DOCSLIB.ORG

An Effective Strategy of Human Tumor Vaccine Modification by Coupling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
An Effective Strategy of Human Tumor Vaccine Modification by Coupling An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules Claudia Haas,1 Christel Herold-Mende,2 Roswitha Gerhards,3 and Volker Schirrmacher1 1German Cancer Research Center, Tumor Immunology Program, Heidelberg, Germany; 2Department of Neurosurgery, University-Clinic, Heidelberg, Germany; and 3Marien-Hospital, Herne, Germany. A new, generally applicable procedure is described for the introduction of defined costimulatory molecules into human cancer cells to increase their T-cell stimulatory capacity. The procedure involves infection with Newcastle disease virus to mediate the cell surface binding of costimulatory molecules (e.g., specially designed bispecific antibodies (bsAb)). The modification is independent of tumor cell proliferation and laborious recombinant gene technology and can be applied directly to freshly isolated and g-irradiated patient-derived tumor cells as an autologous cancer vaccine. Following the infection of tumor cells with a nonvirulent strain of Newcastle disease virus, the cells are washed and then further modified by coincubation with bsAbs, which attach with one arm to the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells. The second specificity of one bsAb (bs HN 3 CD28) is directed against CD28 to augment antitumor T-cell responses by selectively channeling positive costimulatory signals via the CD28 pathway. A second bsAb (bs HN 3 CD3) was produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine) or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T-cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T lymphocytes from either normal healthy donors or cancer patients (autologous system) and induced tumor cytostasis in nonmodified bystander tumor cells. In addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity and T-cell proliferative responses were observed. This tumor vaccine modification procedure is highly specific, quick, economic, and has a broad range of clinical applications. Key words: Cancer vaccine; bispecific antibody; Newcastle disease virus; tumor-associated antigen; T-cell costimulation. here is now much evidence that an antigen (Ag)- come immunogenic after CD80, CD86, and/or cytokine Tspecific, T-cell-mediated immune response requires, gene transfection, and mice that rejected such transfec- apart from the Ag, additional costimulatory signals.1,2 tants developed systemic protective immunity against These signals are normally provided by professional the nontransfected tumor.2–6 Ag-presenting cells (APCs) such as dendritic cells, mac- B7 transfection, however, often does not suffice to rophages, and activated B lymphocytes but not, for transfer immunogenicity to tumor cells such as human instance, by carcinoma cells, which represent the major- carcinoma cells, even when these cells are antigenic and ity of human tumors and are derived from the non-APC- susceptible to cytotoxic T lymphocytes (CTLs).7 This type cells that form the epithelial layers. In the absence may be due in part to the fact that B7 also interacts with of costimulation, encounters with a tumor-associated Ag a negative regulator of T-cell activation, CTLA-4.8,9 An (TAA) can lead to T-cell inactivation or death rather ideal tumor vaccine should selectively channel costimu- than to proliferation and differentiation into effector latory signals via the CD28 pathway. This is achieved in cells. Modern gene therapy strategies, therefore, aim at the human cancer vaccines described here, in which a transforming carcinoma cells into professional APCs by bispecific (bs) anti-CD28 antibody (Ab) that does not transfecting genes that code for T-cell costimulatory interact with CTLA-4 is used for tumor vaccine modifi- molecules, such as CD80 (B7-1),2,3 CD86 (B7-2), and/or 4,5 cation. The vaccine modification procedure does not cytokines. In support of this concept, some nonimmu- require recombinant gene