, particularly of immune recognition and activation of T-cells, allow better design of vaccines. Pre-clinical comparative studies allow evaluation of optimal vaccine strategies which can then be delivered to the clinic. Currently, a range of cancer vaccines are being tested including those using tumour cells, proteins, peptides, viral vectors, DNA or dendritic cells. Ultimately, this research should give rise to an entirely new modality of cancer treatments.

	Introduction

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
Interest in vaccinating against tumours dates back to the 1890s when the New York surgeon William B Coley successfully treated some patients with sarcoma using bacterial toxins¹. In 1909, Paul Ehrlich successfully carried out immunisation in animals with tumour cells and suggested that tumours occur at a high frequency in humans but are kept under control by the immune system². Whilst this may be simplistic, it is clear that many tumour cells can be distinguished from their corresponding normal cells by the existence of tumour antigens that can be recognised by the host immune system.

Recent developments in tumour biology and basic immunology have provided new insights to our understanding of how tumour cells and the immune system interact. Indeed, many animal studies have now established the critical importance of T-cells in mediating antitumour immunity. It is clear that, in man, the process of carcinogenesis generates many changes in tumour cell antigen expression which are potentially, or actually, recognized by host T-cells (human tumour antigens). A detailed knowledge of mechanisms of antigen recognition by T-cells (processed peptides in the context of MHC class I or II molecules), the process of T-cell priming and activation (antigen presenting cells, co-stimulatory molecules, local cytokine environment), has allowed for the development of new cancer immunotherapies (Fig. 1). In cancer, such responses may be suppressed or may not have been optimally activated or have driven selection of tumour escape mechanisms. The aim of current cancer vaccines is, therefore, to induce de novo or potentiate existing antitumour immunity that can destroy autologous cancer cells. This review outlines the relevance of cell-mediated immunity to tumours, the range of potential human tumour antigen targets, and the various means being applied to optimise their use in vaccines. Necessarily, there is also a requirement to assess and develop the means to monitor the desired immunological endpoints in relation to clinical outcome.

View larger version (32K): [in this window] [in a new window]   Fig 1. Four steps to specific anti-T-cell responses. Damage/danger causing local cytokine release, activation of dendritic cells (DCs). DC antigen processing and migration. T-cells recognize, through the T-cell receptor (TCR), a complex of an antigenic peptide (P) (e.g. derived from a viral protein) bound to an HLA glycoprotein (major histocompatibility complex (MHC) class I or II molecules) located on the surface of the APC antigen. HLA polymorphism increases the chances of an individual existing within a population that can express an HLA-peptide complex resulting in protection against a particular pathogen. Processed peptide antigens presented by DC major histocompatibility complex HLA class I or class II molecules to CD8 or CD4 T-cells, respectively, in secondary lymphoid tissues with second signal provided by DC B7 (CD80) interaction with CD28 on the T-cells. Expansion of clones with specific T-cell receptor (TCR) for HLA-peptide complex and delivery of effectors to target tissue. [Adapted with permission from Little AM, Stern PL. Trends Mol Med 1999; 5: 337–42.]

 

