cancer vaccines inducing antibody production: more pros than cons

1281www.expert-reviews.com ISSN 1476-0584© 2011 E Jensen-Jarolim10.1586/ERV.11.105

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Vaccines preventing infections of oncogenic viruses are today well established, for example, for hepatitis B (HBV) or human papilloma virus (HPV) associated cancers, and have a great benefit in human and veterinarian medicine [1– 4] . For virus-independent cancerogenesis there is the need to directly target tumor-associated antigens (TAAs). Active immunotherapy could lead to specific and sustained immunity against tumors, thereby counteracting a lready ongoing malignant growth. Such therapeutic anticancer vaccines may be constituted of patient-specific cellular material, TAAs and derivatives thereof [5], or DNA encoding TAAs [4], all aiming at induction of immunologically mediated tumoricidic or tumoristatic mechanisms. Principally, tumor vaccines might have the capacity to combat already established malignant disease, but it has to be faced that the success of immunological strategies, like of any other anticancer therapy, will indirectly correlate with the tumor load and stage. We propose that the ideal scenario of a tumor vaccine might be the setting of minimal residual disease where, at low numbers of aberrant or cancer stem cells, the actively induced immune mechanisms would have a

fair chance to prevent tumor relapse through reduction of circulating tumor cells and micrometastases [6]. In addition, prophylactic TAA-based vaccines may be conceivable in cases of hereditary predisposition.

Passive versus active antibody therapies in oncologyAmong a l l immunologica l strategies, antibody therapies are today state of the art (and pharmaceutical blockbusters) in oncology, with classics such as trastuzumab (Herceptin®), cetuximab (Erbitux®) and rituximab (Rituxan®) being applied worldwide in cancer patients with a doubling market within the last 5 years [7]. Therefore, passive immunotherapies are generally much more advanced in clinical oncology than vaccines, except the truly prophylactic anticancer vaccines preventing oncogenic virus infections. One great advantage of passive immunotherapy is that it may be discontinued at any point of time. However, even though today’s antibodies are chimeric, humanized or fully humanized, side effects can regularly be observed in clinics. This is due to residual immunogenicity harboring the potency to induce anti-antibodies causing serum sickness or immediate type

Erika Jensen-Jarolim†1,2 and Josef Singer1

1Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria 2Messerli Research Institute of the Veterinary University Vienna, Vienna, Austria †Author for correspondence: Tel.: +431 40400 5120 Fax: +431 40400 6188 erika.jensen-jarolim@ meduniwien.ac.at

To date, passive immunotherapy with monoclonal antibodies is a well-established option in clinical oncology. By contrast, anticancer vaccines are less advanced, with the exception of successfully applied prophylactic vaccines against oncogenic virus infections. The creation of therapeutic vaccines is still a great challenge mostly due to the self-nature of tumor antigens. Therapeutic vaccines may be based on patient-specific material including pulsed effector cells, or tumor-associated antigens and derivatives thereof, such as peptides, mimotopes and nucleic acids. The latter represents a more universal approach, which would set an ideal economic framework resulting in broad patient access. In this article we focus on cancer vaccines for antibody production, in particular mimotope vaccines. The collected evidence suggests that they will open up new treatment options in minimal residual disease and early stage disease.

Keywords: active/passive immunotherapy • antibody therapy • cancer • DNA • IgE • mimotope • passive • Treg • tumor vaccine

Cancer vaccines inducing antibody production: more pros than consExpert Rev. Vaccines 10(9), 1281–1289 (2011)

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hyperreactivity in patients [8]. Oncologists pretreat their patients with antihistamines or corticosteroids to control and prevent side effects [9,10]. Regular applications of antibodies in maintenance strategies are better tolerated than reinjection after a longer interval. In addition, the expression system used for antibody production critically determines the antigenicity of the recombinant immunoglobulins and may contribute to side effects even upon first infusion [11]. It is obvious that vaccines, in contrast, induce complete self-antibodies without these immune-mediated risks. Moreover, serum antibody titers achieved by vaccination vary depending on antigen type and age. Antibody levels range between >1 [12–14], 10 and 30 µg/ml in children, and up to 60 µg/ml in adults [15], taking some typical anti-infectious vaccines as examples. It has been reported that in context with vaccines pathophysiologically relevant levels of specific IgG (>85 µg/ml) are achieved upon hyperimmunization only [16]. Depending on the dosage regimen, nonself antibodies applied by passive immunotherapy accomplish efficacy at serum levels approximately ranging between 20 and 140 µg/ml (see later). The major difference nevertheless is that these antibodies are not self.