transfection or long-term cell nogenic transplantable tumor cells were shown to be- culture and selection procedures. It is a new, quick, and economic procedure involving only two steps that are Received April 16, 1998; accepted August 16, 1998. easy to perform: virus infection and bsAb attachment. Address correspondence and reprint requests to Prof. Volker Schirrma- For virus infection, we used a low dose of Newcastle 10,11 cher, Deutsches Krebsforschungs-zentrum, Abteilung 0710, Im Neuenhei- disease virus (NDV), an antineoplastic agent that mer Feld 280, 69120 Heidelberg, Germany. E-mail address: V. was shown to potentiate tumor vaccine T-cell stimula- Schirrmacher@dkfz-heidelberg-de tory capacity without changing the tumor specificity of © 1999 Stockton Press 0929-1903/99/$12.00/10 the response.12 Postoperative vaccination with NDV- 254 Cancer Gene Therapy, Vol 6, No 3, 1999: pp 254–262 HAAS, HEROLD-MENDE, GERHARDS, ET AL: T-CELL ACTIVATION VIA BISPECIFIC CANCER VACCINE 255 modified autologous tumor cell vaccine (ATV-NDV) Production of bsCD28 vaccine and bsCD3 vaccine was effective in vivo in various animal tumor models to g 13,14 Tumor cells were inactivated with 200 Gy -irradiation via a prevent metastatic spread and to increase survival. 137Cs source (Gammacell 1000, Atomic Energy of Canada), The mechanism of the immunopotentiating effect of this washed, and resuspended in phosphate-buffered saline (1 3 15–17 7 virus was analyzed in detail. Since 1988, a compara- 10 /mL). The cells were incubated for 1 hour at 37°C in a CO2 ble ATV-NDV was developed for clinical application.18,19 incubator in the presence of NDV Ulster (100 hemagglutinat- To obtain a high-quality product with potential clinical ing units) and washed. A total of 1 3 106 NDV-modified tumor efficacy, a number of procedures were developed: mechan- cells (TuN) were incubated with a predetermined saturating m ical dissection and enzymatic digestion to obtain single cells dose of 1 g/mL of the indicated bsAb or mAb and incubated from freshly operated tumors, removal of debris by Percoll for 20 minutes on ice. After washing, the bs vaccine was centrifugation, and removal of tumor-infiltrating leuko- adjusted to the required cell concentration. 20,21 cytes by immunomagnetic beads. Preparation of responder cells The present report summarizes .3 years of work toward the production, purification, and successful func- Human peripheral blood mononuclear cells (PBMCs) were tional testing in vitro of two new bsAbs. These bsAbs isolated from the heparinized blood of healthy donors or from allow for the production of a bsAb-modified, second- the HNO33, NCH92, and DaT45 patients by Ficoll-Hypaque generation vaccine (bs vaccine), because one arm of the (Pharmacia, Uppsala, Sweden) density gradient centrifugation. For enrichment of peripheral blood lymphocytes (PBLs), the bsAb is directed against the viral hemagglutinin-neura- isolated PBMCs were adjusted to 2 3 106 cells/mL in RPMI minidase (HN) molecule that serves as a universal 1640 and incubated for 1 hour at 37°C in tissue culture flasks anchoring molecule of the ATV-NDV vaccine. The to remove adherent cells. The nonadherent lymphocytes were second specificity is directed either against CD28 to carefully washed twice with prewarmed (37°C) complete me- deliver costimulatory signals via CD28 or against CD3 dium. T cells were separated by the sheep red blood cell (as a positive control) to deliver T-cell receptor (TCR) rosetting technique. The purity of the isolated T cells was complex-mediated signals and to achieve maximal stim- .95% as determined by immunofluorescence. ulation in combination with anti-CD28. Our data dem- onstrate potent stimulatory capacity on T cells of human Mixed lymphocyte-tumor cell culture (MLTC) carcinoma cells that are cell surface-modified by agonis- PBMCs and bs vaccine were mixed at a 10:1 ratio and seeded tic anti-CD28 and/or anti-CD3 Abs. into 12- or 6-well plates. After the indicated time interval, cells were washed and stained for FACS analysis. For whole blood cultures, the heparinized