	Immune recognition of human tumour cells

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
Animal models have demonstrated that, although humoral mechanisms may be relevant, it is T-cell-mediated immunity that is of critical importance in transplanted tumours³. This has driven an effort to identify tumour antigens using human T-cells⁴. T-cells recognise antigens on the cell surface of target cells as small peptides presented by class I or class II of the major histocompatibility complex (MHC) molecules (Fig. 1). CD8⁺ cytotoxic T-cells recognise short peptides derived from intracellular cytoplasmic proteins and presented at the cell surface by class I MHC molecules that are expressed by virtually all nucleated cells⁵. In contrast, CD4⁺ helper T-cells recognise longer peptides derived from engulfed extracellular proteins and presented at the cell surface by class II MHC molecules by professional antigen presenting cells (APCs)⁶. APCs are central to the priming of T-cells by specific antigen in which dendritic cells (DCs) are the most potent stimulatory APCs. DCs exhibit several features which are necessary for the generation of T-cell-mediated antitumour immunity⁷. They efficiently capture and take up antigens in peripheral tissues and transport these antigens to the primary and secondary lymphoid organs where they express high levels of MHC class I and II molecules that present the processed peptides to T-cells for the priming of antigen-specific responses. In addition, DCs express high levels of co-stimulatory molecules, that interact with receptors on T-cells, a second signal required to optimally activate antigen-specific T-cells⁸. T-cell recognition results in interleukin 2 (IL-2, a cytokine necessary for T-cell growth) production by stimulated T-cells which, in turn, leads to T-cell proliferation and expansion. T-cells become tolerant (anergic) when they see antigens in the absence of this signal. To initiate the process of antigen presentation by the DCs, the antigen has to be present together with signals of tissue damage, the so-called ‘danger signals’⁹. Stress proteins such as heat shock proteins that chaperone tumour antigens can be regarded as a danger signal and available evidence suggests that heat shock proteins are an important source of antigen processed and presented by DCs under natural conditions¹⁰.

According to the ‘immune surveillance’ hypothesis, expression of tumour antigens during neoplastic transformation should induce an immune response that can control tumour growth¹¹. However, evidence to support this can be demonstrated only in a fraction of tumours¹², and several mechanisms are thought to play important roles in tumour escape from the immune system. For instance, tumour cells can down-regulate or lose the expression of their MHC molecules resulting in inhibition of T-cell recognition¹³. Lack of co-stimulatory molecules on tumours can prevent T-cell activation and lead to T-cell anergy in cancer patients¹⁴. In addition, tumour cells may not be able to provide the danger signal necessary for optimal immune function⁹. The local release of transforming growth factor (TGF-ß1) by progressor tumours can inhibit DC migration and reduce the ability of DC to mature into potent APC¹⁵. Expression of Fas ligand molecules on tumour cells can interact with Fas receptors on T-cells resulting in induction of T cell death (apoptosis)¹⁶. These various escape mechanisms contribute to the lack of effective antitumour immunity in patients, in spite of clear evidence of frequent recognition of a plethora of tumour antigens.

	Identification and classification of human tumour antigens

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
Key studies established that autologous tumour-specific T-cells could be isolated from cancer patients and used to characterise the antigen recognised⁴. In these studies, complementary cDNA libraries generated from tumour cells can be introduced into a target cell expressing an appropriate MHC molecule, and antitumour T-cells can be used to screen for the genes encoding the tumour antigens. Several other approaches can validate potential tumour antigen identification. An in vitro stimulation technique known as ‘reverse immunology’, can be used to generate T-cells that react against proteins known to be over-expressed in certain cancer cells. If cancer cells are recognised by these specific T-cells, then the selected protein may be a useful tumour antigen¹⁷. Tumour antigens can also be discovered by investigating what peptides are eluted from the MHC molecules of tumour cells. Such eluted and concentrated peptides can be sequenced for identification and used to test their ability to generate T-cells¹⁸. A third technique known as SEREX (serologic analysis of recombinant cDNA expression libraries) identifies tumour antigens recognised by patient antibodies¹⁹. In this technique, proteins encoded by complementary cDNA libraries from cancer cells are expressed in bacteria and sera from normal or cancer patients used to screen for tumour-specific antigens.

Tumour antigens recognised by human T cells fall into several general categories. Examples of well-defined tumour antigens from each category are presented in Table 1.

View this table: [in this window] [in a new window]   Table 1. Categories and examples of tumour-associated antigens recognised by human T-cells

 
Cancer testis antigens

Cancer testis antigens are expressed in melanomas and several other tumours, but not in normal tissues except testis. This appears to be due to demethylation of the genes in testes and cancer cells. Since they are frequently expressed in different cancers, these antigens represent attractive targets for specific immunotherapy in cancer patients.

