DOCSLIB.ORG

Phase I Trial of a Novel Intradermal Idiotype Vaccine in Patients with Advanced B-Cell Lymphoma: Specific Immune Responses Despite Profound Immunosuppression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phase I Trial of a Novel Intradermal Idiotype Vaccine in Patients with Advanced B-Cell Lymphoma: Specific Immune Responses Despite Profound Immunosuppression Research Article Phase I Trial of a Novel Intradermal Idiotype Vaccine in Patients with Advanced B-Cell Lymphoma: Specific Immune Responses Despite Profound Immunosuppression Cristina Bertinetti,1 Katja Zirlik,1 Kristina Heining-Mikesch,1 Gabriele Ihorst,2 Heide Dierbach,1 Cornelius F.Waller, 1 and Hendrik Veelken1 1Department of Hematology/Oncology and 2Center of Clinical Trials, Freiburg University Medical Center, Freiburg, Germany Abstract tic anti-lymphoma immunity in animal models (1–4). Depending on The immunoglobulin receptor of B-cell lymphomas constitutes the tumor model and the vaccine formulation, both cellular and humoral immunity may play a role in tumor rejection (5–7). a specific tumor antigen (idiotype) and a target for active immunotherapy. Encouraging results have been reported in Idiotype-specific immune responses and disappearance of phase II trials after s.c. vaccination of follicular lymphoma minimal residual disease (MRD) have been observed after idiotype patients during clinical remission with idiotype produced from immunization in follicular lymphoma patients during clinical eukaryotic cell lines and coupled to an immunogenic carrier remission (8–11). Induction of immunity was associated with macromolecule. We have developed a good manufacturing superior outcome (9, 12). Some objective tumor regressions upon protocol for rapid expression of idiotype vaccines as recombi- idiotype vaccination have also been reported (8, 13, 14). nant Fab fragments in Escherichia coli. The objectives of this With the exception of multiple myeloma and Waldenstrom’s trial were to show safety and feasibility of intradermal macrogobulinemia, where soluble idiotype protein may by purified immunization with this vaccine and to investigate whether from the patient’s serum (15, 16), idiotype vaccines from non- immune responses were induced by this immunization route. secreting lymphomas must be manufactured. Viable lymphoma cells Patients (n = 18) with advanced B-cell malignancies received from a biopsy may be fused with a myeloma cell line by somatic cell repetitive intradermal vaccinations with 0.5 to 1.65 mg hybridization followed by purification of idiotype from the culture supernatant of the resulting heterohybridoma (17). Several strategies recombinant idiotype Fab fragment mixed with lipid-based adjuvant in combination with 150 Mg granulocyte macrophage for production of recombinant idiotype protein in eukaryotic cells colony-stimulating factor s.c. at the same location. The with an appropriate expression system have been proposed (i.e., patients’ immune status was assessed by flow cytometry of expression as an IgG3 in a murine lymphoma cell line, as IgG1 in sf9 peripheral blood lymphocytes and concomitant hepatitis B insect cells, and as scFv fragment in tobacco plants; ref. 18). In vaccination. Cellular and humoral immune responses to the almost all reported clinical trials with these vaccines, the weakly vaccine were assessed by enzyme-linked immunospot and immunogenic idiotype protein was covalently coupled to the potent ELISA. Side effects of a total of 65 vaccinations were mild and immunogenic carrier molecule keyhole limpet hemocyanin (KLH). did not affect the immunization schedule. No patient developed To ease manufacturing of individual idiotype vaccines and to hepatitis B surface antibodies (anti-HBs) after two hepatitis B shorten production times, we have adapted a bacterial expression system for recombinant immunoglobulin Fab fragments to the immunizations. Of 17 evaluable patients, five developed