blood of the HNO33 patient was MATERIALS AND METHODS diluted 1/5 with complete medium plus 2% FCS. Cell lines and production of bsAbs Cytotoxicity test The parental hybridomas for the generation of quadromas For the generation of CTLs, purified T cells were mixed with were OKT3 (anti-CD3),22 15E8 (anti-CD28),22 and HN 1.4 c 23 the bs vaccine at a 10:1 ratio and incubated for 5 days in (anti-HN) . BsAb were produced by fusing 8-azaguanine- complete medium with 2% FCS without interleukin-2 (IL-2) in resistant hypoxanthine phosphoribosyltransferase-negative an- 24-well plates in a 37°C incubator. Next, T cells were washed ti-CD3 or anti-CD28 hybridomas with iodoacetamide-treated three times, counted, and used as effector cells in a 4-hour (5 mM, 30 minutes, 4°C) anti-HN hybridomas via polyethylene cytotoxicity assay. For target cells, NDV-modified Colo205 glycol and then by selecting quadromas in hypoxanthine/ tumor cells were incubated for 1 hour at 37°C with 100 mCi aminopterin/thymidine medium. Supernatants were tested by 51 Na2 CrO4 (DuPont-New England Nuclear, Bad Homburg, fluorescence-activated cell sorter (FACS) analysis for the Germany). The cells were then washed twice in RPMI 1640 presence of both parental immunoglobulin (Ig) isotypes. and counted. The target cells were added to the preactivated Quadromas were grown in miniperm production modules lymphocytes at the indicated effector to target ratio in round- (Heraeus, Osterode, Germany), harvested Abs were purified bottom microtiter plates. The final volume was 200 mL. The over a protein G column, and bsAbs were separated from plates were incubated for 4 hours at 37°C in a CO2 incubator. parental monoclonal Abs (mAbs) by high-performance liquid The mean percentage of specific 51Cr release was calculated chromatography. The mAbs used in this study for FACS from triplicates as described previously.15 analysis were: anti-CD4 phycoerythrin (PE), anti-CD8 PE, anti-CD25 fluorescein isothiocyanate (FITC), and anti-CD69 Tumor cytostasis test FITC (all from PharMingen, Hamburg, Germany).
Load more

Recommended publications
  • Immunology 101
    Immunology 101 Justin Kline, M.D. Assistant Professor of Medicine Section of Hematology/Oncology Committee on Immunology University of Chicago Medicine Disclosures • I served as a consultant on Advisory Boards for Merck and Seattle Genetics. • I will discuss non-FDA-approved therapies for cancer 2 Outline • Innate and adaptive immune systems – brief intro • How immune responses against cancer are generated • Cancer antigens in the era of cancer exome sequencing • Dendritic cells • T cells • Cancer immune evasion • Cancer immunotherapies – brief intro 3 The immune system • Evolved to provide protection against invasive pathogens • Consists of a variety of cells and proteins whose purpose is to generate immune responses against micro-organisms • The immune system is “educated” to attack foreign invaders, but at the same time, leave healthy, self-tissues unharmed • The immune system can sometimes recognize and kill cancer cells • 2 main branches • Innate immune system – Initial responders • Adaptive immune system – Tailored attack 4 The immune system – a division of labor Innate immune system • Initial recognition of non-self (i.e. infection, cancer) • Comprised of cells (granulocytes, monocytes, dendritic cells and NK cells) and proteins (complement) • Recognizes non-self via receptors that “see” microbial structures (cell wall components, DNA, RNA) • Pattern recognition receptors (PRRs) • Necessary for priming adaptive immune responses 5 The immune system – a division of labor Adaptive immune system • Provides nearly unlimited diversity of receptors to protect the host from infection • B cells and T cells • Have unique receptors generated during development • B cells produce antibodies which help fight infection • T cells patrol for infected or cancerous cells • Recognize “foreign” or abnormal proteins on the cell surface • 100,000,000 unique T cells are present in all of us • Retains “memory” against infections and in some cases, cancer.
