Li, G

Rees, RC

English

Nottingham Trent Institutional Repository (IRep)

Meeting Report For reprint orders, please contact reprints@future-drugs.com Progress in vaccination against cancer (PIVAC) 2002 July 18-20, 2002, Nottingham, UK Geng Li and Robert C Rees' 'Author for correspondence: Department of Life Sciences, Nottingham Trent University, Clifton Lane, Clifton, Nottingham NG11 8NS, UK, Tel: +44 115 848 6342, Fax: +44115 848 6636, robert.rees@ntu.ac.uk Expert Rev. Vaccines 1 {3), 261-263 (2002) Progress in Vaccination Against Cancer (PIVAC) 2002 was held in Nottingham, U K , July 18-20, 2002. Over 100 dele-gates from 17 countries attended this sci-entific event. The following review sum-marizes the main issues arising from the presentations at the conference. Identification & characterization of tumor antigens The identification of immunogenic mole-cules which are overexpressed in malig-nant tissues, but not in essential normal cells, such as brain, lung, heart, liver and kidney, is crucial for the development of cancer vaccines. The serological identifi-cation of tumor antigens by a recom-binant expression cloning (SEREX) approach was discussed during the meet-ing. D Schadendorf, Heidelberg, Ger-many, reported that they had identified several antigens by immunoscreening of cDNA libraries constructed from normal testis and cutaneous lymphomas with sera from patients with cutaneous lymphoma. Some of these antigens were only expressed in testis and tumor tissues and also reacted with sera from patients with cutaneous lymphoma [l]. A Miles, Not-tingham, UK, applied a similar approach to identify prostatic carcinoma antigens and isolated three antigens which were overexpressed in normal testes and can-cerous tissues, as determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). SEREX-defined anti-gens were also found in acute myeloid leukemia (B Guinn, London, UK) [2]. Application of mass spectrometric analytical techniques in conjunction with Ciphergen protein chip technology, coupled with trainable artificial neural network programs, may allow the identi-fication of validated biomarkers corre-lated with disease progression, treatment success or tumor escape. These biomark-ers warrant further characterization to assess their suitability as potential thera-peutic targets (S Mian, Nottingham, U K , J Tolson, Tubingen, Germany) [3]. The wide expression of the human tel-omerase catalytic subunit (hTERT) in tumors makes it an interesting universal candidate antigen for cancer immuno-therapy. G Gaudernack, Oslo, Norway, has used several new epitopes of hTERT that can elicit both CD4 and CD8 cell responses against hTERT in a clinical Phase I trial in patients with advanced pancreatic cancer, non-small cell lung cancer and melanoma. No serious adverse effects related to the treatment have been observed and 75% of patients who received high-dose vaccine demon-strated an immune response measured either by delayed-type hypersensitivity (DTH) reaction or in vitro tests. Further-more, a survival advantage was observed for patients receiving the high-dose vac-cine compared with those receiving the lower dose [4]. Proteins encoded by bcr/abl fusion genes generated by t(9;22) transloca-tion in chronic myelogenous leukemia (CML) patients are not expressed in normal cells. G Pawelec, Tubingen, Germany, described synthetic peptides representing sequences encompassing the break point region of both bcr/abl and abl/bcr that were immunogenic for both CD4 and CD8 cells in vitro. Ik Dodi, London, U K , reported on C M L -specific peptides eluted from human leukocyte antigen (HLA)-A3 or H L A -B8 K652 (CML cell line) transfectants as well as from C M L cells isolated from HLA-A3 patients. Tetramers of H L A -A3 and HLA-B8 with the correspond-ing eluted peptides were produced and used to detect antigen-specific cytotoxic T-lymphocytes (CTLs) from HLA-A3 and HLA-B8 patients at various stages of the disease and treatment [5]. A combination of vaccines targeting both tumor endothelial and epithelial cells may lead to vascular collapse and increase extravasation leading to tumor regression. Tie-2 is a receptor tyrosine kinase overexpressed in tumor endothe-lial cells. Both CD4 and CD8 epitopes within Tie-2 were identified. CD8 epitopes can stimulate C T L responses in HLA-A2 transgenic mice and kill endothelial cells overexpressing Tie-2. CD4 epitopes can stimulate a T h l response in vitro. CD55 is overex-pressed in tumor cells and a human anti-idiotypic antibody, 105AD7, that mimics the CD55 antigen has been produced. Colorectal tumor patients immunized with 105AD7 showed T-cell blastogenesis against tumor cells expressing CD55 and a significant increase in tumor cell apoptosis (LG Durrant, Nottingham, UK) [6]. D E Speiser, Lausanne, Switzerland, has vaccinated melanoma patients with Melan-A/MART-1 peptides. The vac-cines were well tolerated. One of 21 patients showed disease stabilization and two out of 21 patients who had the strongest activation and expansion of tumor antigen-specific T-cells experi-enced regression of skin, lymph nodes and lung metastases [7]. J M Rojas, Not-tingham, U K , reported that major histo-compatibility complex (MHC) class II © Future Drugs Ltd. All rights reserved. ISSN 1476-0584 261 Li & Rees epitopes derived from p53 and gplOO were immunogenic in a transgenic mouse model and demonstrated that H L A - D R transgenic mice represent a suitable model for the discovery of M H C class II-restricted epitopes derived from tumor antigens. Dendritic cell-based vaccination Dendritic cells (DCs) play a central role in the immune system. Without optimal D C antigen-presenting function there can be no antitumor immunity. How-ever, it is important to note that DCs that present the relevant MHC-peptide complexes qualify as potential targets and are at risk of being eliminated by the CTLs they have activated. Immature DCs are indeed susceptible to C T L -induced killing, but the mature DCs activated by Anti-CD40 or lipopolysac-charide (LPS) are resistant to this effect. Protection is achieved by expression of a serine protease inhibitor (SPI)-6 and its human homolog PI-9 induced by Anti-CD40 and LPS (R Offringa, Leiden, The Netherlands) [8]. A M Jackson, Leeds, U K , described recombinant mycobacteria expressing tumor antigens able to infect and cause marked maturation of DCs, resulting in cytokine secretion and increased T-cell stimulatory capacity. E Kaminski, Ply-mouth, UK, reported that autologous T-cells treated with interleukin (IL) -15 prior to culture with tumor lysate-pulsed DCs, exhibited a significant increase in T-cell proliferation, interferon (IFN)-y secretion and specific cytotoxicity to tar-get cells. HS Pandha, London, UK, has developed a method of culturing then cryopreserving, monocyte-derived DCs after pulsing with irradiated allogenic prostatic cancer cell lysate. This process increased DC maturation and thus enhanced their antigen-presenting capa-bility. In the study, 14 patients with met-astatic prostatic cancer received the D C vaccines (a Phase I/II clinical trial) and four experienced a PSA response: two with an arrest in PSA levels and two showing reduction in PSA levels. V Cerundolo, Oxford, UK, discussed the strategies that could generate a broad and long-lasting antitumor-specific immunity. They engineered a string of HLA-A2 and -Al-restricted melanoma epitopes which were cloned into naked plasmid D N A , vaccinia virus, modified vaccinia Ankara virus (MVA) and Sem-liki forest virus (SFV) and vaccinated HLA-A2 transgenic mice with different combinations of the polyepitope con-structs. Their results demonstrated that competition for antigen recognition at the surface of antigen-presenting cells (APCs) may significantly skew the immune response and this competition needs to be taken into account for the development of vaccination strategies to optimally induce polyvalent C T L response. They identified two alternative protocols for inducing polyvalent C T L response, based on the injection of either increasing numbers of APCs infected with vaccinia virus encoding the poly-epitope construct, or a mixture of viruses each coding a separate antigen [9]. P Straten, Copenhagen, Denmark, described T C R clonotype mapping uti-lizing RT-PCR and denaturing gradient gel electrophoresis (DGGE). Using these sensitive assays it was demonstrated that predominant T-cell clones infiltrating melanoma tissue do not reflect T-cell populations expanded in vitro from the same tissue. This questions the interpre-tation and potential importance of data obtained on cultured TILs. However, the application of D G G E has shown a corre-lation between circulating T-cell clones and TILs during IL-2 therapy. Tumor escape from immune surveillance Tumor cells develop various strategies to escape immune surveillance and effector cells also express negative regulatory recep-tors which provides further examples of the double-edged sword of immunotherapy. Finding ways of preventing tumor escape by multiple strategies will be the main chal-lenge for immunotherapy of cancer. KJ Malmberg, Stockholm, Sweden, described how hydrogen peroxide (H2O2), released by tumor infiltrating macrophages, can impair the cytokine production and func-tion of T- and natural killer (NK) cells. Exogenous supplied antioxidants, such as high doses of dietary vitamin E, may pro-tect the immune cells from die attack of H2O2 by increasing CD4/CD8 ratio and IL-2 production. He also pointed out that IFN-y treatment of ovarian carcinoma cells protected them from lysis by CTL. This phenomenon was dependent on the enhanced signaling via CD94/NKG2A receptors expressed on the T-cells [10]. On the other hand, IFN-y is essential for tumor resistance in animal models including the Stat-6 knockout model described by S Ostrand-Rosenberg, Baltimore, USA [11]. M Ahmad, Nottingham, U K , reported that direct intratumor injec-tion of disabled herpes simplex viruses, DISC/HSV/mGM-CSR into estab-lished tumors induced tumor rejection in 40-60% of treated animals (regres-sor), while the remaining mice had progressive tumors (progressor). To identify the mechanisms responsible for the failure of immunotherapy, they examined whether the APCs of pro-gressor mice were functional and induced a C T L response - they reported that the APCs from the pro-gressor mice did not support C T L gen-eration. They