Escherichia coli specific anti-vaccine antibodies, and eight developed anti-Fab production of recombinant idiotype vaccines in T-cell responses. T-cell reactivity was independent of the (19, 20). Stimulation of peripheral blood T cells from lymphoma cellular immune status and was idiotype specific as shown patients with such recombinant, lymphoma-derived Fab fragment by statistical regression analysis (P = 0.0024) and epitope resulted in specific, MHC class I–restricted cytotoxic activity mapping studies. Intradermal administration of uncoupled against autologous, idiotype-expressing target cells (21). Because coupling rates to KLH were too variable to fulfill good recombinant idiotype with appropriate adjuvants may over- 3 come profound clinical immunosuppression and induce manufacturing (GMP) criteria, we decided to test alternative specific immune responses. (Cancer Res 2006; 66(8): 4496-502) strategies to obtain high immunogenicity without further chemical vaccine modification. Intradermal vaccination with a reduced antigen dose has recently been shown to be equipotent to a Introduction conventional s.c. influenza vaccine, presumably due to antigen B-cell non-Hodgkin’s lymphomas (B-NHL) are clonal prolifer- delivery to professional antigen-presenting cells (APC) of the skin ations of cells expressing an identical antigen receptor. The hyper- (22). In addition, novel lipid-based adjuvants with superior variable parts of this immunoglobulin form a unique idiotype of immunogenicity, such as MF59, have been introduced into the malignant clone and represent a tumor-specific antigen. Immu- commercially available vaccines (23). Based on these advances in nization with lymphoma idiotype induces protective and therapeu- the design of vaccines against common infectious agents, we chose to apply a mixture of the recombinant idiotype with MF59 via an intradermal injection route. Because this trial tested to our Requests for reprints: Hendrik Veelken, Department of Hematology/Oncology, knowledge for the first time a drug manufactured individually Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany. in E. coli, and because significant toxicities of the intradermal Phone: 49-761-270-7176; Fax: 49-761-270-7177; E-mail: hendrik.veelken@uniklinik- freiburg.de. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-4233 3 F. Simon, unpublished observations. Cancer Res 2006; 66: (8). April 15, 2006 4496 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2006 American Association for Cancer Research. Novel Idiotype Vaccine in Advanced B-Cell Lymphoma Table 1. Patient characteristics, vaccinations, immunologic responses, and time to progression Patient Diagnosis, Gammopathy Prior treatment Prior immunotoxic Time last Remission status c stage* regimens therapy therapy/vaccination (mo) at vaccination A05 FL, IV — 6 F, R 2 >2nd PR A15 FL, IV — 1 — 13 PD A25 CLL, III — 9 F 21 PD A03 LPL, IV — 6 autoSCT, R 8 PD A26 MCL, IV — 2 — 73 PD A27 FL, IV — 7 autoSCT, R, F 1 >2nd PR A28 DLCL, III — 3 R 2 >2nd PR A51 MM, III IgGn 5 autoSCT 6 PD A83 CLL, IV — 4 autoSCT 1 PD A21 MCL, IV — 2 R 9 PD A32 MCL, IV — 1 — 43 PD A55 MM, II IgGn 4 autoSCT 4 2nd PR A60 LPL, IV IgMn 2 F 6 2nd PR A73 FL, III — 4 autoSCT, F 4 >2nd PR A75 MM IgGn 4 autoSCT 12 PD A82 FL, IV — 5 F 6 PD B07 CLL, III — 10 F, R, alloSCT 2 PD A88 CLL, III — 2 F 21 PD Abbreviations: FL, follicular lymphoma; MM, multiple myeloma; MCL, mantle cell lymphoma; LPL, lymphoplasmocytic lymphoma; DLCL, diffuse large cell lymphoma; F, fludarabine; R, rituximab; autoSCT, autologous hematopoietic stem cell transplantation; alloSCT, allogeneic SCT; PD, progressive disease; PR, partial remission; NS, not significant; ND, not done; NA, not applicable due to early disease progression; RF, rheumatoid factor. *Staging system applied: CLL, Rai; MM, Durie and Salmon; all other lymphoma types, Ann Arbor. cA complete course of radiation therapy was counted as one regimen. bThe