    [Show full text]
  • A Dendritic Cell Cancer Vaccine
    MILESTONES MILESTONE 17 to mature. The pulsed dendritic cells are then reinfused into the patient over several cycles. A dendritic cell cancer vaccine Although sipuleucel-T has not been very widely adopted (and is no longer available in the European Union), it was recently announced that the combination of hormonal therapeutics with sipuleucel-T extended the survival of patients with metastatic castration-resistant prostate cancer. Other clinical trials combining sipuleucel-T with radiation, hormo- nal, targeted or other immunothera- pies are ongoing. So far sipuleucel-T remains the only vaccine-based immunotherapy approved for prostate cancer, and is also the only approved cell-based vaccine in the USA. Overall clinical responses to dendritic cell vaccines have been disappointing, but with increasing Credit: Science Photo Library / Alamy Stock Photo Science Photo Library Credit: knowledge, newer and more sophisti- cated strategies are being investigated In 1909 Paul Ehrlich postulated that T cells and induce protective T cell to improve the efficacy of dendritic the immune system may defend responses. If a cancer-specific antigen cell-based vaccines. Improved meth- the host against neoplastic cells and is presented, this can result in an Sipuleucel-T ods to generate more mature and hinder the development of cancers. anti-tumour response. As T cell became in ‘effective’ dendritic cells using ex vivo This concept has been widely recog- responses are indeed crucial for 2010 the first protocols, alternative combinations nized ever since, and eventually led eliciting an immune response against of antigens, optimized loading of to the development of novel cancer cancers, dendritic cells have for a approved dendritic cells and transfection of treatments in more recent years that long time been suggested as potential dendritic cell dendritic cells with RNA or DNA are revolutionized cancer care.
    [Show full text]
  • Can a Virus Cause Cancer: a Look Into the History and Significance of Oncoviruses
    UC Berkeley Berkeley Scientific Journal Title Can A Virus Cause Cancer: A Look Into The History And Significance Of Oncoviruses Permalink https://escholarship.org/uc/item/6c57612p Journal Berkeley Scientific Journal, 14(1) ISSN 1097-0967 Author Rwazavian, Niema Publication Date 2011 DOI 10.5070/BS3141007638 Peer reviewed|Undergraduate eScholarship.org Powered by the California Digital Library University of California CA N A VIRU S CA U S E CA NCER ? A LOOK IN T O T HE HI st ORY A ND SIGNIFIC A NCE OF ONCO V IRU S E S Niema Rwazavian The IMPORTANC E OF ONCOVIRUS E S (van Epps 2005). Although many in the scientific Cancer, a disease caused by unregulated cell community were unconvinced of the role of viruses in growth, is often attributed to chemical carcinogens cancer, research on the subject nevertheless continued. (e.g. tobacco), hormonal imbalances (e.g. high levels of In 1933, Richard Shope discovered the first mammalian estrogen), or genetics (e.g. breast cancer susceptibility oncovirus, cottontail rabbit papillomavirus (CRPV), gene 1). While cancer can originate from any number which could infect cottontail rabbits, and in 1936, John of sources, many people fail to recognize another Bittner discovered the mouse mammary tumor virus important etiology: oncoviruses, or cancer-causing (MMTV), which could be transmitted from mothers to pups via breast milk (Javier and Butle 2008). By the 1960s, with the additional “…despite limited awareness, oncoviruses are discovery of the murine leukemia BSJ virus (MLV) in mice and the SV40 nevertheless important because they represent virus in rhesus monkeys, researchers over 17% of the global cancer burden.” began to acknowledge the possibility that viruses could be linked to human cancers as well.