Eventual induction of autoimmunity as a side effect nourishes sceptic criticism against TAA-based cancer vaccines, but is also observed in other immunotherapeutic approaches such as passive antibody therapy and trials with cytokines as immunomodulators [17]. Evidently, many cancer antigens are self-antigens and are also expressed by healthy cells of the body, although to a lesser extent [18]. There is also evidence that the extent of post-translational modification may contribute to the immunogenicity of cancer antigens such as mucin 1 (MUC1) [19,20]. Therefore, the risk of autoimmunity is justified and has to be weighed against the threats of the malignancy in the individual patient. The phenomenon that other anticancer therapies also regularly lead to autoimmunity [21] is less recognized, possibly because it needs longer survival times to become clinically relevant [22]. However, it is easy to explain from an immunological point of view: radiotherapy, chemotherapy and biologicals, including passive antibody therapies [23], lead to destruction of tumor cells often associated with oxidative stress. In consequence, modified self-antigens are liberated during cancer destruction, taken up by antigen-presenting cells and may to various degrees lead to breaking of tolerance and autoimmunity against many membranous and intracellular antigens that occur in healthy cells as well [24]. Autoimmune gastritis, thyreoiditis [25,26], vitiligo or uveitis [27] may be typical late complications, depending on the origin of the tumor. Therefore, autoimmunity may be a common risk during anticancer therapies. In fact, highly specific autoimmunity is the aim of cancer vaccines [28], and has been associated with prolonged survival in melanoma [29]. Needless to say, that the careful selection of the appropriate TAA is a conditio sine qua non for successful vaccination strategies. Furthermore, the specific epitope of a tumor antigen may critically determine the biological outcome: for instance, in a mouse model, antibodies against the same target, the cytotoxic T-lymphocyte antigen-4 (CTLA-4), had different abilities in

inducing autoimmunity or antitumor defense [30]. Data from animal studies indicate that upon careful selection there may be the chance to vaccinate against cancer without inducing autoimmunity to healthy tissues [31,32].

Antibody therapies: where do we stand?Another argument in favour of vaccines comes from the economic point of view: passive immunotherapies are characterized by restricted duration of action based on the half-life and elimination rate of the applied antibodies [33]. The latter is dependent on the isotype, and may be improved by engineering to adapt fit to Fc-receptors [34].

For instance, trastuzumab is applied at 2–8 mg/kg bodyweight [35], thus achieving dosages between 140 and 560 mg in an average 70 kg patient [36]. For bevacizumab (Avastin®) even higher amounts, 10 mg/kg – that is, 700 mg in the standard patient – are applied every 2 weeks [37]. These huge amounts make antibody therapies the most cost-intensive treatment options available. By contrast, classical vaccines are expected to cost less and could help to overcome these monetary limitations. It has to be stressed that many other immunological treatments are summarized under the term ‘vaccine’ as well, which may distort this assumption. An example is the recently presented US FDA-approved prostate cancer vaccine sipuleucel-T (Provenge®) [38]. This therapy is actually based on extracorporeal culturing and pulsing of patients antigen-presenting cells using PA2024, a recombinant fusion protein of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), and is regarded as a prototype for development of antitumor vaccines [39]. Sipuleucel-T improves survival, although by only approximately 4 months. The complex protocol results in heavy costs of over US$90,000 for a three-step therapy. Similar autologous strategies are attempted successfully for other tumor entities, such as melanoma [40]. Generally, the understanding of the term vaccines has changed in the past as can be seen from the collection of filed patents [41], and is quite discordant with its basic definition in infectiology [42,43]. However, tumor vaccines in the classic sense are economically attractive concepts for health authorities and, consequently, accessible for a larger number of eligible patients.

Since the invention of monoclonal antibody technology [44], the overwhelming majority of antibodies produced by hybridoma technology belong to the IgG class. This also holds true for oncologically applied immunoglobulins, which are all IgG, whereas all other isotypes are more or less neglected [45]. This means that antibody therapies today rely on a very restricted effector cell panel harboring IgG receptors. For instance, IgA [46,47] and IgE anticancer antibodies may have excellent tumoricidic properties [48–50]. By contrast, vaccines produce polyclonal antibody responses that simultaneously take advantage of multiple receptors and different types of highly specific effector cells. However, the resulting immune response can be biased towards Th1, Th2 or Th3 by usage of different adjuvants and the choice of route [51]. We have shown recently that subcutaneous vaccination with HER-2 mimotope peptides

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resulted in IgG antibodies in BALB/c mice [52], whereas orally gavaged peptides also induced HER-2-specific IgE harboring tumoricidic properties [53].