Differentiation antigens

These reflect the expression of normal products of a particular lineage which are associated with a particular point in differentiation and which might be found at relatively low concentration or on a small subset of cells. In cancer, the clonal expansion of the tumour and abnormal differentiation can provide a potential target for the immune system. There are several examples of such normal proteins controlling melanogenesis that are expressed on melanomas and also in normal melanocytes. Several peptides from these self antigens have been found to be targets for T-cells infiltrating tumours. Vaccination with these antigens can result in an immune response that may destroy normal tissues. T-cell-mediated vitiligo was demonstrated in melanoma patients after infusion with MART-1 specific CD8⁺ T-cell clones providing direct evidence that antigen-specific immunotherapy with such antigens can target not only antigen-positive tumour cells in vivo but also normal tissues expressing the tumour antigen²⁰.

Tumour-specific antigens

These are unique antigens specific for each individual tumour. They represent normal proteins that contain mutations or gene fusions that result in the generation of unique proteins. They potentially provide ideal targets for vaccination since the immune response generated will be specific and is unlikely to cause damage to normal tissues.

Over-expressed ‘self’ antigens

These are normal ‘self’ proteins that are expressed constitutively in tumour cells. Two major factors have to be taken into consideration when using this type of antigen in vaccination: the possibility of induction of auto-immunity as well as the existence of immunological tolerance (anergy), which may make successful vaccination impossible.

Viral antigens

Some human malignancies are strongly associated with viruses. Viral proteins expressed on tumour cells can serve as specific targets for immune attack. Vaccines containing this type of antigen are highly likely to be immunogenic as they are foreign antigens. Elimination of these infectious agents may also be a strategy to help prevent cancer.

	Vaccination with tumour antigens

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
The identification of human tumour antigens has made possible innovative approaches to antigen-specific vaccination. Several aim to combine selected tumour antigens and appropriate routes for delivering these antigens to the immune system in an attempt to optimise vaccination in humans.

Tumour cell-based vaccines

Whole tumour cells have been used to vaccinate humans with cancer. The fact that tumour itself is not able to induce an adequate immune response in patients in the first place, led to attempts to overcome such unresponsiveness by introduction of cytokine genes or co-stimulatory molecules, into the genome of the vaccine tumour cells. This should create micro-environmental conditions that prevent anergy and allows tumour destruction to take place. One important cytokine is the granulocyte macrophage colony-stimulating factor (GM-CSF) which is known to contribute to the maturation of DCs, which in turn enhances antigen presentation in vivo. The use of patient's autologous tumour cells transfected with GM-CSF as a vaccine has been explored in phase I/II human clinical trials for melanoma²¹, renal carcinoma²², and prostate cancer²³. These trials have shown some success in generating specific immune responses against tumours. However, production of such vaccine is rather labour-intensive, slow, and logistically difficult. Allogeneic tumour cell vaccination offers an alternative approach in which cell lines derived from the tumour type that is the target of therapy can be established in vitro, genetically modified, and used as a single reagent. Several clinical trials have been carried out with different allogeneic tumour types transduced with different cytokine genes. A recent phase I clinical trial treated 14 patients with pancreatic cancer with escalating doses of allogeneic GM-CSF-secreting pancreatic tumour cell vaccine followed by adjuvant radiation and chemotherapy²⁴. No toxicity was recorded and, in 3 patients given the highest dose, there was an increased delayed-type hypersensitivity (DTH) response to autologous tumour cells. Interestingly, these 3 patients were disease-free at least 25 months after diagnosis.

Peptide-based vaccines

Effective peptide vaccination depends on the in vivo loading of empty MHC molecules on professional APC expressing co-stimulatory molecules. A peptide-based vaccine that contains several T-cell epitopes, covering a wide range of MHC types, is likely to be successful in inducing polyclonal T-cell responses. Peptide vaccination for a number of tumours is being tested in clinical trials. Two phase I/II trials carried out in patients with metastatic melanoma^25,26 using peptides derived from gp100 and MAGE-3 and resulted in specific immunity and/or clinical responses in a significant number of patients. Phase I/II trials have also been performed in patients with cervical cancer using two HPV16 E7 HLA-A2 binding peptides and a pan-MHC class II helper peptide^27,28. The clinical responses observed in these trials were linked to T-cells against the helper peptide and not to the HPV16 derived peptides.

