The second international conference on “Cancer Vaccines/Adjuvants and Delivery”, CVADD 2007 was organized at the German Cancer Research Center (DKFZ), Heidelberg, Germany. The main aims were to review the state of the art of cancer vaccination with special attention to clinical application in cancer patients. This report provides a short overview of novel concepts, strategies, and clinical developments in the field following the first CVADD congress (Lisbon, Portugal, 2005). About 180 participants from academia and pharma companies were attracted by the scientific program that consisted of keynote lectures and presentations from 50 international experts. Chairman of the symposium was V. Schirrmacher who was supported by an International Scientific Advisory Board and a local organizing committee. Good memories may remain not only from the lively discussions of 11 scientific sessions and 40 posters, but also from the beauty of Heidelberg in autumn colors and the social evening in the Altstadt (Kulturbrauerei) with local food, drinks and music. The conference bags contained a timely issue of “Vaccine” (Vol. 25, Suppl. 2, 27 Sept. 2007), celebrating 25 years of publication. The topic “Therapeutic Vaccines for Cancer” of this issue includes eight reviews from experts in the field.
Session 1: Opening plenary session
The first session reviewed different basic and translational aspects of anti-tumor vaccination. T.-C. Wu (Johns Hopkins University, Baltimore, Maryland, USA) pointed out that effective cancer immunotherapy using DNA or peptide vaccination should be combined with the inhibition of tumor immune evasion mechanisms such as down-regulation of MHC class I expression, accumulation of suppressive cytokines and up-regulation of regulatory molecules such as VCAM-1. F. Stevenson (University of Southampton, UK) focused on the design and delivery of DNA fusion gene vaccines. She argued that besides genes coding for tumor antigens (TAs), DNA vaccines should contain CpG sequences to stimulate innate immunity and additional immunoenhancing genes. At the end of the session, D. Schadendorf (DKFZ, Heidelberg, Germany) presented a broad overview of the current vaccination approaches in melanoma patients. These strategies include injection of whole tumor cells or tumor lysate, vaccination with tumor specific peptides or dendritic cells (DC) loaded with peptides or RNA, and adoptive transfer of tumor specific T cells, NK or NKT cells.
Session 2: Plenary session
This session started with a presentation by A. Enk (University of Heidelberg, Germany) who reported on tumor-induced tolerance and vaccination in melanoma. Depletion of regulatory CD4 T cells with a recombinant interleukin 2/diphtheria toxin conjugate (ONTAK) was followed by vaccination with Melan A and gp100-derived peptides. Another new approach involves DC targeting with antibodies to DEC-205 coupled with TRP-2 derived peptide and CpG. Tumor-induced tolerance was discussed also in the presentation of I. Borrello (Johns Hopkins University, Baltimore, MD, USA) who focused on the immunosuppressive role of myeloid derived suppressor cells (MDSC) in mouse tumors and in patients with hematological malignancies. MDSC are characterized by the production of TGF-β and expression of CD11b, IL4R-α, Gr1 as well as nitric oxide synthase (NOS)-2, and arginase (ARG)-1. He demonstrated that the phosphodiesterase-5 (PDE5) inhibitor sildenafil reversed immunosuppression induced by MDSC, stimulated anti-tumor immune responses and reduced tumor outgrowth. V. Umansky (DKFZ, Heidelberg, Germany) presented an overview on transgenic mouse melanoma models, which in contrast to tumor transplantation models closely resemble human melanoma with respect to tumor genetics, histopathology, and clinical development. New strategies of melanoma immunotherapy using these models like (1) adoptive transfer of re-stimulated bone marrow memory T cells and DC, (2) depletion of regulatory T cells, and (3) inhibition of suppressive tumor microenvironment were discussed.