    [Show full text]
  • Recombinant DNA Vaccines Protect Against Tumors That Are Resistant to Recombinant Vaccinia Vaccines Containing the Same Gene
    Gene Therapy (2001) 8, 128–138 2001 Nature Publishing Group All rights reserved 0969-7128/01 $15.00 www.nature.com/gt RESEARCH ARTICLE Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene C-H Chen1,2, T-L Wang3,HJi3, C-F Hung3, DM Pardoll1, W-F Cheng3, M Ling3 and T-C Wu1,3,4,5 Departments of 1Oncology, 3Pathology, 4Obstetrics and Gynecology and 5Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA; and 2Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan Antigen-specific cancer immunotherapy involves the delivery ing against challenge with a more stringent subclone of TC-1 of tumor-associated antigen to the host for the generation of (TC-1 P2) established from TC-1 tumors that survived initial tumor-specific immune responses and antitumor effects. We Sig/E7/LAMP-1 vaccinia vaccination. Immunological assays hypothesized that different delivery systems may influence revealed that both vaccines induced comparable levels of the pattern of antigen-specific immune response and the CD8+ T cell precursors and anti-E7 antibody titers. Interest- outcome of antitumor effect. We therefore evaluated recom- ingly, Sig/E7/LAMP-1 vaccinia induced both E7-specific IFN- binant vaccinia virus and naked DNA for the generation of ␥- and IL4-secreting CD4+ T cell precursors while antigen-specific immune responses and antitumor effects. Sig/E7/LAMP-1 DNA induced only E7-specific IFN-␥- We previously found that recombinant vaccinia and naked secreting CD4+ T cell precursors. We also found that IL-4 DNA vaccines containing the chimeric Sig/E7/LAMP-1 gene knockout C57BL/6 mice vaccinated with Sig/E7/LAMP-1 were capable of controlling the growth of HPV-16 E7- vaccinia exhibited a more potent antitumor effect than vacci- expressing tumor cells (TC-1).
    [Show full text]
  • Therapeutic Vaccines for Cancer: an Overview of Clinical Trials
    REVIEWS Therapeutic vaccines for cancer: an overview of clinical trials Ignacio Melero, Gustav Gaudernack, Winald Gerritsen, Christoph Huber, Giorgio Parmiani, Suzy Scholl, Nicholas Thatcher, John Wagstaff, Christoph Zielinski, Ian Faulkner and Håkan Mellstedt Abstract | The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy. Melero, I. et al. Nat. Rev. Clin. Oncol. 11, 509–524 (2014); published online 8 July 2014; doi:10.1038/nrclinonc.2014.111 Centro de Investigación Medica Aplicada (CIMA) Introduction and Clínica Universitaria (CUN), Universidad de Immunotherapies against existing cancers include active, unstable leading to numerous changes in the repertoire Navarra, Spain (I.M.). passive or immunomodulatory strategies. Whereas active of epitopes (so-called neo-antigens) they present, sug- Department of Immunology, immunotherapies increase the ability of the patient’s gesting that, in theory, tumours should be ‘visible’ to The Norwegian Radium own immune system to mount an immune response T lymphocytes. Hospital, Cancer to recognize tumour-associated antigens and eliminate The mechanisms required to mount effective anti­ Research Institute, University of Oslo, malignant cells, passive immunotherapy involves admin- tumour responses have been reviewed by Mellman and Norway (G.G.).
    [Show full text]
  • Cancer Vaccines
    © 1998 Nature Publishing Group http://www.nature.com/naturemedicine REVIEW Drew Pardoll (Johns Hopkins Oncology Center) examines prospects for therapeutic cancer vaccines. Considering how it is that the immune system fails to recognize and destroy cancer cells, Pardoll discusses contemporary vaccine approaches aimed at exposing cancer antigens to the cellular arm of the immune system, and the first, promising steps toward therapeutic cancer vaccines. Cancer vaccines Since the turn of the century, scientists ... .................... .. .......................... ,. ,. .... ,. ,, . ignorance, anergy or physical dele­ have studied the interactions between the DREW M. PARDOLL tion 1•-1 6. What determines the outcome immune system and cancer cells so that of antigen encounter is the context in antitumor immunity could be amplified as a means of cancer which that antigen is presented to the immune system. Thus, therapy. In the 1890s, William Coley began to treat cancer pa­ the outcome of inflammation or tissue destruction that occurs tients with bacterial extracts (Coley's toxins) to activate general during viral or bacterial infection (or when antigen is mixed systemic immunity, a portion of which might be directed against with the appropriate adjuvant) is typically activation. When the tumor1• One hundred years later, the molecular understand­ antigen is expressed endogenously, in the absence of the dan­ ing of immune recognition and immune regulation provides op­ ger signals that accompany tissue destruction and inflamma­ portunities that Coley never had to create cancer vaccines with tion, the typical outcome is immunologic tolerance (Fig. 1). much greater potency and specificity for tumor cells and dimin­ Ultimately, it appears that the immune response at the T­ ished toxicity for normal tissues.