Recombinant virus-based vaccines

Tumour antigen vaccines can be delivered by recombinant viral vectors. One advantage of the use of such viral vectors is their intrinsic ability to initiate immune responses, with inflammatory reactions occurring as a result of the viral infection creating the danger signal necessary for immune activation. An ideal viral vector should be safe and should not introduce an anti-vector immune response to allow for boosting antitumour specific responses. Recombinant viruses (review by Bonnet et al²⁹) such as vaccinia viruses, herpes simplex viruses, adenoviruses, adeno-associated viruses, retroviruses and avipox viruses have been used in animal tumour models and based on their encouraging results, human clinical trials have been initiated. These trials have demonstrated that recombinant viruses are safe in humans, and can break immune tolerance against self and/or weakly immunogenic tumour antigens. A phase I clinical trial with a vaccinia virus vector encoding the CEA (rV-CEA) antigen was carried out in patients with advanced colorectal cancer³⁰. Although anti-CEA specific T-cell responses could be generated, no significant antitumour effect was observed. One main reason for the lack of a clinical efficacy in these trials may be attributed to the prior exposure of the patients to the vaccinia virus. Reduced vaccine delivery as a result of memory responses to viral antigens following repeated doses of the vaccine could reduce the effect of boosting. To avoid possible immunisation to the virus vectors, avipox virus vectors have been developed, as humans have not previously been exposed to these viruses and they cannot replicate in human tissues. A phase I clinical trial with recombinant avipox virus vector encoding the CEA antigen (avipox-CEA) was carried out in patients with advanced carcinoma³¹. Again, although a significant increase in the number of anti-CEA specific T-cell precursors was recorded in most patients, no true objective antitumour effects were seen. Alternative promising approaches include prime-boost schedules with different vaccine vehicles. Recently, a phase I clinical trial³² has indicated that the combination of rV-CEA and avipox-CEA in a diversified prime and boost protocol was superior to the reverse order in the generation of anti-CEA specific T-cells responses.

DNA-based vaccines

Direct vaccination with DNA encoding a tumour antigen has the advantage of simplicity and low cost of production. Such immunisation can induce both humoral and T-cell mediated immunity as the whole antigen is being delivered. DNA vaccines encoding weakly immunogenic antigens can be improved by vaccination with DNA encoding a protein antigen fused to a cytokine such as GM-CSF or the constant region of a foreign immunoglobulin³³, or a known highly immunogenic carrier protein such as fragment C (FrC) of tetanus toxin³⁴. The use of these ‘adjuvant-like’ elements has been shown to improve vaccine efficacy in experimental animals, and they are now being evaluated in human clinical trials. A phase I clinical trial using DNA encoding the variable fragment of B-cell lymphoma idiotype was carried out in 7 patients with low grade non-Hodgkin's lymphoma³⁵. Escalating doses of the vaccine given intramuscularly did not result in muscle damage or anti-DNA antibodies, with the exception of minor redness in the skin and muscle ache. However, no anti-idiotypic specific immune response could be detected in these patients. The use of the idiotypic DNA without an adjuvant and the fact that these patients were immunosuppressed prior to vaccination may have contributed to such unresponsiveness. A further phase I/II clinical trial in remission patients with non-Hodgkin's lymphoma is being conducted at this centre with escalating doses of vaccine incorporating the idiotypic scFv encoding DNA fused to the gene of FrC of tetanus toxin.