Session 3: Trials
In the presentation of M. Mitchell (University of Texas, El Paso, USA), the treatment of stage III melanoma patients with Melacine (melanoma lysate with the adjuvant DETOX™) and low-dose INTRON A was compared with standard high-dose INTRON A therapy. No differences were found in the patients’ survival. V. Schirrmacher (DKFZ, Heidelberg, Germany) presented the concept and clinical experience with the virus-modified autologous tumor cell vaccine ATV-NDV. Newcastle disease virus (NDV) was used to modify patients’ tumor cells for the introduction of costimulatory molecules and double-stranded RNA as danger signal to increase tumor immunogenicity. Results from phase II/III studies in patients with glioblastoma, head and neck as well as colorectal carcinoma showed stimulation of tumor-reactive memory T cells and significant clinical benefits including improved survival. F. Lehmann (GlaxoSmithKline Biologicals, Rixensart, Belgium) reported on a phase II trial in melanoma patients vaccinated with the MAGE-A3 melanoma antigen. Clinical responses were reviewed in relation to particular gene expression profiles in melanomas. J.L. Murray (M.D. Anderson Cancer Center, Houston, Texas, USA) presented first results of another trial using HER2/neu MHC class II peptide vaccination of breast cancer patients demonstrating significant in vitro and in vivo immune responses to this peptide. A randomized trial comparing the peptide plus GM-CSF versus GM-CSF alone is ongoing. New methods for monitoring CTL activity in vaccination trials were reported by A. Malyguine (NCI-Frederick, MD, USA). He demonstrated that a combination of Granzyme B ELISPOT assay and flow cytometric cytotoxicity assay allows evaluation of effector functions of low frequency tumor-specific CTL.
Session 4: Cancer immunotherapy
The session was opened by V.G. Brichard (Cancer vaccines, Clinical RD and RD departments GlaxoSmithKline Biologicals, Rixensart, Belgium) who described the history of current GSK melanoma vaccines based on recombinant virus-encoded melanoma-antigen MAGE of almost a whole decade-from the characterization of tumor antigens, via vaccine formulations to promising randomized clinical phase II trials. Recent advances include new tools for monitoring the anti-cancer immune responses and the development of biomarkers for treatment selection. U. Sahin (University of Mainz, Germany) demonstrated that integrated data mining using a semi-automated procedure (Position-specific-iterated basic local alignment search tool) and experimental validation approach allowed the identification of new tumor cell-restricted cell surface antigens such as PLAC1 or claudin being accessible for therapeutic antibodies that are currently developed. Afterwards, D. Hoon (John Wayne Cancer Institute, Santa Monica, USA) discussed the need for more sensitive methods to identify signs for treatment response in case of minimal residual disease. Hoon identified circulating tumor-associated methylated DNA in serum samples from patients undergoing tumor immunotherapy. He pointed out that quantitative methylation-specific PCR (qMSP) is a sensitive tool to monitor the course of subclinical disease during therapeutic interventions.
Session 5: Plenary session
This session comprised a selection of recent experimental findings regarding tumor–immune interactions. J. Kan-Mitchell (University of TX, El Paso, USA) described the characterization of new immunogenic epitopes from TAs such as MUC1 or HIV by the scan of large nonameric combinatorial peptide libraries by antigen-specific CTL lines. P. Beckhove (DKFZ, Heidelberg, Germany) demonstrated how tumor endothelium in human pancreatic carcinoma promotes selective accumulation of CD4+ CD25+ regulatory T cells via a peculiar pattern of adressins which are met by respective homing receptors on regulatory T cells, allowing for increased Treg transmigration. M. Manjili (VCU Massey Cancer Center, Richmond, USA) exploited a rat neu-transgenic mouse model of breast cancer and its congenic non-transgenic parental strain, FVB, to explore anti-tumor efficacy of immune responses against self neu versus nonself neu proteins under dangerous or non-dangerous conditions. These studies suggested that an effective vaccine should encompass both danger signals and high-affinity T cells against tumors. T. Woelfel (University of Mainz, Germany) pointed out the possibility that current vaccination strategies boost pre-existing T cell responses rather than induce new ones and that the knowledge about those TAs that are recognized spontaneously by the patients may be a requirement for more successful vaccinations. He demonstrated that in melanoma patients tumor-specific CTL responses are highly individual and polyvalent and recognize both common shared tumor antigens, such as cancer testis antigens and mutated neoantigens. P. Fournier (DKFZ, Heidelberg, Germany) discussed potential mechanisms of tumor rejection by Newcastle disease virus. Based on tumor–immune cell cocultures he demonstrated that virus infection of tumor cells caused not only oncolysis of human breast carcinoma cell lines to some extent, but also induced a strong induction of tumor lysis by a variety of immune cells, including T cells and NK cells. He pointed out that this indirect tumor rejection by an activation of specific and unspecific cytotoxic effector mechanisms might play a more important role than direct oncolytic effects of the virus.