planned dose escalation was discontinued at the third level. xNormal range for RF = 0 to 16 IU/L. k>50% cross-reactivity with control Fabs. {Patient with preexisting seropositive rheumatoid arthritis. formulation could not be excluded, we conducted a clinical phase I Treatment schedule. One vaccination consisted of an intradermal trial to show feasibility and tolerability of such a vaccination and to injection of 10 Ag/AL idiotype solution mixed 5:1 (v/v) with MF59 adjuvant investigate the immunogenicity of this idiotype vaccine. (Chiron Behring, Marburg, Germany; ref. 23). The minimum dose of idiotype protein was 0.5 mg per vaccination and was planned to be increased Patients and Methods according to the modified Fibonacci design after treatment of three patients at each dose level without relevant side effects. In addition, 150 Ag granu- Subject eligibility. In a typical phase I design, patients with B-cell locyte macrophage colony-stimulating factor (GM-CSF; molgramostim; malignancies in advanced stages that had relapsed or progressed after a Leucomax; Novartis, Nuernberg, Germany) were injected s.c. at the same full treatment course with anthracyclin- or fludarabine-containing or high- anatomic location. Vaccinations were given in weeks 0, 3, 5, and 9. dose chemotherapy with autologous stem cell transplantation were Beginning with the fourth patient enrolled, anti-HBs-negative patients enrolled after giving informed consent. Patients were at least 18 years received a standard hepatitis B vaccine (Gen-HB-Vax; Aventis Pasteur, old and had a life expectancy of at least 6 months. Exclusion criteria were Frankfurt, Germany) at the first and third idiotype vaccination. Staging severe concomitant illnesses or infections, active central nervous system according to National Cancer Institute criteria (24) with bidimensional involvement, and immunosuppressive or antineoplastic therapy (including measurement of lymphomatous masses or by quantitative
Load more

Recommended publications
  • Treatment of Patients with Malignant Lymphomas with Monoclonal Antibodies
    Bone Marrow Transplantation (2000) 25, Suppl. 2, S50–S53 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Treatment of patients with malignant lymphomas with monoclonal antibodies H Tesch, A Engert, O Manzke, V Diehl and H Bohlen Klinik I fuer Innere Medizin, Universitaet zu Koeln, Koeln, Germany Summary: Results and discussion Malignant lymphomas represent a heterogenous group of B and T cell-derived malignancies. Most lymphomas Native monoclonal antibodies are sensitive to chemo- and radiotherapy, however many patients will eventually relapse. Immunothera- Since the first description of therapy using monoclonal anti- peutic approaches including monoclonal antibodies, bodies in 1979, several phase I and II trials have been cytokines or vaccination approaches may offer an alter- initiated to evaluate both safety and antitumoral activity of native treatment of chemotherapy-resistant residual this approach. Native MoAbs can kill a tumor cell through cells especially in cases with low tumor burden or various mechanisms including complement activation, anti- residual disease following chemo- or radiotherapy. body-dependent cellular cytotoxicity (ADCC), phago- Monoclonal antibodies have been successfully applied in cytosis of antibody-coated tumor cells, inhibition of cell their native form, or coupled with radioisotopes or tox- cycle progression, and induction of apoptosis.2,3 Alterna- ins to selectively destroy lymphoma cells and promising tively, MoAbs can eliminate a tumor cell by inhibiting results in early clinical trials have been obtained. Alter- growth factor receptors or molecules involved in signal natively, bispecific antibodies and idiotypic vaccination transduction and cell proliferation. strategies are used to target autologous T cells to elimin- The group of R Levy at Stanford reported on promising ate lymphoma cells.