Dendritic cells vaccines

Several strategies have been used to load DCs with tumour antigens including peptides³⁶, proteins³⁷, tumour cell lysates³⁸ or tumour-derived RNA³⁹. Other strategies include DCs transfected with viral vectors expressing tumour antigens⁴⁰ or fused with the whole tumour cells⁴¹. The demonstration that immunisation of animals with DC-based vaccines can lead to rejection of established tumours, and the fact that functional DCs can be generated in vitro in large quantities from cancer patients, have made DCs an attractive vehicle to be used in human clinical trials. Hsu et al³⁷ vaccinated 4 B-cell lymphoma patients with autologous DC-pulsed ex vivo with idiotypic protein. Patients received 3–4 infusions of the DC-protein together with subcutaneous soluble protein. No significant side-effects were recorded and all patients developed an anti-idiotypic immune response. Three patients had either partial or total regression of the disease. A phase I/II clinical trial of DC-based vaccine was carried out in patients with prostate cancer³⁶ using DCs loaded with PSMA peptides given once every 6 weeks. In addition to induction of anti-PSMA specific T-cell activity, the numbers of the DCs given correlated with the duration of the immune response, with the majority of the patients (58%) still responding at the end of the follow-up period. In a clinical study of 16 patients with advanced melanoma, DCs were pulsed with either tumour lysate or peptides derived from (MART-1, gp100, MAGE-1 or MAGE-3) antigens in conjunction with KLH as a CD4⁺ helper and immunological tracer antigen⁴². A peptide-specific DTH response was induced in 11/16 patients and 5/16 patients had objective responses with regression of metastases in several organs. One of the most interesting clinical trials was recently reported by Kugler et al⁴¹ in 17 patients with advanced renal cell carcinoma. In this trial, the tumour cells were fused with normal allogeneic donor DCs and were given as subcutaneous injections over several months. A 41% response rate (with 4 patients showing a prolonged complete response) was recorded. Interestingly, 65% of patients developed DTH reactions and CD8⁺ T-cells were shown to migrate to the site of vaccination in which T-cells clones with specificity to the MUC-1 antigen could be isolated. The rational behind the use of such vaccines is the ability of the tumour-allogeneic DC hybrid to stimulate CD4⁺ helper allo-reactive T-cells to release cytokines. These cytokines can contribute to activation and proliferation of tumour-specific CD8⁺ cytotoxic T-cells which then lyse tumour targets.

	Evaluation and monitoring of vaccine-induced immunity

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
Because it is still not yet clearly known which are the most important immune effectors induced after vaccination, both humoral and cellular immune responses should be measured. For an antibody response, an established standard technique – the enzyme-linked immunosorbent assay (ELISA) – is the most reliable assay that can be used to look for antitumour activity. For T-cells, the frequency of tumour-specific T-cells is difficult to assess using standard assays. Two sensitive in vitro assays namely IFN- ELISpot and HLA-tetramers are being used⁴³. Fresh peripheral blood mononuclear cells can be used directly in the assays. However, a single round of in vitro stimulation can be carried out in the case of weak responses⁴⁴. The fact that HLA-tetramers detect both antigen-stimulated and naive T-cells and IFN- ELISpot only measures the number of memory and effector cells⁴³ makes the latter a more appropriate and reliable technique for discriminating between naive and vaccine-induced T-cells. Finally, the in vivo assay DTH⁴⁵ is being used in several clinical trials and DTH responses seem to correlate with clinical responses.

	Potentiating the immune response to tumour antigens

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 
Optimisation of techniques to produce optimally functional DCs in vitro is very important as many injections may be needed in order to break tolerance and sustain responses to poorly immunogenic tumour antigens. A recent clinical trial⁴⁶ demonstrated that treatment of advanced cancer patients with flt3 ligand, a hematopoietic growth factor, expanded circulating DCs 20-fold in vivo.

Generation of sustained CD8⁺ cytotoxic T-cell responses with antitumour effect usually requires help from CD4⁺ helper T-cells⁴⁷. The constant region of a foreign immunoglobulin³³, or a known highly immunogenic carrier protein such as fragment C (FrC) of tetanus toxin³⁴ and KLH as an immunological tracer antigen⁴², may be used as a CD4⁺ helper target.

Administration of DC activators and immunomodulating cytokines along with a DC-based vaccine may result in benefit. For example, in vitro activation of DCs with commercially available CD40 ligand or introduction of the gene encoding CD40 ligand into DCs should enhance the potency of a DC-based vaccine⁴⁸. The gene encoding IL-12, a cytokine produced by activated DCs, may also be introduced into DCs. This should allow Th1 cell activation which, in turn, recruits CD8⁺ cytotoxic T-cell responses in addition to its enhancement of natural killer cell cytotoxicity⁴⁹.