Today a great number of cancer vaccine trials between Phase II and III [54] are ongoing and registered in the National Cancer Institute database [201]. The clinically tested antigens specifically derived from cancer cells include whole tumor cells, pulsed dendritic cells (DCs) or Langerhans cells, TAAs in native or modified form, proteins, carbohydrates, vaccines, glycoproteins or glycopeptides, gangliosides, RNA as well as DNA and B- or T-cell epitope peptides. The usage of whole tumor antigens may be hampered by the fact that besides beneficial specificities, tumor-promoting antibodies may also be induced [45,55–57]. Therefore, in some cases epitope-specific immunization may be desired.

The principle of mimotope vaccinesA method to achieve epitope-specific vaccines is the in silico creation of synthetic subunits [58] or generation of mimotopes, reviewed by Zhao et al. in this journal [59]. We and others have previously developed mimotopes as vaccine candidates for several important tumor targets, such as EGFR [60,61] or EGFR variants [62], human epidermal growth factor receptor-2 (HER-2) [52,53,63–65], carcinoembryonic antigen (CEA) [66], MG7-AG in gastric cancer [67], human high molecular weight-melanoma-associated antigen (HMW-MAA) [68–70], CD20 in lymphoma [71], disialoganglioside GD2 [72–76], the melanoma cell adhesion molecule Mel-CAM [77] and most recently for the prostate-specific antigen (PSA) [78]. Considering the increasing numbers of mimotope studies, needless to say that there is an urgent need for specific data repositories such as MimoDB [79]. The efforts so far to design the optimal mimotope vaccine and the putative mechanism of action are depicted in Figure 1. Mimotopes have been applied in preclinical studies as single epitope [80], multiple antigenic peptide (MAP) [66] or multiepitope vaccine [81], in protein or DNA [73] form. Mimotope vaccines were constructed using synthetic peptides chemically coupled to different carrier and display systems such as keyhole limpet hemocyanin (KLH), expression of fusion proteins and assembly of adenovirus particles [82], fusion constructs with immunoglobulin Fc domains [75], with promiscuous T-helper epitopes [73], or immunostimulatory cytokines such as IL-15 and IL-21 [83]. Mimotope vaccines have been applied naked [66], or using Salmonella as a ‘Trojan horse’ for oral vaccine formulation [67,73]. Generally, prime-boost regimens or multi-epitope vaccines induced higher affinities and functional antitumor effects [69,81,82]; molecular modeling and mutagenesis studies [84] or docking experiments [73] may also help to select and improve the potential of a mimotope.

Mimotope peptides may be selected from random peptide phage display, combinatorial or synthetic libraries by an antibody of choice. They can also be used for epitope definition [71,80,85]. When a clinically approved antibody is chosen for selection, a mimotope will be generated that resembles its epitope [86]. There is no need for consensus amino acid sequence of the mimotope, because molecular mimicry via, for example, amino acid charges is sufficient to shape an electron cloud specifically recognized by