    [Show full text]
  • Anti-Idiotype Antibody Generation and Application in Antibody Drug Discovery
    Anti-idiotype Antibody Generation and Application in Antibody Drug Discovery Liusong Yin, PhD Senior Scientist, Group Leader Antibody Discovery, Antibody Department, GenScript [email protected] Apr 21st, 2016 Presentation Overview Anti-idiotype antibody introduction 1 2 Anti-idiotype antibody application 3 Anti-idiotype antibody development 4 Anti-idiotype antibody case study Make Research Easy 2 Structural overview of antibodies PDB ID: 1HZH Liusong Yin, 2014, A Dissertation Make Research Easy 3 Antibody ‘-types’ Isotype (species specific)– the phenotypic variations in the constant regions of the heavy and light chains Allotype (animal specific)– the genetically determined difference in antibodies between individuals in the same species, mainly a couple AA differences in constant region Idiotype (antigen specific)– the antigen binding specificity defined by the distinctive sequence in the variable region of antibodies Make Research Easy 4 ‘-topes’ in anti-idiotype antibodies (anti-IDs) Idiotope – the antigenic determinants in or close to the complementarity determining region (CDR) in variable region Epitope Paratope Paratope – the part of an Ab that recognizes an antigen, the antigen-binding site of an Ab Epitope – the part of the antigen to which the paratope binds Anti-IDs – anti-idiotype antibodies which recognize the shared feature of idiotopes Make Research Easy 5 Different types of Anti-IDs Antigen-blocking Non-blocking Complex-specific Anti-ID Drug Target Anti-ID Anti-ID Antibody drug Antibody drug Antibody drug
    [Show full text]
  • In the United States Court of Federal Claims OFFICE of SPECIAL MASTERS Filed: July 28, 2020
    In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS Filed: July 28, 2020 * * * * * * * * * * * * * * * * MICHAEL PAVAN, next friend of * J.P., a minor, * PUBLISHED * Petitioner, * No. 14-60V * v. * Special Master Gowen * SECRETARY OF HEALTH * Entitlement; Significant AND HUMAN SERVICES, * Aggravation; Varicella; * Chronic Inflammatory Respondent. * Demyelinating Polyneuropathy * * * * * * * * * * * * * * * * (“CIDP”). Scott W. Rooney, Nemes Rooney P.C., Farmington Hills, MI, for petitioner. Kyle E. Pozza, United States Department of Justice, Washington, DC, for respondent. DECISION1 On January 24, 2014, Michael Pavan (“petitioner”), as next friend of J.P., a minor, filed a petition in the National Vaccine Injury Compensation Program.2 Petitioner alleges that as a result of J.P. receiving the varicella vaccination on January 28, 2011, he suffered a significant aggravation of his Chronic Inflammatory Demyelinating Polyneuropathy (“CIDP”). Amended Petition at ¶¶ 4, 5, & 16 (ECF No. 26); Petitioner’s (“Pet.”) Post-hearing Brief at 2 (ECF No. 151). Based on a full review of the evidence and testimony presented, I find that petitioner has not established by a preponderance of the evidence that the varicella vaccination significantly aggravated J.P.’s CIDP and therefore, compensation must be denied and the petition dismissed. 1 In accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 (2012), because this opinion contains a reasoned explanation for the action in this case, this opinion will be posted on the website of the United States Court of Federal Claims. This means the opinion will be available to anyone with access to the internet. As provided by 42 U.S.C.
    [Show full text]
  • Idiotype-Recognizing T Helper Cells That Are Not Idiotype Specific*
    IDIOTYPE-RECOGNIZING T HELPER CELLS THAT ARE NOT IDIOTYPE SPECIFIC* BY MARY McNAMARA AND HEINZ KOHLER From the Department of Molecular Immunology, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, NY 14263 The network hypothesis (1) postulates that B and T cells interact via comple- mentary idiotypic structures (2). This assumption creates a satisfying symmetry in the immune system by which both compartments would use similar receptor structures encoded by a single pool of variable genes. Experimental support for the sharing of idiotypes between B and T cells has been substantial (3-6). Most of this evidence comes from the demonstration that an antiidiotype antibody functionally interacts with T cells or can bind to T cells or T cell factors. These findings, however, do not prove that T cell receptors or factors use the same genes as B cells. On the contrary, the recent failure to detect active gene rearrangements in specific T cell clones (7, 8) indicates that T cells use other than Ig genes (9). One approach to studying T cell receptors is to analyze their specificity and compare it with the specificity of B cells for the same determinant. With respect to the T-B interaction in the immune network, a comparative analysis of how B and T cells recognize idiotypes would address the question of T cell receptor specificity. In a previous study we found (10) that T helper cells which recognize idiotypes as carriers for a hapten-specific antibody response recognize the TEPC-15 (T 15) 1 proteins and MOPC-167 (M 167) equally well.