The method for antigen loading of DCs should be selected to suit an appropriate vaccine. Certainly, the incorporation of relatively more easily produced RNA or DNA may offer a viable alternative to peptide or protein and viral-based vaccines.

The route of DC administration can also be selected to induce a desirable humoral or cellular immune response. Antibody responses may be important for antigens expressed at the cell surface of tumours, such as the idiotypic immunoglobulin in B-cell lymphomas, whereas T-cell responses are necessary for intracellular antigens such as bcr/abl in CML. The intradermal and intralymphatic routes can lead to Th1 cellular immunity whereas the intravenous route favours humoral immunity with antibody production⁵⁰.

	Key points for clinical practice

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 

1. Over 50% of patients diagnosed with cancer will ultimately die of their disease. Alternative modes of treatment are undoubtedly needed.
   
2. There is clear evidence that tumours are immunogenic; however, in patients who develop cancer, the immune response to most tumours is by definition insufficient.
   
3. The ideal tumour antigen is one that is tumour specific and expressed on all tumour cells; most currently identified tumour antigens are expressed to some degree on normal tissues.
   
4. Vaccination with tumour antigens that are not tumour specific carries the risk of induction of autoimmunity, the consequences will depend on the distribution of the cross-reacting antigen. Autoimmune responses to major organs (such as the heart) are potentially disastrous whereas induction of treatable diseases (such as diabetes in association with curative cancer therapy) may be acceptable.
   
5. Whilst safety issues are routinely addressed using patients for whom no conventional treatment is available, it is anticipated that vaccines will be most effective when given to patients with minimal disease.
   
6. A number of different types of cancer vaccines are being developed in preclinical and clinical studies. The optimal vaccine, route and immunisation schedule remain to be determined. It is as yet unclear if all tumour types will be able to be successfully treated with vaccine therapy. Immune escape strategies of tumours will not always be circumventable.
   
7. As our understanding of the immunological mechanisms underlying antitumour immunity increases, there is increasing hope that cancer vaccines will offer a valuable new mode of treatment.
   

	Footnotes

 
Correspondence to:Dr Peter L Stern, Department of Immunology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK

	References

Top Abstract Introduction Immune recognition of human... Identification and... Vaccination with tumour antigens Evaluation and monitoring of... Potentiating the immune response... Key points for clinical... References

 