    [Show full text]
  • Recent Developments in Therapeutic Cancer Vaccines Michael a Morse*, Stephen Chui, Amy Hobeika, H Kim Lyerly and Timothy Clay
    REVIEW www.nature.com/clinicalpractice/onc Recent developments in therapeutic cancer vaccines Michael A Morse*, Stephen Chui, Amy Hobeika, H Kim Lyerly and Timothy Clay SUMMARY INTRODUCTION: THE GAP BETWEEN THEORY AND REALITY IN THE CLINICAL Therapeutic cancer vaccines are being developed with the intention RESULTS FOR CANCER VACCINES of treating existing tumors or preventing tumor recurrence. While the Therapeutic cancer vaccines, or so called active results of clinical trials, predominantly in the metastatic setting have been specific immunotherapies, are intended to acti- sobering, the central hypothesis of active immunotherapy i.e. that the vate the immune system to treat existing tumors human immune system can be activated to recognize and destroy tumor or prevent tumor recurrence. While we (and cells, remains a viable one. We believe that a fundamental shift in how others1) believe that the central hypothesis of clinical trials are performed, and what concepts they test is required to active immuno therapy, i.e. that the human make meaningful strides towards future clinical use of cancer vaccines. immune system can be activated to recognize First, we must reappraise whether the metastatic setting is the appropriate arena to test these agents. Second, we must arrive at a consensus on the and destroy tumor cells, remains viable, the field most important biologic endpoints and rapidly test vaccines for their of active specific immunotherapy is clearly at a ability to achieve these endpoints. Third, we need to expend more effort on crossroads, with pessimism for current vaccines expressed by some leaders in the field,2 and more understanding how to manipulate the immune system beyond the initial 3,4 stimulation provided by a vaccine.
    [Show full text]
  • Peptide Vaccines for Cancer Therapy
    Send Orders for Reprints to [email protected] 38 Recent Patents on Inflammation & Allergy Drug Discovery 2015, 9, 38-45 Peptide Vaccines for Cancer Therapy Daniela Cerezo, María J. Peña, Michael Mijares, Gricelis Martínez, Isaac Blanca and Juan B. De Sanctis* FOCIS Center of Excellence, Instituto de Inmunología, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela Received: October 13, 2014; Accepted: January 21, 2015; Revised: January 24, 2015 Abstract: For around four decades, vaccines of different kinds have been developed to treat different types of cancer. However, promising results encountered in the early phase contrasted with the results recorded in clinical studies. Recent discoveries in the vaccine field, adjuvants and delivery systems, and antigen presentation have lead to new patented approaches. The current review is focused on gen- eral description of peptide vaccines involving cancer antigen presentation, specific immune response, cell death dependent pathways, and target therapy for modified or mutated oncogenes. A rapid evolving research in the area may evolve in fruitful outcomes in the near future. Keywords: Adjuvants, antigen presentation, cancer, immune response, peptide, vaccines. INTRODUCTION antigens generated through nonstandard transcriptional and translational mechanisms may also be presented by MHC-I The key issue in inducing immune response is antigen [2-5]. presentation [1]. Antigen presentation is a complex process that involves intracellular compartments with a sequence of Antigen presentation by tumor cells is different from nor- events from degradation of a complex pathogen, or cell up to mal cells and therefore analysis of tumor antigens and cryptic binding to major histocompatibility complex proteins (MHC) tumor antigens differs enormously between them [2-5].
    [Show full text]
  • Advances in the Development of Personalized Neoantigen-Based
    REVIEWS Advances in the development of personalized neoantigen- based therapeutic cancer vaccines Eryn Blass1 and Patrick A. Ott1,2,3,4 ✉ Abstract | Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour- specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy. Vaccines have traditionally been used for the prevention for the prediction of MHC class I (MHC I)- binding of infectious diseases; however, the ability of such agents epitopes has paved the way for the identification of to elicit and amplify antigen-specific immune responses potentially immunogenic neoepitopes.