Session 6: Immunity and enhancement
This session was opened by V. Vonka (Inst. of Hematology and Blood Transfusion, Prague, Czech Republic) with a talk about the induction of immunity in mice against BCR–ABL-transformed cells. DNA vaccines based on the junctional zone exhibited a very low immunogenicity. On the other hand, combination of chemo- and immunotherapy resulted in cure of a large portion of the treated animals. A. Märten (University of Heidelberg, Germany) demonstrated that “signaling lymphocyte activation molecule” (SLAM, CD150) is a co-stimulatory receptor involved in T cell activation. She showed that up-regulation of CD150 was accompanied by increased cytotoxic activity against tumor cells. Treatment of xenografted mice with CD150 over-expressing lymphocytes decelerated tumor growth significantly. C. Gouttefangeas (University of Tuebingen, Germany) presented the latest results of the CIMT-monitoring panel. Based on their findings that immunomonitoring results strongly differed between institutions, she demonstrated that independent analysis of the same set of test samples by the immunomonitoring units of CIMT member institutions allowed to identify key requirements for sensitive and specific detection of antigen-specific T cells by HLA-tetramer analysis and IFN-γ Elispot and thereby to optimize and homogenize monitoring results among the partners. V. Schirrmacher (DKFZ, Heidelberg, Germany) demonstrated that stimulation of CD28 and IL-2R by bi-, and tri-specific antibodies crosslinking T cells to NDV-infected tumor cells resulted in generation of large numbers of long lived activated CTL with anti-tumor activity and might be an appropriate tool to overcome T cell exhaustion and immunosuppression frequently encountered in tumor patients. M. Perales (Memorial Sloan Kettering Cancer Center, New York, USA) showed that immunization of allogeneic stem cell recipients against tissue-restricted Ags using DNA vaccines after donor lymphocyte infusion decreased the risk of relapse without enhancing graft versus host disease (GVHD) in a tumor mouse model. A. Dietrich (University of Leipzig, Germany) investigated the effect of intra-operative intra-splenic or subcutaneous vaccination with IL-12 modified, irradiated tumor cells on tumor progression in a mouse model and concluded that intra-operative whole-cell vaccination with autologous tumor cells yields promising data, and could be considered as a future option in adjuvant cancer therapy. S. Ward (Onyvax Ltd, St. George`s University of London, UK) presented promising data from clinical phase II studies with an allogeneic whole-cell vaccine, given with Bacillus Calmette–Guerin (BCG) as adjuvant, for the treatment of prostate cancer. The company also develops immunologic profiles by artificial neural network analysis of serum samples to select patients who may benefit from vaccination.