    [Show full text]
  • Anti-Idiotypic Agonistic Antibodies: Candidates for the Role of Universal Remedy
    antibodies Review Anti-Idiotypic Agonistic Antibodies: Candidates for the Role of Universal Remedy Aliya K. Stanova 1, Varvara A. Ryabkova 1 , Sergei V. Tillib 2,3, Vladimir J. Utekhin 1, Leonid P. Churilov 1,4,* and Yehuda Shoenfeld 1,5 1 Department of Pathology and Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, 199034 Saint Petersburg, Russia; [email protected] (A.K.S.); [email protected] (V.A.R.); [email protected] (V.J.U.); [email protected] (Y.S.) 2 Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] 3 Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia 4 Saint Petersburg Research Institute of Phthisiopulmonology, 191036 Saint Petersburg, Russia 5 Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Tel Aviv University School of Medicine, Tel-Hashomer, Ramat Gan 52621, Israel * Correspondence: [email protected] Received: 30 April 2020; Accepted: 26 May 2020; Published: 28 May 2020 Abstract: Anti-idiotypic antibodies (anti-IDs) were discovered at the very beginning of the 20th century and have attracted attention of researchers for many years. Nowadays, there are five known types of anti-IDs: α, β, γ, ", and δ. Due to the ability of internal-image anti-IDs to compete with an antigen for binding to antibody and to alter the biologic activity of an antigen, anti-IDs have become a target in the search for new treatments of autoimmune illnesses, cancer, and some other diseases. In this review, we summarize the data about anti-IDs that mimic the structural and functional properties of some bioregulators (autacoids, neurotransmitters, hormones, xenobiotics, and drugs) and evaluate their possible medical applications.
    [Show full text]
  • Targeting Lymphoma with Precision Using Semisynthetic Anti-Idiotype Peptibodies
    Targeting lymphoma with precision using semisynthetic anti-idiotype peptibodies James Torchiaa, Kipp Weiskopfa, and Ronald Levya,1 aDepartment of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305 Contributed by Ronald Levy, March 16, 2016 (sent for review December 14, 2015; reviewed by Sherie Morrison and Thomas Waldman) B-cell lymphomas express a functionally active and truly tumor- peptides can cluster BCR and trigger signaling that results in specific cell-surface product, the variable region of the B-cell apoptosis of lymphoma cells in vitro (17). Because they can be receptor (BCR), otherwise known as idiotype. The tumor idiotype produced rapidly and inexpensively by solid-phase synthesis, idi- differs, however, from patient to patient, making it a technical otype-binding peptides might represent a practical anti-idiotype challenge to exploit for therapy. We have developed a method of therapy; however, they are cleared quickly from serum, as is typ- targeting idiotype by using a semisynthetic personalized thera- ical for small peptides, and are therefore not sufficient to induce peutic that is more practical to produce on a patient-by-patient tumor clearance in vivo. To overcome this limitation, we designed basis than monoclonal antibodies. In this method, a small peptide a system to effect a chemical fusion between idiotype-binding with affinity for a tumor idiotype is identified by screening a library, peptides and a recombinant Ig Fc domain, yielding a semisynthetic chemically synthesized, and then affixed to the amino terminus of a peptibody (Fig. 1B). This modular design allows for the synthetic premade IgG Fc protein. We demonstrate that the resultant semi- production of the patient-specific oligopeptide and bulk biologic synthetic anti-idiotype peptibodies kill tumor cells in vitro with production of the patient-invariant biologic Fc domain.
