Special Issue "Cancer Vaccines and Immunotherapy"

Guest Editor
Prof. Dr. W. Martin Kast
Walter A. Richter Cancer Research Chair, Professor of Molecular Microbiology & Immunology, Obstetrics & Gynecology and Urology, Norris Comprehensive Cancer Center (NRT 7507), University of Southern California, 1450 Biggy Street, MC 9601, Los Angeles, CA90033, USA
Website: http://www.usc.edu/programs/pibbs/site/faculty/kast_w.htm
E-Mail: mkast@usc.edu
Phone: +1 323 442 3870
Fax: +1 323 442 7760
Interests: design of HPV immunotherapeutics; developing new and effective therapies for cervical cancer; prostate cancer and melanoma

Guest Editor
Prof. Dr. Maurizio Chiriva-Internati
Division of Hematology and Oncology, Texas Tech University Health Sciences Center, 3601 4th St STOP, 6591, Lubbock, TX 79430, USA
E-Mail: maurizio.chiriva@ttuhsc.edu
Phone: +1-806-743-3155.ext. 279
Fax: +1-806-743-3148
Interests: tumor immunology, developing therapeutic and preventive tumor vaccine; ovarian cancer, multiple myeloma, breast cancer, prostate cancer

Dear Colleagues,

Despite intense ongoing research, many cancers are still incurable. Tumor cells induce immune tolerance, which represents a major obstacle for the application of cancer immunotherapy. Therefore, a current challenge for the field of cancer immunotherapy is to develop new approaches capable of breaking tumor-induced tolerance and inducing the (re-)activation of spontaneous and/or vaccine-triggered anti-tumor immune responses.

The exciting news this year is that we are now experiencing that cancer immunotherapy is finally becoming part of FDA approved cancer therapies. Cancer immunotherapy may provide a more effective and safer alternative approach to standard treatments, since unlike these currently available standard treatments, vaccines exploit natural anti-tumor immune surveillance, and offer the potential to provide durable control of primary and metastatic cancers.

Therefore, we invite research and review manuscripts in the field of cancer vaccines/cancer immunotherapy and topics related to new tumor antigen discovery, novel developments in therapeutic and preventive cancer vaccines, T regulatory cells, dendritic cell vaccines, T cell vaccines, B cell vaccines, pharmacological therapy, gene therapy, tumor-associated cancer testis antigens, immunosuppressive mechanisms, immune-regulatory applications and the regulation of immune surveillance against cancer as well as multi modality cancer approaches in which cancer vaccines/cancer immunotherapies play a role.

We are looking forward to your vital contributions.

Dr. W. Martin Kast
Dr. Maurizio Chiriva Internati
Guest Editors

Submission

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• cytotoxic T lymphocytes
• dendritic cells
• therapeutic cancer vaccines
• preventive cancer vaccines
• cancer immunotherapy
• immunomodulation

Type of Paper: Article
Title: Possible Decrease of DC Vaccine Therapeutic Efficacy as a Consequence of Regulatory T Cell Contamination
Authors: Grégory Driessens, Lise Nuttin and Catherine Bruyns
Affiliations: LCCE-IRIBHM, Faculty of Medicine, Université Libre de Bruxelles (ULB), route de Lennik 808, 1070 Bruxelles, Belgium;
E-Mail: cbruyns@ulb.ac.be (C.B.)
Abstract: For several years now we have successfully developed in the lab an efficient therapeutic vaccination strategy combining bone-marrow (BM)-derived DC vaccines and GM-CSF secreting tumor cell vaccines in murine models (Driessens G. et al, Cancer Res 2004, Cancer Immunol Immunother 2009, J Immunother 2009 and Cancer Immunol Immunother 2010). Recently, to better correlate with the clinical situation in human, we have had the original idea to derive the BM-DC vaccines from tumor-bearing animals instead of, as classically done, from naïve animals. We have observed that the combined vaccines using BM-DC derived from tumor-bearing rats were quite less efficient in vivo than their naïve counterparts to cure rats from a pre-implanted tumor. We have shown that the BM-DC derived from tumor-bearing rats were contaminated by functional regulatory T cells (Treg) that expand during culture of the DC and that the depletion of total T cells in the DC preparations restores the therapeutic efficacy of the vaccines. In the same way, an in vivo treatment of the tumor-bearing rats with a low-dose metronomic témozolomide regimen before generating BM-DC reduces the number of functional Treg in the BM-DC vaccines derived from tumor-bearing rats and restores their therapeutic efficacy to the level of BM-DC vaccines derived from naïve rats. Retrospectively, such an unknown contamination in Treg of DC vaccines derived from adherent circulating monocytes of cancer patients could explain the relative failure in tumor regression along clinical trials.

Type of Paper: Review
Title: Prostate Cancer Immunotherapy: Exploiting the HLA Class II Pathway in Vaccine Design
Author: Azizul Haque
Affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB201, Charleston, SC 29425, USA;
E-Mail: haque@musc.edu
Abstract: Prostate cancer is the second most diagnosed cancer in men and current treatment of advanced prostate cancer is ineffective. Immunotherapy has emerged as a promising treatment option for metastatic prostate cancer but its clinical application is still in the early stages of development. In order to treat metastatic prostate tumors, new directions must be taken to improve current immunotherapeutic strategies. These include the identification of effective tumor antigens (Ags), the induction of the HLA class II pathway for Ag processing and CD4+ T cell activation, and the ability of tumor cells to act like Ag presenting cells. In this review, we suggest a model for tumor Ag selection, epitope modification and self processing for presentation by class II proteins as a means of restoring immune activation and tumor clearance. We also outline the importance of a Gamma-IFN-inducible lysosomal thiol reductase (GILT) in Ag and modified peptide processing by tumor cells and generation of functional epitopes for T cell recognition. Taken together, this review provides a framework for the future development of novel cancer vaccines and the improvement of existing immunotherapeutics in prostate cancer.