suggest that either the presence of suppressor elements in the progressor paranchymal A P C fraction or the APCs from progressor mice do not effectively present antigens to CTLs [12]. As mentioned in the section on DC-based vaccination, DCs protect themselves against lysis by the CTLs they induced by expressing PI-9/SPT6. Unfortunately, a variety of human and murine tumor cells also express PI-9/ SPI-6, resulting in the resistance of tumor cells to CTL-mediated killing. Loss or downregulation of TAP expression prevents presentation of the tumor antigens on the surface of tumor cells and therefore allows them to avoid recognition by CTLs. WA Jefferies, Van-couver, Canada, described how transfec-tion of mouse melanoma B16F10 (TAP-deficient) cells with vaccinia vector car-rying TAP1 could enhance tumor-spe-cific T-cell generation and reduce tumor burden in mice. Inclusion of TAP in cancer therapy might provide a general method for increasing immune responses against tumors regardless of the antigenic complement of tumor or the M H C haptotypes of the host [13]. 262 Expert Rev. Vaccines 1(3), (2002) Vaccination against cancer Acknowledgements We acknowledge support from The Brit-ish Society for Immunology. Special thanks are extended to Sandra Lowne, Ben Stanley (BSI) and Glenda K i l l (Not-tingham Trent University, U K ) for their References 1 Eichmuller S, Usener D, Dummer R, Stein A, Thiel D , Schadendorf D. Serological detection of cutaneous T-cell lymphoma-associated antigens. Proc. Natl Acad. Sci. Z/iM 98, 629-634 (2001). 2 Guinn B-A, Collin JF, L i G, Rees RC, Mufti GJ. Optimised SEREX technique for the identification of leukemia-associated antigens. J. Immunol. Methods 264, 207-214 (2002). 3 Ball G, Mian S, Holding F et al. An integrated approach utilizing artificial neural networks and SELDI mass spectrometry for the classification of human tumours and rapid identification of potential biomarkers. Bioinformatics 18, 395-404 (2002). 4 Saeboe-Larssen S, Fossberg E, Gaudernack G. mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T-lymphocyte responses against the telomerase catalytic subunit (hTEKT). J. Immunol. Methods 259, 191-203 (2002). 5 Clark RE, Dodi IA, Hill SC et al. Direct evidence that leukemic cells present H L A -associated immunogenic peptides derived help i n organizing the meeting. We wish to acknowledge support by grants from The Cancer and Polio Research Fund and The John and Lucille van Geest Foundation. from the BCR-ABL b3a2 fusion protein. ^00^98, 2887-2893 (2001). 6 Durrant LG, Parsons T, Moss R, Spendlove I, Carter G, Carr F. Human anti-idiotypic antibodies can be good immunogens as they target FC receptors on antigen-presenting cells allowing efficient stimulation of both helper and cytotoxic T -cell responses. Int. J. Cancer 92, 414-420 (2001). 7 Pittet M J , Zippelius A, Valmori D , Speiser DE, Cerottini JC, Romero P. Melan-A/ MART-1-specific CD8T-cells: from thymus to tumor. Trends Immunol. 23, 325-328 (2002). 8 Medema JP, Schuurhuis D H , Rea D et al. Expression of the serpin serine protease inhibitor 6 protects dendritic cells from cytotoxic T-lymphocyte-induced apoptosis: differential modulation by T-helper Type 1 and Type 2 cells. J. Exp. Med. 194, 657-667 (2001). 9 Palmowski MJ , Choi E M , Hermans IF et al. Competition between C T L narrows the immune response induced by prime-boost vaccination protocols. J. Immunol. 168,4391-4398(2002). 10 Malmberg KJ, Arulampalam V, Ichihara F et al. Inhibition of activated/memory (CD45RO(+)) T-cells by oxidative stress associated with block of NF-kappaB activation. J. Immunol. 167, 2595-2601 (2001). 11 Ostrand-Rosenberg S, Grusby M J , Clements VK. Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J. Immunol. 165, 6015-6019 (2000). 12 Ali SA, Lynam J, McLean CS et al. Tumor regression induced by intratumor therapy with a disabled infectious single cycle (DISC) herpes simplex virus (HSV) vector, DISC/HSV/murine granulocyte-macrophage colony-stimulating factor, correlates with antigen-specific adaptive immunity. J. Immunol. 168, 3512-3519 (2002). 13 Alimonti J, Zhang QJ, Gabathuler R, Reid G, Chen SS, Jefferies WA. TAP expression provides a general method for improving the recognition of malignant cells in vivo. Nat. Biotechnol. 18, 515-520 (2000). www.future-drugs.com 263 

Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma.

Expression of the serpin serine protease inhibitor 6 protects dendritic cells from cytotoxic T-lymphocyte-induced apoptosis: differential modulation by T-helper Type 1 and Type 2 cells.

immune response induced by primeboost vaccination protocols.

Inhibition of activated/memory (CD45RO(+)) T-cells by oxidative stress associated with block of NF-kappaB activation.

Melan-A/ MART-1-specific CD8T-cells: from thymus to tumor.

Tumor regression induced by intratumor therapy with a disabled infectious single cycle (DISC) herpes simplex virus (HSV) vector, DISC/HSV/murine granulocytemacrophage colony-stimulating factor, correlates with antigen-specific adaptive immunity.

Progress in vaccination against cancer (PIVAC) 2002

Progress in vaccination against cancer (PIVAC) 2002

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