1. Coley W. Further observations upon the treatment of malignant tumours with the toxins of erysipelas and Bacillus prodigiosus with a report of 160 cases. Bull Johns Hopkins Hosp 1896; 7: 57
2. Ehrlich P. Uber den jetzigen Stand der Karzinomforschung. Ned Tijdschr Gneneesk 1909; 53: 273–90
3. Melief CJM. Tumour eradication by adoptive transfer of cytotoxic T lymphocytes. Adv Cancer Res 1992; 58: 143–75[Web of Science][Medline]
4. Rosenberg SA. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999; 10: 281–7[Web of Science][Medline]
5. Grey HM, Ruppert J, Vitiello A et al. Class I MHC-peptide interactions: structural requirement and functional implications. Cancer Serv 1995; 22: 37–49
6. Pieters J. MHC class II restricted antigen processing and presentation. Adv Immunol 2000; 75: 159–208[Web of Science][Medline]
7. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol 1997; 9: 10–6[Web of Science][Medline]
8. June C, Bluestone JA, Nadler LM et al. The B7 and CD28 receptor families. Immunol Today 1994; 15: 321–31[Web of Science][Medline]
9. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13: 114–9[Web of Science][Medline]
10. Colaco CA. Why are dendritic cells central to cancer immunotherapy? Mol Med Today 1999; 5: 14–7[Web of Science][Medline]
11. Thomas L. On immunosurveillance in human cancer. Yale J Biol Med 1982; 55: 329–33[Web of Science][Medline]
12. Penn I. Depressed immunity and the development of cancer. Cancer Detect Prev 1994; 18: 241–52[Web of Science][Medline]
13. Brady CS, Bartholomew JS, Burt DJ et al. Multiple mechanisms underlie HLA dysregulation in cervical cancer. Tissue Antigens 2000; 55: 401–11[Web of Science][Medline]
14. Speiser DE, Miranda R, Zakarian A et al. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J Exp Med 1997; 186: 645–53[Abstract/Free Full Text]
15. Halliday GM, Le S. Transforming growth factor-beta produced by progressor tumors inhibits, while IL-10 produced by regressor tumors enhances, Langerhans cell migration from skin. Int Immunol 2001; 13: 1147–54[Abstract/Free Full Text]
16. Rabinowich H, Reichert TE, Kashii Y et al. Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes. J Clin Invest 1998; 101: 2579–88[Web of Science][Medline]
17. Kawashima I, Hudson SJ, Tsai V. the multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumour-associated antigens expressed on solid epithelial tumors. Hum Immunol 1989; 59: 1–14
18. Hunt DF, Henderson RA, Shabanowitz J et al. Characterisation of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992; 255: 1261–3[Abstract/Free Full Text]
19. Sahin U, Türeci Ö, Pfreundschuh M. Serological identification of human tumour antigens. Curr Opin Immunol 1997; 9: 709–16[Web of Science][Medline]
20. Yee C, Thompson JA, Roche P et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 2000; 192: 1637–44[Abstract/Free Full Text]
21. Soiffer R, Lynch T, Mihm M et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 1998; 95: 13141–6[Abstract/Free Full Text]
22. Simons JW, Jaffee EM, Weber CE et al. Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res 1997; 57: 1537–46[Abstract/Free Full Text]
23. Simons JW, Mikhak B, Chang JF et al. Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 1999; 59: 5160–8[Abstract/Free Full Text]
24. Jaffee EM, Hruban RH, Biedrzycki B et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001; 19: 145–56[Abstract/Free Full Text]
25. Rosenberg SA, Yang JC, Schwartzentruber DJ et al. Immunological and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4: 321–7[Web of Science][Medline]
26. Marchand M, van Baren N, Weynants P et al. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 1999; 80: 219–30[Web of Science][Medline]
27. Ressing ME, van Driel WJ, Brandt RM et al. Detection of T helper responses, but not of human papillomavirus-specific cytotoxic T lymphocyte responses, after peptide vaccination of patients with cervical carcinoma. J Immunother 2000; 23: 255–66
28. Muderspach L, Wilczynski S, Roman L et al. A phase I trial of human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive. Clin Cancer Res 2000; 6: 3406–16[Abstract/Free Full Text]
29. Bonnet MC, Tartaglia J, Verdier F et al. Recombinant viruses as a tool for therapeutic vaccination against human cancers. Immunol Lett 2000; 74: 11–25[Web of Science][Medline]
30. McAneny D, Ryan CA, Beazley RM et al. Results of phase I trial of recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer. Ann Surg Oncol 1996; 3: 495–500[Web of Science][Medline]
31. Marchand JL, Hawkins MJ, Tsang KY et al. Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 1999; 17: 332–7[Abstract/Free Full Text]
32. Marshall JL, Hoyer RJ, Toomey MA et al. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant virus and recombinant non-replicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol 2000; 18: 3946–73[Abstract/Free Full Text]
33. Syrengelas AD, Chen TT, Levy R. DNA immunization induces protective immunity against B-cell lymphoma. Nat Med 1996; 2: 1038–41[Web of Science][Medline]
34. King CA, Spellerberg MB, Zhu DL et al. DNA vaccines with single chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat Med 1998; 4: 1281–6[Web of Science][Medline]
35. Hawkins RE, Russell SJ, Marcus R et al. A pilot study of idiotypic vaccination for follicular B-cell lymphoma using a genetic approach. Hum Gene Ther 1997; 8: 1287–99[Web of Science][Medline]
36. Tjoa BA, Simmons SJ, Bowes VA et al. Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides. Prostate 1998; 36: 39–44[Web of Science][Medline]
37. Hsu FJ, Benike C, Fagnoni F et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 1996; 2: 52–5[Web of Science][Medline]
38. Nair SK, Boczkowski D, Snyder D et al. Antigen-presenting cells pulsed with unfractionated tumor-derived peptides are potent tumor vaccines. Eur J Immunol 1997; 27: 589–97[Web of Science][Medline]
39. Boczkowski D, Nair SK, Snyder D et al. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 1996; 184: 465–72[Abstract/Free Full Text]
40. Specht JM, Wang G, Do MT et al. Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. J Exp Med 1997; 186: 1213–21[Abstract/Free Full Text]
41. Kugler A, Stuhler G, Walden P et al. Regression of human metastatic renal cell carcinoma and vaccination with tumor cell-dendritic cell hybrids. Nat Med 2000; 6: 332–6[Web of Science][Medline]
42. Nestle FO, Alijagic S, Gilliet M et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4: 328–32[Web of Science][Medline]
43. Pittet MJ, Valmori D, Dunbar PR et al. High frequencies of naive Melan-A/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals. J Exp Med 1999; 190: 705–15[Abstract/Free Full Text]
44. Gnjatic S, Nagata Y, Jager E et al. Strategy for monitoring T cell responses to NY-ESO-1 in patients with any HLA class I allele. Proc Natl Acad Sci USA 2000; 97: 10917–22[Abstract/Free Full Text]
45. Harris JE, Ryan L, Hoover Jr HC et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol 2000; 18: 148–57[Abstract/Free Full Text]
46. Fong L, Hou Y, Rivas A et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 2001; 98: 8809–14
47. Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4⁺ T-helper and a T-killer cell. Nature 1998; 393: 474–8[Medline]
48. Kuniyoshi JS, Kuniyoshi CJ, Lim AM et al. Dendritic cell secretion of IL-15 is induced by recombinant huCD40LT and augments the stimulation of antigen-specific cytolytic T cells. Cell Immunol 1999; 193: 48–58[Web of Science][Medline]
49. Chen Y, Emtage P, Zhu Q et al. Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12. Gene Ther 2001; 8: 316–23[Web of Science][Medline]
50. Fong L, Brockstedt D, Benike C et al. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 2001; 166: 4254–9[Abstract/Free Full Text]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				T. I. Naslund, C. Uyttenhove, E. K. L. Nordstrom, D. Colau, G. Warnier, M. Jondal, B. J. Van den Eynde, and P. Liljestrom Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor J. Immunol., June 1, 2007; 178(11): 6761 - 6769. [Abstract] [Full Text] [PDF]