the antibody. We believe that vaccination with these mimotopes may overcome tolerance-cell mediated immune escape of the natural tumor antigen, as they are similar, but not identical to the original tumor antigen. In addition, mimotopes for T-cell epitopes of tumor antigens have been generated in the past [87–90]. In fact, the only clinical study so far was successfully performed with T-cell mimotopes in two human patients for cutaneous lymphoma [88]. However, like the original T-cell epitopes, T-cell mimotopes depend on the HLA type of the individual patient, which restricts their applicability largely. Therefore, B-cell epitope-based mimotopes may represent a more universal vaccine concept. For phage-displayed mimotopes, the immunogenic mechanism in mice has been recently identified as being regulated under MyD88 and depending on TLR-9 signaling, independent on CpG contamination in the phage preparations [91]. Being processed and presented by antigen-presenting cells, the immune response towards mimotopes depends on T-helper cells providing bystander help [92], whereas the B-cell mimotopes rarely contain antigen-specific T-cell epitopes [77]. However, as a consequence of peptide mimotope immunizations, an increase of T-cell populations could be observed, which also responded with IFN-g production upon IL-12 stimulation, favoring antitumor immunity [93]. Interestingly, in the same study cyclophosphamide administration supported the vaccine success paralleled by enhanced T-cell (CD8+ and CD4+) activity against the tumor cells. This is in line with the recently reported phenomenon that chemotherapy may enhance the efficacy of tumor vaccines due to increased sensitivity towards cytotoxic effector T cell (CTL)-mediated killing [94]. Furthermore, Monzavi-Karbassi et al. report that the improved efficacy of the mimotope vaccine upon pretreatment with chemotherapy involves the induction of leucopenia affecting Treg levels at the tumor site [93]. Tregs play a prominent role within the immunosuppressive tumor environment, for example, via IL-10 secretion [95], which has been correlated with inferior prognosis in stage III melanoma patients [96]. It has been suggested that Tregs especially hamper the breakthrough of most anticancer vaccination approaches [97]. On the other hand, TAA-specific T-cell tolerance being independent on Treg participation has been demonstrated by depletion experiments of the CD4+ CD25+ population in vivo in mice [98]. Even if the role of Tregs is not ultimately clear, evidence that they might be exploited by reprogramming represents an intriguing concept. This has been suggested recently based on vaccination studies using antigen formulated with a TLR-9 ligand, rendering conversion of Tregs into pre-activated T-helper cells that were then able to activate CD8+ CTLs [99]. In their model, reprogramming could be blocked by indoleamine 2,3-dioxygenase (IDO) derived from plasmocytoid DCs and activating Tregs [100,101] and restored by IDO inhibition. These results may also significantly impact mimotope vaccine design and open perspectives how to concretely interfere in future approaches with the immunosuppressive environment created by the tumor.

The lack of activation of antigen-specific T lymphocytes by B-cell mimotopes has been addressed by fusion constructs of mimotopes with Fcg receptor domains, which achieved forced

Cancer vaccines inducing antibody production: more pros than cons

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uptake of mimotopes by DCs and in consequence CTL activation [75]. Sometimes unexpectedly, a B-cell mimotope vaccine may induce truly antigen-specific CD8+ T-cells by itself, for instance against an antigenetically crossreactive tumor antigen, as recently demonstrated for GD2 [74,76].

As the B-cell epitope mimics induce immune responses similar to the antibody originally used for mimotope selections,

its biological effect should be predictable. However, peptide mimotopes represent only a part of the original antibody epitope. Therefore, the induced antibodies may still, due to sub-epitope differences and ‘motif-surrounding amino acids’, induce distinct biological functions [71,102]. Consequently, mimotope selections follow stringent criteria [103] and a recent study on HMW-MAA mimotopes suggested that the

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Figure 1. Specific immune events occurring during vaccination with mimotopes. (A) Antibody production can be achieved via vaccination with the whole TAA (a) or with mimotopes, which in contrast to TAA resemble only one epitope. Mimotope vaccines for epitope-specific antibody [52,53,60] or T-cell induction [87–90] need antigen density to achieve immunogenicity. Mimotopes can thus be applied either as multiple antigenic peptides (b) [66], displayed on phages when selected from phage display peptide libraries (c) [86], synthesized and chemically coupled to different carrier systems such as keyhole limpet hemocyanin (d) [60], presented on the surface of adeno-associated viruses (e) [82], as fusion constructs with immunoglobulin Fc-domains (f) [75] or in DNA form (g) [73]. (B) T-cell mimotopes can directly address T-effector cells via their TCR and thereby activate T-effector cell clones targeted against tumor cells [87–89]. This mechanism is dependent on HLA display of mimotopes to achieve full TCR activation capacity. This again depends on the HLA type of the individual patient and may require extracorporal peptide-pulsing of DCs, as presently applied in the US FDA-approved vaccine sipuleucel-T [38]. (C) B-cell mimotopes primarily address B lymphocytes where mIg recognize them due to conformational similarity with the original epitope. B cells respond with formation and secretion of antibodies, which may bind via Fc receptors to antigen-presenting cells, such as DCs. Mimotope vaccines may then be taken up either directly or in antibody-mediated endocytosis, and processed. The resulting peptides represent novel, TAA-independent T-cell epitopes, which are presented by HLA II and can activate bystander T-helper cells; via HLA I cross-presentation CTLs can also be activated. Cytokine release from Th cells is relevant for improved antibody production by B lymphocytes as well as for activation of CTLs [93]. (D) The isotype of the resulting antibodies that crossreact with the original TAA epitope is dependent on the type of adjuvants [51] or route of application [52,53]. Induced antibodies can lead to all immunological effects known and exploited in passive immunotherapy with monoclonal antibodies, such as CDC, ADCC [35] (in context with granulocytes or NK cells) or ADCP [8] of tumor cells, especially by monocytes [49]. Furthermore, antibodies can in a nonimmunological manner lead to tumor cell growth arrest or inhibition of spreading and invasion, such as growth factor receptor downregulation or silencing of growth factor signaling [35].ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP: Antibody-dependent cell-mediated phagocytosis; CDC: Complement-dependent cytotoxicity; CTL: Cytotoxic effector T cell; DC: Dendritic cell; mIg: Membrane immunoglobulin; TAA: Tumor-associated antigen; TCR: T-cell receptor.

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characterization of the functional properties of mimotope-induced antibodies is a conditio sine qua non in vaccine development [104].

Taken together, (B-cell) mimotope strategies are in line with successful antibody therapies in oncology mentioned previously and may represent valuable complementary medications when all state-of-the-art treatment options are exploited, to prevent tumor recurrence. Last not least, by the choice of the appropriate adjuvant and route, one may determine the effector class of antibodies induced upon vaccination [53,105]. In this respect, several groups, including our own, are concentrating on the role of IgE and Th2 responses in general in tumor surveillance [106]. The advantage may be the exclusive panel of IgE effector cells with high cytotoxic potential and their ability to penetrate solid tissues being much higher than any other antibody class.

Expert commentaryAmong the therapeutic options for cancer patients, passive immunotherapy with engineered antibodies belongs today to standard of care for many cancer entities. Furthermore, prophylactic vaccines against oncogenic viruses (HBV and HPV) are so effective that they represent important cornerstones in public health. By contrast, therapeutic vaccination in oncology is much less settled. There are two major lines of vaccination strategies in oncology today:

• Personalized strategies: injections of patient’s cancer cells, or antigen-pulsed effector cells from the periphery;

• More globally applicable strategies: tumor-specific antigens (TAAs), which are directly used as vaccine.

The overall success of a novel therapy is not only determined by its efficacy, but also by the economic framework. Although personalized strategies are promising and possibly most effective for the individual patient, their application may be restricted by

monetary reasons. Therefore, more ‘global’ approaches using TAAs and their derivatives such as mimotopes for vaccination may facilitate that more patients receive the appropriate therapy.

Five-year viewAlthough FDA approval of TAA-based anticancer vaccines has yet to be achieved in humans, and only a single anticancer vaccine (Oncept™) has been approved for canine melanoma patients [5], an overwhelming list of candidates is in the pipeline. Thus, we are convinced that TAA vaccines will, in the near future, be established as supplementary therapy options for many important cancer entities. It should be emphasized that vaccines might ideally protect patients from tumor recurrence especially in the minimal residual disease setting. We further expect that in silico created epitope peptides or mimotopes will be especially suitable for cancer vaccine design, because they allow the determination of the exact antibody specificity induced by the vaccination. This precaution is imperative in situations where antibodies may inhibit or promote tumor growth depending on their epitope specificity.

AcknowledgementThe authors would like to express their gratitude to Anton Jäger for assisting in designing Figure 1.

Financial & competing interests disclosureThis work was supported by the Austrian Science Fund, project W1205-B09, and by Biomedical International R&D, Vienna. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Cancer vaccines inducing antibody production: more pros than cons

Key issues

• Cancer is a major concern in healthcare systems worldwide with limited therapy options, of which many are elaborate and cost intensive.

• Vaccines are examples of elementary, highly effective and relatively inexpensive treatments with great impact for public health.

• Vaccines against hepatitis B virus or human papilloma virus are thus highly effective in inhibiting malignant diseases of liver and cervix, respectively. Both vaccines act prophylactic, but show no effect in established malignancies.

• Monoclonal antitumor antibodies may directly inhibit vital growth signals for the tumor cell. Additionally immunoglobulins can attract immune cells to the site of the tumor, thus mediating cytotoxicity or phagocytosis. Antibodies induced by vaccinations may do the same, but use a broader effector cell panel due to their polyclonal nature.

• The efficacy of passive antibody therapies is limited by the half-life time of the immunoglobulins, resulting in the need for regular reinjections and enormous costs. Vaccines induce memory function that like anti-infectious vaccination can be boosted regularly which is relatively cheap.

• The antibody levels reached by vaccines are usually lower than in passive application, reducing the risk of side effects. Moreover, these antibodies are completely self, thereby excluding the risk of anaphylaxis.

• Antibodies against tumor-associated antigens like growth factor receptors may act tumor-promoting (e.g., via crosslinking and stabilizing the growth signal) or -inhibiting (e.g., via blockage of the growth factor binding site or via receptor internalization). As these effects depend on their epitope specificity, it will be crucial in vaccine development to target tumor inhibitory epitopes only. This could be achieved via in silico created epitope peptides or mimotopes.

• All therapeutically applied monoclonal antibodies are of the IgG class. A vaccine can principally induce all natural immunoglobulin subclasses including IgE and IgA molecules by using different adjuvants or routes. Thereby the anticancer effector mechanisms of several immunoglobulin classes could be utilized.

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•• Differentroutesofapplicationcaninfluencetheimmuneresponseoutcome.Inthisarticle,anorallygavagedHER-2mimotopevaccineinduced,likeafoodallergen,specifictitersofspecificIgEantibodiesproducingcytotoxiceffectsonHER-2-overexpressingcancercells in vitro.

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60 Riemer AB, Kurz H, Klinger M, Scheiner O, Zielinski CC, Jensen-Jarolim E. Vaccination with cetuximab mimotopes and biological properties of induced anti-epidermal growth factor receptor antibodies. J. Natl Cancer Inst. 97(22), 1663–1670 (2005).

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71 Perosa F, Favoino E, Vicenti C et al. Two structurally different rituximab-specific CD20 mimotope peptides reveal that rituximab recognizes two different CD20-associated epitopes. J. Immunol. 182(1), 416–423 (2009).

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73 Fest S, Huebener N, Weixler S et al. Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases. Cancer Res. 66(21), 10567–10575 (2006).

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83 Kowalczyk A, Wierzbicki A, Gil M et al. Induction of protective immune responses against NXS2 neuroblastoma challenge in mice by immunotherapy with GD2 mimotope vaccine and IL-15 and IL-21 gene delivery. Cancer Immunol. Immunother. 56(9), 1443–1458 (2007).

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96 Mahipal A, Terai M, Berd D et al. Tumor-derived interleukin-10 as a prognostic factor in stage III patients undergoing adjuvant treatment with an autologous melanoma cell vaccine. Cancer Immunol. Immunother. 60(7), 1039–1045 (2011).

97 Gross S, Geldmacher A, Sharav T, Losch F, Walden P. Immunosuppressive mechanisms in cancer: consequences for the development of therapeutic vaccines. Vaccine 27(25–26), 3398–3400 (2009).

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99 Sharma MD, Hou DY, Baban B et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33(6), 942–954 (2010).

• Uponvaccinationwithtumor-associatedantigensincombinationwithTLR-9ligands,thisstudycouldclearly

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100 Munn DH, Sharma MD, Hou D et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114(2), 280–290 (2004).

101 Sharma MD, Baban B, Chandler P et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117(9), 2570–2582 (2007).

102 Perosa F, Favoino E, Vicenti C, Merchionne F, Dammacco F. Identification of an antigenic and immunogenic motif expressed by two 7-mer rituximab-specific cyclic peptide mimotopes: implication for peptide-based active immunotherapy. J. Immunol. 179(11), 7967–7974 (2007).

103 Riemer A, Scheiner O, Jensen-Jarolim E. Allergen mimotopes. Methods 32(3), 321–327 (2004).

104 Latzka J, Gaier S, Hofstetter G et al. Specificity of mimotope-induced anti-high molecular weight-melanoma associated antigen (HMW-MAA) antibodies does not ensure biological activity. PLoS One 6(5), e19383 (2011).

105 Schijns VE, Lavelle EE. Trends in vaccine adjuvants. Expert Rev. Vaccines 10(4), 539–550 (2011).

106 Cancer and IgE. Introducing the concept of AllergoOncology. Penichet M, Jensen-Jarolim E (Eds). Humana Press, NY, USA (2010).

Website

201 National Cancer Institute: www.cancer.gov/clinicaltrials

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cancer vaccines inducing antibody production: more pros than cons

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