    [Show full text]
  • Anti-Idiotype Antibodies: Powerful Tools for Antibody Drug Development
    Anti-Idiotype Antibodies: Powerful Tools for Antibody Drug Development Michelle Parker, Ph.D. [email protected] Table of Contents 1 What is an Anti-Idiotype Antibody? 2 Anti-Idiotype Antibody Applications 3 Obstacles & Solutions to the Generation of Anti-Idiotype Abs 4 Downstream Assay Development 5 Features of GenScript’s Anti-Idiotype Antibody Services 6 GenScript Anti-Idiotype Antibody Packages Make Research Easy 2 Antibody: Structure and Function Antibody (Ab): Recognition proteins found in the serum and other bodily fluids of vertebrates that react specifically with the antigens that induced their formation. Overall structure: • 2 identical light chains (blue) • 2 identical heavy chains (green/purple) Variable regions and constant regions 5 classes of Abs: • IgG, IgA, IgM, IgD, IgE • All contain either λ or κ light chains • Biological effector functions are mediated by the C domain Chemical structure explains 3 functions of Abs: 1. Binding versatility 2. Binding specificity 3. Biological activity Make Research Easy 3 Antibody Binding Regions Idiotope – the antigenic determinants in or close to the variable portion of an antibody (Ab) Paratope – the part of an Ab that recognizes an antigen, the antigen-binding site of an Ab or complementarity determining region (CDR) Epitope – the part of the antigen to which the paratope binds Make Research Easy 4 Anti-Idiotype Antibodies Anti-idiotype antibodies (Anti-IDs) – Abs directed against the paratope (or CDR region) of another Ab Hypervariable regions (or the idiotype
    [Show full text]
  • Unresolved Issues in Theories of Autoimmune Disease Using Myocarditis As a Framework
    Journal of Theoretical Biology 375 (2015) 101–123 Contents lists available at ScienceDirect Journal of Theoretical Biology journal homepage: www.elsevier.com/locate/yjtbi Unresolved issues in theories of autoimmune disease using myocarditis as a framework Robert Root-Bernstein a,1, DeLisa Fairweather b,n a Michigan State University, Department of Physiology, 2174 Biomedical and Physical Sciences Building, East Lansing, MI 48824, USA b Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 N. Wolfe Street, Room E7628, Baltimore, MD 21205, USA HIGHLIGHTS Clinical and experimental evidence support some aspects of all theories. Critical comparative studies differentiating between theories and models needed. Theories monocausal but animal models suggest multi-factorial cause of disease. Theories do not adequately explain adjuvant, innate immunity or sex differences. New synthetic theory needed integrating anomalies, innate and adaptive immunity. article info abstract Article history: Many theories of autoimmune disease have been proposed since the discovery that the immune system Received 10 July 2014 can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen Received in revised form theory, T cell bypass, T cell–B cell mismatch, epitope spread or drift, the bystander effect, molecular 10 November 2014 mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically Accepted 20 November 2014 review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All Available online 4 December 2014 theories share the common assumption that autoimmune diseases are triggered by environmental Keywords: factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are Autoimmune disease theories and modeling unifactorial assuming single-agent causation of disease.
    [Show full text]
  • Human Anti-Idiotype Antibodies in Cancer Patients
    Proc. Nati. Acad. Sci. USA Vol. 81, pp. 216-219, January 1984 Immunology Human anti-idiotype antibodies in cancer patients: Is the modulation of the immune response beneficial for the patient? (internal image of antigen/gastrointestinal cancer/monoclonal antibody) HILARY KOPROWSKI*, DOROTHEE HERLYN*, MICHAEL LUBECK*, ELAINE DEFREITAS*, AND HENRY F. SEARSt *The Wistar Institute, 36th and Spruce Streets, Philadelphia, PA 19104; and tAmerican Oncologic Hospital, Fox Chase Cancer Center, Central and Shellmire Avenues, Philadelphia, PA 19111 Communicated by John R. Brobeck, August 31, 1983 ABSTRACT Inoculation of human subjects with mouse (8). When these animals were challenged with T. rhode- monoclonal antibody results in the production of anti-idiotype siense, specific idiotype appeared in all animals, some of antibody that reacts with the binding site of the monoclonal which had the specific idiotype even before challenge. antibody. This reaction is hapten-inhibited, suggesting that an In the present paper, we describe the development of anti- internal image of the antigen is produced by the anti-idiotype Id in sera of patients with gastrointestinal cancer who were response. The anti-idiotype antibody isolated from sera of treated with mouse mAb. Furthermore, we show that bind- three patients showed significant crossreactivity. Patients who ing between the anti-Id and mAb can be inhibited by hapten. developed the anti-idiotype antibody improved clinically and This suggests that the anti-Id is the internal image of the anti- had long remission from their disease. The possible presence of gen expressed by the cancer cells. Finally, we discuss these the internal image of cancer antigen on the human immuno- findings in relation to the outcome of mAb treatment of gas- globulin molecule may change the conditions under which the trointestinal cancer.