Session 7: Adjuvants and delivery
Several adjuvants have been described as stimulating innate and adaptive immunity and giving rise to novel therapeutics for anti-cancer vaccination. J.Vollmer (Coley Pharmaceutical GmbH, Düsseldorf, Germany) described the use of TLR7 and TRL8 agonists. Different classes of RNA oligonucleotides were reported to have specificities for either TLR7, TLR8 or both receptors. They were able to stimulate different effector cell types, to upregulate co-stimulatory molecules on antigen presenting cells and to stimulate strong cytokine induction in vivo. They appeared in different tumor models to be effective as strong adjuvants. Another novel adjuvant called IC31 which consists of a mixture of two chemically defined components [an antimicrobial peptide (KLK) and a single-stranded oligodeoxynucleotide (ODN1a) forming a suspension via ionic interactions] was presented by J. Sommer (Intercell AG, Vienna, Austria). IC31combined with antigen was able to induce potent immune responses. This adjuvant was evaluated with a subunit tuberculosis vaccine in completed phase I clinical trial. IC31 appears a promising adjuvant for cancer vaccine since it has been shown able to counteract immune suppression in cancer patients, to induce a specific and sustained response and to be compatible with many antigen types. A fungal protein called Fve has been highlighted by K.Y. Chua (University of Singapore, Singapore) to have potent immunomodulatory properties. When added to HPV antigen E7, it induced both humoral and cellular immune responses and increased the potency of the E7 based vaccine both in prophylactic and therapeutic mouse tumor models.
Delivery is also an important issue in tumor vaccination. T. Luby (MGI Pharma, Lexington, USA) showed the adjuvant effect of electroporation after intra-muscular delivery of DNA encoding the cytochrome P450 1B1 antigen encapsulated inside of PLGA microparticles. An open-labelled, single arm phase I trial showed six immune responders (among 18 patients) in terms of induction of a specific immune response against this target. Both endpoints of this trial (safety and immune response) were met. C. Ottenmeiers (University of Southampton, UK) reported very encouraging data of an ongoing Phase I/II study performed on prostate cancer patients. The trial involves electroporation of different fusion DNA vaccines based on the PSMA antigen after intra-muscular injection. Very interestingly, F. Triebel (Immutep S.A., Orsay, France) presented the rationale, the design and the first results of a dose-escalating single blind chemo-immunotherapy phase I clinical trial as a first line therapy for metastatic breast cancer. This study is based on the observation that the presence of soluble LAG-3 has been associated with better prognosis and Th1 polarization in patients. IMP321 is a recombinant protein derived from this molecule as a very strong non-TLR T cell response immunopotentiator. It was reported to act by inhibiting Treg suppressive activity through competition with membrane-bound LAG-3 on Tregs. To date, 16 patients have been treated by repeated s.c. injection of this molecule (eight with low dose and eight with high dose) following first-line paclitaxel chemotherapy. A strong increase of activated cytotoxic CD8 T cells was seen in three patients. The concept of new RNA-based adjuvants (RNAdjuvant) that are a class of natural ligands for a number of well-defined pattern recognition receptors (PRRs) has been introduced by T. Kramps (CureVac, Tübingen, Germany). This novel class of RNA-molecules can be obtained by modification of their sequence, their motifs and their formulation to enhance their immunostimulation capacity. A second class of products (RNActive) for gene therapy is based on mRNA stabilization, enhancement of the corresponding protein expression and of its pharmacokinetics. Such constructs have been shown to enable humoral and cellular immune response. CureVac’s vaccine pipeline is based on the successful establishment of the production capacity under cGMP protocol. A new microdelivery system for intradermal delivery of vaccines and other therapeutic agents was presented by J. Kuhns (BD Technologies, NC, USA). The technology is a proprietary delivery system for intradermal (ID) injections, in which a 1.5 mm microneedle is used to reproducibly deliver compounds intradermally. Based on IR imaging and flow cytometry, the use of this microneedle system for the ID delivery of a dendritic cell vaccine in a porcine model showed greater dendritic cell migration to the lymph node when compared to subcutaneous delivery. C. Moser (Pevion Biotech, Bern, Schwitzerland) presented the virosome technology which is a market-approved carrier system for the delivery of immunologically active substances either for MHCII presentation and CD4 T cell activation via endosomal degradation (PeviPRO™) or for MHCI presentation and CD8 T cell activation via cytoplasmic delivery (PeviTER™). A phase I clinical trial using this technology aiming at the induction of a humoral response against Her-2 started this year in collaboration with the University of Vienna (Austria).