				G. Shi, J. Mao, G. Yu, J. Zhang, and J. Wu Tumor Vaccine Based on Cell Surface Expression of DcR3/TR6 J. Immunol., April 15, 2005; 174(8): 4727 - 4735. [Abstract] [Full Text] [PDF]

				K. Teramoto, K. Kontani, Y. Ozaki, S. Sawai, N. Tezuka, T. Nagata, S. Fujino, Y. Itoh, O. Taguchi, Y. Koide, et al. Deoxyribonucleic Acid (DNA) Encoding a Pan-Major Histocompatibility Complex Class II Peptide Analogue Augmented Antigen-specific Cellular Immunity and Suppressive Effects on Tumor Growth Elicited by DNA Vaccine Immunotherapy Cancer Res., November 15, 2003; 63(22): 7920 - 7925. [Abstract] [Full Text] [PDF]

				S. J. Russell and K.-W. Peng Primer on Medical Genomics Part X: Gene Therapy Mayo Clin. Proc., November 1, 2003; 78(11): 1370 - 1383. [Abstract] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (27) Request Permissions Disclaimer Google Scholar Articles by Dermime, S. Articles by Stern, P. L Search for Related Content PubMed PubMed Citation Articles by Dermime, S. Articles by Stern, P. L Related Collections Immunology Oncology Drugs Social Bookmarking          What's this?

Online ISSN 1471-8391 - Print ISSN 0007-1420

Copyright © 2010 Oxford University Press

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics