DOCSLIB.ORG

A Phase I/II Trial Comparing Autologous Dendritic Cell Vaccine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Phase I/II Trial Comparing Autologous Dendritic Cell Vaccine Sarivalasis et al. J Transl Med (2019) 17:391 https://doi.org/10.1186/s12967-019-02133-w Journal of Translational Medicine PROTOCOL Open Access A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma Apostolos Sarivalasis1, Caroline Boudousquié1, Klara Balint1,5, Brian J. Stevenson2, Philippe O. Gannon1, Emanuela Marina Iancu1, Laetitia Rossier1,5, Silvia Martin Lluesma1,5, Patrice Mathevet3, Christine Sempoux4, George Coukos1,5, Urania Dafni6, Alexandre Harari1,5, Michal Bassani‑Sternberg1,5† and Lana E. Kandalaft1,5*† Abstract Background: Most ovarian cancer patients are diagnosed at a late stage with 85% of them relapsing after surgery and standard chemotherapy; for this reason, new treatments are urgently needed. Ovarian cancer has become a candidate for immunotherapy by reason of their expression of shared tumor‑associated antigens (TAAs) and private mutated neo‑ antigens (NeoAgs) and the recognition of the tumor by the immune system. Additionally, the presence of intraepithelial tumor infltrating lymphocytes (TILs) is associated with improved progression‑free and overall survival of patients with ovarian cancer. The aim of active immunotherapy, including vaccination, is to generate a new anti‑tumor response and amplify an existing immune response. Recently developed NeoAgs‑based cancer vaccines have the advantage of being more tumor specifc, reducing the potential for immunological tolerance, and inducing robust immunogenicity. Methods: We propose a randomized phase I/II study in patients with advanced ovarian cancer to compare the immunogenicity and to assess safety and feasibility of two personalized DC vaccines. After standard of care surgery and chemotherapy, patients will receive either a novel vaccine consisting of autologous DCs pulsed with up to ten peptides (PEP‑DC), selected using an agnostic, yet personalized, epitope discovery algorithm, or a sequential combi‑ nation of a DC vaccine loaded with autologous oxidized tumor lysate (OC‑DC) prior to an equivalent PEP‑DC vaccine. All vaccines will be administered in combination with low‑dose cyclophosphamide. This study is the frst attempt to compare the two approaches and to use NeoAgs‑based vaccines in ovarian cancer in the adjuvant setting. Discussion: The proposed treatment takes advantage of the benefcial efects of pre‑treatment with OC‑DC prior to PEP‑DC vaccination, prompting immune response induction against a wide range of patient‑specifc antigens, and amplifcation of pre‑existing NeoAgs‑specifc T cell clones. Trial registration This trial is already approved by Swissmedic (Ref.: 2019TpP1004) and will be registered at http://www. clini caltr ials.gov before enrollment opens. *Correspondence: [email protected] †Michal Bassani‑Sternberg and Lana E. Kandalaft are co‑last authors 1 Department of Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sarivalasis et al. J Transl Med (2019) 17:391 Page 2 of 10 Keywords: Ovarian cancer, Dendritic cell vaccine, Neoantigen, Neoepitope, Cancer immunotherapy, Cyclophosphamide Background extensively used for clinical therapies against malignan- Ovarian cancer (OC) is the primary cause of gynecologic cies [21]. Unfortunately, DC vaccines have demonstrated cancer-related deaths, with more than 300,000 expected limited efcacy in patients with advanced recurrent dis- new cases, and more than 190,000 estimated deaths ease [22]. Some promising results however suggest a need worldwide in 2020 [1]. New treatment approaches for for further optimization, including combination of difer- ovarian cancer care are urgently needed, as current thera- ent immunotherapy technologies and multiple antigens. pies, including cytoreductive surgery and platinum-based Key factors leading to the poor immune response in chemotherapy, do not cure most patients with advanced ovarian cancer include lack of well-characterized tumor epithelial ovarian cancer [2]. antigens, molecular heterogeneity, selective tumor anti- Te host immune system can recognize and target gen-loss (immuno-editing) and the immunosuppressive ovarian cancer [3], in which a variety of tumor-associated nature of the tumor microenvironment [23]. When vac- antigens (TAAs) have been demonstrated (HER-2/neu cines target defned non-mutated self-antigens or shared [4]; p53 [5, 6]; the folate binding protein [7], sialyated antigens that are overexpressed in the tumor, vaccine ef- TN [8], MUC-1 [9], NY-ESO-1 [10] or mesothelin [11] cacy is often low because T cell reactivity to self-antigens among others). Furthermore, patients presenting TILs is naturally reduced due to central tolerance [24]. Alter- in their ovarian cancer tissue show longer progression- natively, neoantigens (NeoAgs) that arise from somatic free and overall survival (PFS and OS) [3], indicating that DNA alterations as a result of genetic instability are can- tumor growth is under the surveillance of the immune cer-specifc and can be strongly immunogenic [25]. Neo- system, and suggesting that ovarian cancer is a good can- Ags are likely to be efective targets for tumor infltrating didate for immunotherapy [12]. Nevertheless, the efcacy T cells and can lead to successful immunotherapy treat- of immunotherapy may be decreased by the involvement ments [26], hence synthetic vaccines targeting patient- of various mechanisms of immune evasion in the tumor specifc NeoAgs can display increased efcacy against microenvironment including high expression of PD-L1 tumors with moderate or high mutation load. Tree [13], production of IDO [14], recruitment of regulatory recent phase I studies using personalized NeoAg-based T-cells (Tregs) [15, 16], or local and systemic dysfunction vaccines reported immunogenicity and interesting clini- of plasmacytoid dendritic cells (pDCs) [17]. cal safety and efcacy results [27–30]. Cancer vaccines Whole tumor lysate vaccines Cancer vaccines are intended to “educate” the patient’s An alternative source of personalized antigens is the own immune system to generate efector T-cells spe- whole tumor lysate. In the case of ovarian cancer, tumor cifcally for tumor cells to be detected and destroyed. A cells can be easily recovered by cytoreductive surgery tailored cancer vaccine aims to target multiple patient- and tumor antigens can be obtained directly from the specifc tumor antigens and reduce side-efects by pro- patient’s own tumor cells by preparing a tumor lysate that tecting normal tissue and keeping tumors under immune contains both the TAAs and the private NeoAg without memory regulation for as long as possible [18]. Den- the hurdles of target identifcation and preparation [31]. dritic cell (DC)-based vaccines are a particularly attrac- Te immunogenicity of whole-tumor antigen vaccines tive option for immunotherapy, due to their low toxicity can be enhanced by diferent tumor lysate preparation profle, lack of invasive procedures and their potential to methods [31, 32]. During the fnal culture stage, tumor induce long-term efects through immunological mem- lysate is loaded onto the DCs and then the DC vac- ory [19]. DCs are unique immune cells responsible for cine is presented to the immune system via intranodal processing and presenting cancer antigens, and are capa- injection(s). Te advantage of these whole tumor vac- ble of initiating and regulating both innate and adaptive cines is that they target a whole range of antigens thus immunity [20]. DCs can present endogenous antigens reducing the chance of tumor escape compared to single as human leukocyte antigen (HLA) class I peptides and epitope vaccines. Tey are independent of HLA type and exogenous antigens as either HLA class II peptides or consist of epitopes for CD8+ cytotoxic T-cells (CTLs) HLA class I peptides by cross presentation, thus efec- and CD4+ T helper (T) cells, leading to a more integral tively inducing antigen-driven T-cell responses. Mono- immune response [33]. Previous studies with DC vac- cyte-derived human DCs pulsed with TAAs have been cines loaded with whole tumor lysate have already dem- onstrated that patients with measurable disease, in cases Sarivalasis et al. J Transl Med (2019) 17:391 Page 3 of 10 such as non-Hodgkin’s lymphoma [34], melanoma [35], NeoAgs in ovarian cancer or renal cancer [36], may obtain clinical beneft. We also Early preclinical evidence suggested that ovarian can- reported previously on a vaccine generated using autol- cer was unsuitable for NeoAg-specifc vaccination [41]. ogous monocyte-derived DCs pulsed with autologous Subsequent analysis of human ovarian cancer speci- tumor lysate produced from tumor tissue dissociated into mens, however, indicated that ovarian cancer tissues single cells, oxidized and lysed using freeze–thaw cycles
Load more

Recommended publications
  • Therapeutic PD-1 Pathway Blockade Augments with Other Modalities of Immunotherapy to Prevent Immune Decline in Ovarian Cancer
    Author Manuscript Published OnlineFirst on August 23, 2013; DOI: 10.1158/0008-5472.CAN-13-1550 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Therapeutic PD-1 Pathway Blockade Augments with other Modalities of Immunotherapy to Prevent Immune Decline in Ovarian Cancer Jaikumar Duraiswamy1, Gordon J. Freeman2 and George Coukos1,3* 1Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, PA, USA 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 3Department of Oncology and Ludwig Center for Cancer Research, University Hospital of Lausanne, Switzerland Running Title: PD-1 blockade restores immune function in ovarian cancer *Correspondence: Dr. George Coukos MD, PhD Email: [email protected] Abbreviations: ID8, ovarian cancer model; TIL, tumor-infiltrating lymphocytes; PD-1, programmed death-1; PD-L, programmed death-1 ligands; TAM, tumor associated macrophages; DC, dendritic cells; MDSC, myeloid derived suppressor cells; Tregs, Foxp3+CD4+CD25+T cells; ID8-GVAX or ID8-FVAX, ID8 tumor cells transduced to express GM-CSF or Flt3-ligand Words in text (excluding references): 5493 Number of Figures: 7 Number of supplementary figures: 8 References: 56 1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 23, 2013; DOI: 10.1158/0008-5472.CAN-13-1550 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The tumor microenvironment mediates induction of the immunosuppressive programmed death-1 (PD-1) pathway, targeted interventions against which can help restore antitumor immunity.
    [Show full text]
  • Characterization of the CCL21-Mediated Melanoma-Specific Immune Responses and in Situ Melanoma Eradication
    1755 Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication Laura Novak, Olga Igoucheva, Stephanie Cho, Introduction and Vitali Alexeev The incidence of cutaneous malignant melanoma is increasing at a faster rate than any other cancer, both Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, globally and in the United States (1). Immunotherapy has Pennsylvania emerged as one of the most promising treatments of this melanocytic malignancy. Various vaccine therapies to achieve immune-based melanoma rejection have been Abstract successfully tested in preclinical animal models and several Previous studies have shown that secondary lymphoid clinical trials. However, clinical studies have shown that chemokine, CCL21, can be used for modulation of tumor- existing therapeutic approaches are generally ineffective or specific immune responses. Here, using B16F0 melanoma prohibitively expensive. cells stably expressing CCL21 under the control of Recently, chemokines have attracted considerable interest cytomegalovirus and ubiquitin promoters, we showed that within the field of tumor immunotherapy. Chemokines are CCL21-activated immune responses depend on the small proteins that are involved in immune and inflamma- amount of melanoma-derived chemokine, which, in turn, tory responses. One of them, secondary lymphoid chemo- depends on the strength of the promoter. We showed that kine CCL21 (also known as SLC or C6kine), is prominently ubiquitin promoter–driven expression of CCL21 enabled expressed in high endothelial venules and within T-cell + À + massive infiltration of tumors with CD4 CD25 , CD8 zones of secondary lymphoid organs, where it recruits + T lymphocytes, and CD11c dendritic cells, and conse- naive T cells and antigen-presenting cell (APC), such as quent activation of cellular and humoral immune dendritic cell, via a mechanism known as chemoattraction.
    [Show full text]
  • Cancer Vaccines in Ovarian Cancer: How Can We Improve?
    biomedicines Review Cancer Vaccines in Ovarian Cancer: How Can We Improve? Silvia Martin Lluesma 1, Anita Wolfer 2, Alexandre Harari 1 and Lana E. Kandalaft 1,3,* 1 Center of Experimental Therapeutics, Ludwig Center for Cancer Res, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; [email protected] (S.M.L.); [email protected] (A.H.) 2 Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; [email protected] 3 Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA * Correspondence: [email protected]; Tel.: +41-(0)21-314-7823 Academic Editor: Ghaith Bakdash Received: 21 March 2016; Accepted: 19 April 2016; Published: 3 May 2016 Abstract: Epithelial ovarian cancer (EOC) is one important cause of gynecologic cancer-related death. Currently, the mainstay of ovarian cancer treatment consists of cytoreductive surgery and platinum-based chemotherapy (introduced 30 years ago) but, as the disease is usually diagnosed at an advanced stage, its prognosis remains very poor. Clearly, there is a critical need for new treatment options, and immunotherapy is one attractive alternative. Prophylactic vaccines for prevention of infectious diseases have led to major achievements, yet therapeutic cancer vaccines have shown consistently low efficacy in the past. However, as they are associated with minimal side effects or invasive procedures, efforts directed to improve their efficacy are being deployed, with Dendritic Cell (DC) vaccination strategies standing as one of the more promising options. On the other hand, recent advances in our understanding of immunological mechanisms have led to the development of successful strategies for the treatment of different cancers, such as immune checkpoint blockade strategies.
    [Show full text]
  • Vaccination with NY-ESO-1 Protein and Cpg in Montanide Induces Integrated Antibody/Th1 Responses and CD8 T Cells Through Cross-Priming
    Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming Danila Valmori*†, Naira E. Souleimanian*, Valeria Tosello*, Nina Bhardwaj‡, Sylvia Adams‡, David O’Neill‡, Anna Pavlick‡, Juliet B. Escalon‡, Crystal M. Cruz‡, Angelica Angiulli‡, Francesca Angiulli‡, Gregory Mears§, Susan M. Vogel§, Linda Pan¶, Achim A. Jungbluth¶, Eric W. Hoffmann¶, Ralph Venhaus¶, Gerd Ritter¶, Lloyd J. Old¶ʈ, and Maha Ayyoub*† *Ludwig Institute Clinical Trial Center, Columbia University, New York, NY 10032; ‡New York University School of Medicine, New York, NY 10016; §Division of Medical Oncology, Columbia University Medical Center, New York, NY 10032; and ¶Ludwig Institute for Cancer Research, New York, NY 10158 Contributed by Lloyd J. Old, April 12, 2007 (sent for review February 22, 2007) The use of recombinant tumor antigen proteins is a realistic helper type 1 (Th1)-type immunity (7). In humans, they can approach for the development of generic cancer vaccines, but the directly activate B lymphocytes and plasmacytoid dendritic cells ,(potential of this type of vaccines to induce specific CD8؉ T cell and also indirectly activate myeloid dendritic cells (mDCs responses, through in vivo cross-priming, has remained unclear. In increasing antigen cross-presentation and stimulating adaptive this article, we report that repeated vaccination of cancer patients immune responses (8–10). with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG In this study, we have assessed the immune response elicited ODN 7909, a potent stimulator of B cells and T helper type 1 by repeated vaccination with a NY-ESO-1 recombinant protein (Th1)-type immunity, resulted in the early induction of specific (rNY-ESO-1) administered with CpG 7909 in a water–oil emul- integrated CD4؉ Th cells and antibody responses in most vacci- sion with Montanide ISA-51.
    [Show full text]
  • Is There a Role for Radiation Therapy and Immunotherapy?
    IS THERE A ROLE FOR RADIATION THERAPY AND IMMUNOTHERAPY? S. Lewis Cooper, M.D. Assistant Professor, Radiation Oncology Hollings Cancer Center Medical University of South Carolina (MUSC) DISCLOSURE Abney Clinical Scholar OBJECTIVES • Review mechanisms of immune escape by cancer cells • Review radiation effects on the immune system • Review current strategies to combine RT and immunotherapy • IL-2 • Dendritic cell production • Tumor antigen vaccine • CTLA-4 antibody/PD-1antibody • TLR agonist • TGF-β antibody CANCER IMMUNOEDITING CD8+ NKT CD8+ T cell cell T cell • Three phases: NK CD4+ T cell • Elimination – Innate and adaptive immune systems detect INF-γ IL-12 and destroy developing tumor before it is clinically TNF TRAIL apparent. Mφ Perforin γδ T DC CD8+ IL-12 cell T cell CD4+ INF-γ T cell • Equilibrium – The immune system maintains residual tumor cells in a functional state of dormancy. Protection Mφ CD8+ NK T cell TGF-β PD-L1 IL-6, IL-10 • Escape – Tumor cells that aquire the ability to escape Galactin-1 IDO Antigen Loss immune recognition and destruction emerge as growing MHC Loss tumors. CD8+ T cell CTLA-4 CTLA-4 PD-1 PD-1 CD8+ MDSC Treg Science . 2011;331:1565-70 T cell MECHANISMS OF ESCAPE • Loss of tumor antigen expression 1. Tumor cells that do not express strong rejection antigens. 2. Loss of MHC class 1 proteins that present these antigens 3. Loss of antigen processing function • Immunosuppresive state in the tumor microenvironment 1. Production of immunosuppresive cytokines (VGEF, TGF-β, galectin, IDO) 2. Recruitment of immunosuppressive cells (Treg, MDSCs, TAMs) Science .
    [Show full text]
  • Transfer of Vaccine-Primed and Costimulated Autologous T Cells Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Combin
    Published OnlineFirst February 11, 2014; DOI: 10.1158/1078-0432.CCR-13-2817 Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells Aaron P. Rapoport, Nicole A. Aqui, Edward A. Stadtmauer, et al. Clin Cancer Res 2014;20:1355-1365. Published OnlineFirst February 11, 2014. Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-2817 Supplementary Access the most recent supplemental material at: Material http://clincancerres.aacrjournals.org/content/suppl/2014/02/25/1078-0432.CCR-13-2817.DC1.html Cited Articles This article cites by 50 articles, 27 of which you can access for free at: http://clincancerres.aacrjournals.org/content/20/5/1355.full.html#ref-list-1 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected]. Permissions To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from clincancerres.aacrjournals.org on March 4, 2014. © 2014 American Association for Cancer Research. Published OnlineFirst February 11, 2014; DOI: 10.1158/1078-0432.CCR-13-2817 Clinical Cancer Cancer Therapy: Clinical Research Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells Aaron P. Rapoport1, Nicole A.
    [Show full text]
  • Selective Tumor Antigen Vaccine Delivery to Human CD169+ Antigen-Presenting Cells Using Ganglioside-Liposomes
    Selective tumor antigen vaccine delivery to human CD169+ antigen-presenting cells using ganglioside-liposomes Alsya J. Affandia, Joanna Grabowskaa, Katarzyna Oleseka, Miguel Lopez Venegasa,b, Arnaud Barbariaa, Ernesto Rodrígueza, Patrick P. G. Muldera, Helen J. Pijffersa, Martino Ambrosinia, Hakan Kalaya, Tom O’Toolea, Eline S. Zwarta,c, Geert Kazemierc, Kamran Nazmid, Floris J. Bikkerd, Johannes Stöckle, Alfons J. M. van den Eertweghf, Tanja D. de Gruijlf, Gert Stormg,h, Yvette van Kooyka,b, and Joke M. M. den Haana,1 aDepartment of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; bDC4U, 3621 ZA Breukelen, The Netherlands; cDepartment of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; dDepartment of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam and University of Amsterdam, 1081 LA Amsterdam, The Netherlands; eInstitute of Immunology, Centre for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; fDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; gDepartment of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, The Netherlands; and hDepartment of Biomaterials, Science and Technology, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands Edited by Peter Cresswell, Yale University, New Haven, CT, and approved September 3, 2020 (received for review April 2, 2020) Priming of CD8+ T cells by dendritic cells (DCs) is crucial for the consuming, and costly process, research is shifting toward tar- generation of effective antitumor immune responses.
    [Show full text]
  • Cr75th Anniversary Commentary
    CR 75th Anniversary Commentary Special Lecture Combine and Conquer: Double CTLA-4 and PD-1 Blockade Combined with Whole Tumor Antigen Vaccine Cooperate to Eradicate Tumors Krisztian Homicsko1,2,3, Jaikumar Duraiswamy4, Marie-Agnes Doucey1, and George Coukos1,2 þ See related article by Duraiswamy et al., Cancer Res 2013;73: cells was approximately double among the single PD-1 (PD- þ À þ þ 3591–603. 1 CTLA-4 ) TILs relative to the double-positive (PD-1 CTLA-4 ) Cancers hijack the normal regulatory pathways of normal TILs. In addition, the single-positive TILs were the only popula- inflammatory reactions. Dysregulation of fundamental immune tion to proliferate in response to peptide, whereas the double- checkpoints is present virtually in all tumors with underlying positive population failed to proliferate. The double-positive immune recognition and is crucial in the development and main- population also expressed higher levels of additional inhibitory tenance of cancer immune tolerance. The dissection of immune receptors, such as 2B4, LAG-3, and TIM-3, and exhibited higher checkpoints showed that cancers can corrupt not one but multiple levels of CD44 and lower levels of CD62L and CD127, suggesting immune control mechanisms. Prior research showed that disin- that the double-positive TILs represent an antigen-experienced, hibiting malfunctioning immune checkpoints (1) could help in functionally exhausted effector cell phenotype. Importantly, PD-1 mounting an antitumor immunity. In light of the multiple poten- blockade alone enhanced the proliferation of single PD-1 positive tial checkpoint targets, the article by Duraiswamy and colleagues and weakly that of double-positive TILs in response to peptide.
    [Show full text]
  • Review Generation of Cellular Immune Responses to Antigenic Tumor
    CMLS, Cell. Mol. Life Sci. 57 (2000) 290–310 1420-682X/00/020290-21 $ 1.50+0.20/0 © Birkha¨user Verlag, Basel, 2000 Review Generation of cellular immune responses to antigenic tumor peptides G. A. Pietersza,*, V. Apostolopoulosb and I. F. C. McKenziea aThe Austin Research Institute, Studley Rd, Heidelberg, Victoria, 3084 (Australia) bDepartment of Molecular Biology, Scripps Research Institute, 10550 Nth Torrey Pines Rd (BCC-206), La Jolla (California 92037, USA), Fax +1 613 9287 0600, e-mail: [email protected] Received 28 June 1999; received after revision 13 October 1999; accepted 26 October 1999 Abstract. Tumor immunotherapy is currently receiving generated endogenously or given exogenously can enter close scrutiny. However, with the identification of tu- the class I pathway, but a number of other methods of mor antigens and their production by recombinant entering this pathway are also known and are discussed means, the use of cytokines and knowledge of major in detail herein. While the review concentrates on induc- histocompatibility complex (MHC) class I and class II ing cytotoxic T cells (CTLs), it is becoming increasingly presentation has provided ample reagents for use and apparent that other modes of immunotherapy would clear indications of how they should be used. At this be desirable, such as class II presentation to in- time, much attention is focused on using peptides to be duce increased helper activity (for CTL), but also presented by MHC class I molecules to both induce and activating macrophages to be effective against tumor be targets for CD8+ cytolytic T cells. Many peptides cells.
    [Show full text]
  • Mimicking Pathogens to Augment the Potency of Liposomal Cancer Vaccines
    pharmaceutics Review Mimicking Pathogens to Augment the Potency of Liposomal Cancer Vaccines Maarten K. Nijen Twilhaar 1, Lucas Czentner 2, Cornelus F. van Nostrum 2, Gert Storm 2,3,4 and Joke M. M. den Haan 1,* 1 Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; [email protected] 2 Department of Pharmaceutics, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; [email protected] (L.C.); [email protected] (C.F.v.N.); [email protected] (G.S.) 3 Department of Biomaterials, Science and Technology, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands 4 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore * Correspondence: [email protected]; Tel.: +31-20-4448058; Fax: +31-20-4448081 Abstract: Liposomes have emerged as interesting vehicles in cancer vaccination strategies as their composition enables the inclusion of both hydrophilic and hydrophobic antigens and adjuvants. In addition, liposomes can be decorated with targeting moieties to further resemble pathogenic particles that allow for better engagement with the immune system. However, so far liposomal cancer vaccines have not yet reached their full potential in the clinic. In this review, we summarize recent preclinical studies on liposomal cancer vaccines. We describe the basic ingredients for liposomal Citation: Nijen Twilhaar, M.K.; Czentner, L.; van Nostrum, C.F.; cancer vaccines, tumor antigens, and adjuvants, and how their combined inclusion together with Storm, G.; den Haan, J.M.M.
    [Show full text]
  • HLA Class I Restricted Epitopes Prediction Of
    HLA class I restricted epitopes prediction of common tumor antigens in Caucasoid and Oriental ethnic populations: implication on antigen selection for tumor specic CD8+ T cellular immunotherapy and cancer vaccine design Wei Hu Sun Yat-Sen University First Aliated Hospital Department of Liver Surgery He Meifang Sun Yat-Sen University Li Liangping ( [email protected] ) Research article Keywords: Tumor antigen, Immunotherapy, CD8+ T cell, HLA allele frequency Posted Date: June 13th, 2019 DOI: https://doi.org/10.21203/rs.2.10261/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/10 Abstract Background Tumor antigens processed and presented by human leukocyte antigen (HLA) Class I alleles are important targets in tumor immunotherapy. Clinical trials showed that CD8+ T cells specic to tumor associated antigens (TAAs) and tumor neoantigens is one of the main factors resulting tumor regression. Anity prediction of tumor antigen epitopes to HLA is an important reference index for peptide selection which is highly individualized. Results In this study, we selected 6 CTAs (cancer-testis antigens) commonly used in cancer immunotherapy and top 95 hot mutations from the Cancer Genome Atlas for analyzing potential epitopes with high anities to the common HLA class I molecules in Caucasoid and Oriental ethnic population respectively. The results showed that the overall difference of CTAs epitope prediction is small between the two populations. Meanwhile, there is a linear relationship between the CTAs peptide length and the relative overall epitope occurrence. However, the difference is bigger for epitopes prediction of missense mutations between the two populations.
    [Show full text]
  • Applying Biodegradable Particles to Enhance Cancer Vaccine Efficacy
    Immunol Res DOI 10.1007/s12026-014-8537-9 IMMUNOLOGY AT THE UNIVERSITY OF IOWA Applying biodegradable particles to enhance cancer vaccine efficacy Kawther K. Ahmed • Sean M. Geary • Aliasger K. Salem Aliasger Salem Ó Springer Science+Business Media New York 2014 Abstract One of the primary goals of our group and our collaborators here at the University of Iowa is to develop therapeutic cancer vaccines using biodegradable and biocompatible polymer-based vectors. A major advantage of using discretely packaged immunogenic cargo over non-encapsulated vaccines is that they promote enhanced cellular immunity, a key requirement in achieving antitumor activity. We discuss the importance of co-encapsulation of tumor antigen and adjuvant, with specific focus on the synthetic oligonucleotide adjuvant, cytosine–phosphate–guanine oligodeoxynucleo- tides. We also discuss our research using a variety of polymers including poly(a-hydroxy acids) and polyanhydrides, with the aim of determining the effect that parameters, such as size and polymer type, can have on prophylactic and therapeutic tumor vaccine formulation efficacy. Aside from their role as vaccine vectors per se, we also address the research currently underway in our group that utilizes more novel applications of biodegradable polymer-based particles in facilitating other types of immune-based therapies. Keywords Cancer vaccine Á Biodegradable polymer Á Poly(a-hydroxy acids) Á CpG Á PLGA Introduction metastases, and chemotherapy is often limited by its highly toxic side effects and the capacity of tumor cells to develop Cancer remains a challenging health problem and is the multidrug resistance [4]. Therefore, improved therapies are second leading cause of death in the USA [1].
    [Show full text]