Session 8 : DNA vaccines and electroporation
This session was composed of presentations based on immunization with a plasmid DNA encoding an antigen. The first generation of DNA vaccination was shown in human trials not to be effective in contrast to previous data from animal models. The new generation of DNA vaccines are based on better expression, a higher immunogenicity and an effective delivery. Electroporation provides a means for safe, accurate, and reproducible administration using different routes. The results of non-clinical studies to date indicate that the risk benefit ratio of electroporation mediated DNA immunization is favourable, leading to the initiation of a certain number of clinical studies. D. Hannaman (Ichor Medical Systems Inc, San Diego, USA) presented a delivery system for intra-muscular DNA drug delivery (called TRiGrid delivery system) that is ensured through the calibration of the device according to the fat thickness. Based on some proof of concept studies and some non-clinical safety studies in small animals, phase I human study in melanoma has been initiated in April 2007 in collaboration with the Memorial Sloan Kettering Cancer Center. T. Tjelle (Inovio, Oslo, Norway) presented another device (“TwinInjector”) recently developed for injection into muscle. It is based on two needles allowing application of small volume of DNA and application of a low electrical field between both needles. There are now five different clinical trials (phase I or I/II) using electroporation. One of them is with TwinInjector. N.Y. Sardesai (VGX Pharmaceuticals, Blue Bell, PA, USA) presented experimental data obtained in non-human primate models of HIV and showed the enhanced and sustained broad immune response to DNA vaccine after intra-muscular injection and electroporation using the CELLECTRATM adaptive constant current device. He also showed pre-clinical tumor protection and efficacy data in the aggressive TC-1 challenge model for a therapeutic cervical cancer vaccine in development based on IM-EP delivered E6/E7 (HPV16/18). A.K. Roos (Karolinska Institute, Stockholm, Sweden /Cytopulse Inc, Glen Burnic, USA) reported that high levels of CTLs, antibodies, and tumor protection could be obtained using the DERMA VAX device (having a needle array electrode for intradermal electrovaccination) in various cancer models based on different tumor antigens (PSA, CEA, and Her-2). She announced the start of three different clinical phase I trials with DNA encoding, respectively, the rhesus PSA, HER-2, and CEA. A.D. King (NIH, Baltimore, USA) showed in animal models that the fusion of the target antigen with the MIP3α chemokine could further improve the anti-tumor immunity by targeting the antigen to chemokine receptors present on APC.
Session 9 : Industrial vaccine developments
N. La Monica (Institut di Ricerche di Biologia Molecolare (IRBM), Rome, Italy) showed interesting results of vaccination performed in different animal tumor models and based on priming with a DNA plasmid encoding an antigen and boost with adenovirus encoding the same antigen (both steps performed using the electroporation device from Inovio). The need for potentiating immune responses to recombinant or subunit antigens has prompted GlaxoSmithKline Biologicals to develop various adjuvant systems for the design of prophylactic and therapeutic vaccines. Adjuvant systems are the formulations of classical adjuvants mixed with immunomodulators, specifically adapted to the antigen and the target population. The ASO4 adjuvant system has been designed to enhance immunogenicity and increase the duration of protection through activation of innate and adaptive immunity and M. Deschamps (GlaxoSmithKline Biologicals, Belgium) presented data showing that the ASO4 adjuvant system indeed induces high and sustained levels of high quality immunity as a basis for long term protection against cervical cancer. J.Y. Bonnefoy (Transgene, Strassbourg, France) presented an overview of the different approaches and recent clinical data obtained with therapeutic cancer vaccines. He highlighted the product pipeline of Transgene which is based on four different products reaching the stage of “proof of concept”. The most advanced (TG4001/R3484) have been tested successfully in a phase IIa for therapy of pre-cancerous lesions of the cervix and is undergoing further development in association with Roche. The tested product consists in a viral suspension of recombinant vaccinia virus