    [Show full text]
  • Sabin Vaccine Report
    Volume VIII, Number 1 Sabin Vaccine Spring 2005 EPORT The newsletter of the Albert B. Sabin Vaccine InstituteR — dedicated to disease prevention www.sabin.org FDA Clears Human Hookworm Vaccine for Phase I Safety Trials Sabin/GW Researchers Receive Word on Investigational New Drug Status for Vaccine Clinical trials to test the safety of a gin safety trials is a major milestone for in individuals who suffer from hook- first-of-its-kind human hookworm vac- the human hookworm vaccine project,” worm infection.” cine will begin in the Washington, DC Hotez said. “It has taken an amazing Human hookworm infection is caused area in the coming weeks after the U.S. amount of our team’s effort to get us to by parasitic worms that fasten onto the Food and Drug Administration conferred the current stage of vaccine develop- inner layers of the small intestine using investigational new drug status on the ment. Of course, our ultimate goal is to their teeth-like projections and cause vaccine this past January. No current take this research to developing coun- blood loss at the attachment site. vaccine is available to prevent hook- tries where the vaccine will be tested Hookworm disease refers to the iron worm disease, which is one of the most Continued on page 4 common chronic infections of humans with an estimated 740 million cases in The village of Americaninhas, areas of rural poverty in the tropics in a rural part of Minas Gerais and subtropics. state in Brazil, is the focus of a The Human Hookworm Vaccine Ini- field study of hookworm dis- tiative (HHVI) is sponsored by the ease burden, being conducted Albert B.
    [Show full text]
  • Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach
    International Journal of Molecular Sciences Review Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach Chang-Gon Kim 1,†, Yun-Beom Sang 2,† , Ji-Hyun Lee 1 and Hong-Jae Chon 2,* 1 Yonsei Cancer Center, Department of Internal Medicine, Division of Medical Oncology, Yonsei University College of Medicine, Seoul 03722, Korea; [email protected] (C.-G.K.); [email protected] (J.-H.L.) 2 CHA Bundang Medical Center, Medical Oncology, CHA University School of Medicine, Seongnam 13497, Korea; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines. Citation: Kim, C.-G.; Sang, Y.-B.; Keywords: therapeutic cancer vaccine; combination immunotherapy; immune checkpoint inhibitor; Lee, J.-H.; Chon, H.-J. Combining tumor microenvironment Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach.
    [Show full text]
  • Vaccines Innovative
    2013 MeDiciNes iN DeVelopmeNT REPORT Vaccines A Report on the Prevention and Treatment of Disease Through Vaccines PRESENTED BY AMERICA’s biopharmACEUTICAL RESEARCH COMPANIES Nearly 300 Vaccines Are in Development; Research Focuses on Prevention and Treatment For many years, vaccines have been used • A monoclonal antibody vaccine that to successfully prevent devastating infec- targets both pandemic and seasonal tious diseases such as smallpox, measles influenza. and polio. According to data from the • A genetically-modified vaccine designed Vaccines in Development* U.S. Centers for Disease Control and for the treatment of pancreatic cancer. Prevention (CDC), 10 infectious diseases Application Submitted have been at least 90 percent eradicated • An irradiated vaccine for protection in the United States thanks to vaccines. Phase III against malaria. This has protected millions of children Phase II and families from needless illness. The development and regulatory path that these vaccine candidates face is Phase I These public health triumphs illustrate the complex. As with the development of all major contributions that vaccines have drugs, the majority of vaccines must pre- 137 made in saving countless lives around vail through years of clinical testing before the world. In the past several years, they can be approved for use by the gen- through our growing understanding of eral public. However, advances in other the molecular underpinnings of disease scientific fields, such as genomics and and technological advances, many new manufacturing technologies, are becom- vaccines have been developed, including ing increasingly useful in the development one against human papillomavirus (HPV) of new vaccines. The continued efforts 99 infections that can lead to cervical cancer, of researchers within biopharmaceutical a vaccine to guard against the anthrax companies and across the ecosystem, virus before exposure, and a vaccine to who are pursuing new techniques and prevent pneumococcal infections in high- strategies in vaccine development, cre- risk populations.
    [Show full text]