Type of Paper: Review
Title: The Immune Suppression in the Tumor Microenvironment as an Obstacle for the Clinical Efficacy of Cancer Vaccines
Author: Pierre van der Bruggen
Affiliation: Ludwig Institute for Cancer Research. Av. Hippocrate 74-75. B - 1200 Brussels, Belgium; E-Mail: Pierre.vanderbruggen@bru.licr.org
Abstract: Antigen-expressing human tumors are not spontaneously eliminated by the immune system and therapeutic vaccination of cancer patients with defined antigens is followed by tumor regressions only in a small minority of the patients. The poor vaccination effectiveness could be explained by an immunosuppressive tumor micro-environment. Because T cells that do infiltrate tumor metastases have an impaired ability to lyse target cells or to secrete cytokine, many researchers are trying to decipher the underlying immunosuppressive mechanisms. We will review them here, in particular those considered as potential therapeutic targets. A special attention will be given to galectins, a family of carbohydrate binding proteins. These lectins have often been implicated in inflammation and cancer and may be useful targets for development of new anti-cancer therapies.

Type of Paper: Review
Title: Approaches to Immunotherapy for HPV Associated Cancer
Authors: Anne-Sophie Bergot; Ian Frazer and Deepak Mittal
Affiliations: UQ Diamantina Institute, Frazer Lab, Level 4, R-wing, Building 1, Princess Alexandra Hospital, Brisbane QLD, 4102 Australia;
E-Mail: a.bergot@uq.edu.au (A.-S.B.)
Abstract: Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the capacity to reduce a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection.  However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to  HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumours expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials.

Type of Paper: Review
Title: Immunomodulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines
Author: Marc Mansour
Affiliation: ¹ ImmunoVaccine Technologies, Inc., 1721 Lower Water Street, Halifax, NS B3J 1S5, Canada; E-Mail: mkarkada@imvaccine.com
² Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada
Abstract: Chemotherapy was the first and only line of treatment for cancer for many years.  Despite the successes made so far, the cure rate with chemotherapy is unsatisfactory and the associated severe side effects remain a concern.  Recent understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies including therapeutic cancer vaccines.  Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity.  Inclusion of adjuvants has helped to alleviate this disadvantage and increase their potency, but even still cacner vaccines have a poor clinical track record.  It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma.  Chemotherapies could be used to condition the immune system by reducing tumor-induced immune suppression and thereby creating an environment where cancer vaccines have a better chance of success.  Other types of immunotherapies could also be used to modulate the immune system.  This review will discuss how immune modulation by chemotherapy or immunotherapy can be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.

Type of Paper: Review
Title: DNA Vaccination Against ErbB2 Positive Tumors: From Mouse to Man
Authors: Elena Quaglino, Federica Riccardo, Marco Macagno, Silvio Bandini, Rodica Cojoca, Elisabetta Ercole, Guido Forni and Federica Cavallo
Affiliations: Molecular Biotechnology Center, Department of Clinical and Biological Science, University of Turin, 10126 Turin, Italy; E-Mails: elena.quaglino@unito.it (E.Q.); federica.riccardo@unito.it (F.R.); marco.macagno@unito.it (M.M.) ; silvio.bandini@unito.it (S.B.); rodica73@libero.it (R.C.); elisabetta.ercole@unito.it (E. E.); guido.forni@unito.it (G.F.); federica.cavallo@unito.it (F.C.)
Abstract: DNA vaccination is a relatively simple and very versatile technique for the generation of effective immune responses providing protection against both microbial and tumor-associated antigens (TAAs). The effectiveness of a DNA vaccine is enhanced by application of an electrical shock at its inoculation site (electroporation). Since DNA vaccine delivery is a critical issue, we exploited DNA electroporation against ErbB2 with a new electroporation device, approved for human use. We chose ErbB2 since it constitutes an ideal oncoantigen, i.e. a TAA essential for tumor progression, overexpressed by several carcinomas. Since oncoantigens are self-tolerated molecules, to trigger a response circumventing tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human extracellular and transmembrane (EC-TM) proteins. The efficacy of RHuT and HuRT was compared with that of plasmids coding for the fully rat or human EC-TM proteins and tested in wild type and in ErbB2 tolerant mice. In most cases, RHuT and HuRT elicited a stronger anti-tumor response. This suggests that the presence of heterologous moieties blunts immune tolerance and could be exploited as a promising clinical strategy. In principle, this strategy, applied to ErbB2, could be used towards any other oncoantigen. An initial clinical trial protocol against ErbB2-positive carcinomas of the oral cavity, oropharynx and hypopharynx is awaiting the approval of the Italian authorities.
Keywords: Her2; DNA vaccines; chimeric DNA vaccines; oncoantigens; tolerance; transgenic mice; autochthonous mammary tumors