encoding the HPV E6 and E7 antigens and the cytokine IL-2. Data were presented as a proof of concept for therapeutic effect. R.F. Burns (Celldex Therapeutics Inc, Philippsburg, USA) presented the cancer vaccine CDX-110 targeting the tumor specific form of the EGFR (EGFRvIII) in glioblastoma. The specific component of this vaccine is a 14-amino-acid snippet that precisely mimics the sequence created by the EGFR sections flanking the mutant´s missing chunk. In collaboration with the Duke Comprehensive Cancer Center and M.D. Anderson Cancer Center (Houston, USA), a phase IIa study (n = 23) showed in comparison to matched historical controls, a >100% improvement of survival rates in the vaccinated cohort. Very interestingly, tumor relapse samples had lost EGFRvIII expression. The vaccine’s success suggests that the blood–brain barrier may not be the obstacle to immunotherapy as it once seemed. A randomized phase IIb/III study investigating further anti-cancer activity of the addition of CDX-110 vaccine to standard care maintenance chemotherapy with temozolomide has been initiated in 2007 and the first interim analysis will occur in mid-2008.
Session 10: New vaccines
H.G. Hans-Georg Rammensee (University Tübingen, Germany) summarized their work on peptides for cancer vaccines. Based on the polymorphism of HLA-I alleles (>1,000), the repertoire of CD8 peptide epitopes is very large and highly individual. To identify CD8 peptide epitopes from HLA-class I of renal cell carcinoma a new technology has been developed in Tübingen which allows one to address not only highly expressed epitopes but also the respective genes and the relative copy-number of m-RNA in tumor cells. Even for highly expressed tumor peptides no T cell recognition was observed in non-immunized patients, but priming was possible in vitro. Thus, with effective peptide vaccination novel anti-tumor immune responses may be induced. The mass-spectrometry (MS) technology is now being performed with differently labelled peptides from tumor and normal samples to identify post-translational modifications. The technology has to be improved for the detection of mutations. Predictions from genomics suggest that there will be about 90 mutant genes per individual tumor. The future aim would be to apply a customized combination for cancer therapy. H. Singh (Immatics Biotechnologies, Tübingen, Germany) presented results of a phase I study with IMA 901, a therapeutic cancer vaccine based on multiple novel synthetic tumor associated peptides identified as being naturally presented in primary renal cell carcinoma (RCC) tissues with a technology platform originally developed in the lab of H.G. Rammensee (see above). It was concluded that this vaccine is safe, well tolerated, and immunogenic. It induced T cell responses in majority of advanced RCC patients. The overall tumor assessment in patients with measurable disease revealed that eight patients (35 %) demonstrated a clinical benefit (1 PR + 7 SD). Patients eliciting multiple responses showed a significantly higher clinical benefit rate and lower Treg-levels. L.G. Durrant (Scancell Ltd, Nottingham, UK) reported on immunobodies as a novel vaccine approach to stimulate high avidity CTL and helper T cell anti-tumor immune responses. Based on the observation that monomeric IgG-1 antibodies are capable of inducing cell-mediated immune responses they have developed a novel system whereby T cell epitopes of interest form a part of an antibody structure. Such reagents are termed immunobodies. In the reported study CTL epitopes incorporated into the CDR antibody domain were derived from TRP-2 melanoma antigen and from universal T-helper epitope. Via immunobodies these epitopes were delivered directly to antigen presenting cells via the high affinity Fc-γR-I (CD64) receptor. Upon DNA immunization with the immunobody construct, mice generated substantial epitope specific CTL responses. These were of high avidity and capable to induce tumor cell lysis in vitro and in vivo. The ability to break tolerance to self antigens and to elicit an effective tumor specific response demonstrates the potential for the immunobody system to be used as a multivalent vaccine for many other cancer types. C. Leclerc (Institute Pasteur, Paris, France) reported on the eradication of large tumors in mice by a tri-therapy targeting the innate, adaptive and regulatory components of the immune system. She used the TC-1 tumor model, an aggressively growing tumor cell line that expresses the HPV-16 E6 and E7 proteins and started immunotherapy very late, namely 25–30 days after tumor graft when the tumor had recruited elevated levels of Treg and other suppressor cells. The treatment consisted a combination of (1) vaccination using CyaA-E7 DNA-vaccine that targets dendritic cells, (2) adjuvant oligo-nucleotides containing CpG sequences complexed with cationic lipids, and (3) a low dose of the chemotherapy agent cyclophosphamide that is known to decrease the number and activity of Treg. While each of these three treatments alone had no or only slight effects, a strong anti-tumor response was achieved when all three components were administered simultaneously. This tri-therapy was able to induce eradication of large established tumors in around 90% of treated animals. M.A. Suckow (University of Notre Dame, Indiana, USA) presented a talk on tissue vaccine for prevention and treatment of prostate cancer. Tissue vaccines are composed of material harvested directly from tumors and are used to immunize the animal or the patient. They comprise not only neoplastic cells but supporting stromal matrix as well. Studies to evaluate the prophylactic efficacy of tissue vaccines were conducted in Lobund Wistar (LW) rat model of prostate adenocarcinoma. Large adenocarcinomas develop in the prostatic complex spontaneously in male LW rats at approximately 24 months. Data were presented to demonstrate that tissue vaccines can effectively prevent the development of prostate cancer in animal models. In addition a tissue vaccine prepared from a xenogeneic source could be used against tumors associated with human prostate cancer cell line. It was argued that in case of a xenogeneic preparation, the immune system is presented with antigen that is homologous but recognized as foreign thus breaking immunologic tolerance.
Session 11: Closing plenary session
The Conference concluded with a presentation by E. Gilboa (University of Miami, USA) with the title: Cancer vaccines: where are we going from here? He started with referring to a cancer vaccine meeting a year ago in Italy (near Sienna) in which a depressing impression dominated when two talks had been presented from large melanoma vaccination trials with negative results. This was contrasted by positive results presented from vaccination trials with the autologous virus modified vaccine ATV-NDV. Gilboa then discussed problems related to the persistence of antitumor immunity and the role of various suppressive cells and factors which are tumor-induced or tumor-derived and interfere with anti-tumor immunity. One example was given by Treg cells. These have been manipulated either with the immuno-toxin ONTAK or they have been manipulated by immunization against FoxP-3 with FoxP-3 RNA transfected dendritic cells. This latter work of Gilboa’s lab revealed in the B16 skin melanoma model that co-vaccination against a melanoma tumor antigen and against FoxP-3 resulted in 40% tumor free animals. Most remarkably was the finding that after this immunization the Treg content of tumor infiltrating lymphocytes was reduced by 85% while the Treg level in the periphery was not affected. Gilboa then turned his attention to T cell costimulation and summarized the experience of people using agonistic antibodies against CD40 or 4-1BB. While the development of such antibody reagents for clinical application is very difficult and requires the input from big pharma, he introduced a provokingly new concept to create similar reagents with high affinity and specificity via oligo-nucleotide libraries. This aptamer approach was suggested to be more effective, faster, and less expensive. It was found that aptamers can be selected to have affinity similar to antibodies and they can be dimerized to costimulate T cells. They might have a superior pharmacology, tumor penetration, lack immunogenicity and are amenable to modification. He presented an experiment in the P815 mastocytoma mouse tumor model in which the application of 4-1BB aptamers caused tumor rejection.
Conclusion
This CVADD 2007 conference has witnessed that the field of cancer vaccine design and applications is moving from simple immunization schemes to combinations of vaccine application with special adjuvants and delivery systems. There was a general feeling that in order to be successful in a tumor-bearing host, immunotherapy with cancer vaccines has to target innate, adaptive, and regulatory components of the immune system.