    [Show full text]
  • Anti-Idiotype Antibodies in Cancer Treatment
    Oncogene (2007) 26, 3594–3602 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Anti-idiotype antibodies in cancer treatment ALo´ pez-Dı´ az de Cerio, N Zabalegui, M Rodrı´ guez-Calvillo, S Inoge´ s and M Bendandi Lab of Immunotherapy, Oncology Division, Center for Applied Medical Research and Cell Therapy Area, University Clinic, University of Navarra, Pamplona, Spain As a cancer immunotherapy tool, idiotypes (Ids) have been tiny amount of them normally present in any individual used in different ways over the last three decades, is insufficient to elicit self-tolerance, whereas allotopes depending on the actual human tumor cell target.It all can be also recognized as foreign, but rather because started with passive, monoclonal, anti-Id antibody treat- they are not shared by different individuals (Bendandi, ment of B-cell lymphoma, a setting in which results were 2001). To date, the patient-specific Id borne by a tantalizing, but logistics unsustainable.It then moved number of different B-cell lymphoma subtypes is the toward the development of anti-Id vaccines for the sole, complete, tumor-specific antigen we know (Bend- treatment of the same tumors, a setting in which we have andi, 2004). recently provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine.Meanwhile, it also expanded in the direction of Id-based immunotherapy strategies for the treatment of exploiting the antigenic mimicry of some Ids with Id- cancer unrelated, tumor-associated antigens for the immunother- The most obvious application of such a tumor-specific apy of a number of solid tumors, a setting in which clinical antigen would be of course that consisting in targeting it results are still far from being consolidated.All in all, over by means of therapeutic antibodies.
    [Show full text]
  • Genetic Fusion of Chemokines to a Self Tumor Antigen Induces Protective, T-Cell Dependent Antitumor Immunity
    © 1999 Nature America Inc. • http://biotech.nature.com RESEARCH Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity Arya Biragyn, Kenji Tani1, Michael C. Grimm1, Steven Weeks, and Larry W. Kwak2* Science Application International Corporation, National Cancer Institute, Frederick, MD 21702. 1Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702. 2Department of Experimental Transplantation and Immunology, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892. *Corresponding author (e-mail: [email protected]). Received 24 September 1998; accepted 29 December 1998 We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotac- tic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv–chemokine fusion proteins elicit- ed chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two inde- pendent models, vaccination with DNA constructs encoding the corresponding fusions generated supe- rior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen pre- http://biotech.nature.com senting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruit- • ment of APC to tumor by the chemokine.
    [Show full text]
  • Regulation of Natural Antiallotype Antibody Responses by Idiotype Network-Induced Auto- Antiidiotypic Antibodies*
    REGULATION OF NATURAL ANTIALLOTYPE ANTIBODY RESPONSES BY IDIOTYPE NETWORK-INDUCED AUTO- ANTIIDIOTYPIC ANTIBODIES* BY L. SCOTT RODKEY AND FRANK L. ADLER From the Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, Houston, Texas 77025; and Division of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 Immunoglobulin (Ig) idiotypes have been the focus of intense study since they were first recognized by Kunkel et al. (1) and by Oudin and Michel (2) in 1963. Idiotypic epitopes may be involved in the complex array of self-limiting regulatory mechanisms that the immune system imposes upon itself. Regulation at the level of idiotype recognition has been postulated by Niels Jerne (3) to be a fundamental specificity- associated immunoregulatory system capable of controlling immune responses at both the afferent and efferent limbs. Idiotype network interactions have been shown to involve both the B cell and T cell compartments (4). Cosenza et al. (5) showed that helper T cells can express idiotypes and Hetzelberger and Eichmann (6), Eichmann et al. (7), and Bona (8) have shown that helper T cells can express antiidiotypic specificity. Suppressor T cells can express idiotypes as shown by Lewis and Goodman (9) and are also capable of expressing antiidiotype specificity as shown by Bona and Paul (10). T cells mediating delayed-type hypersensitivity have also been shown to express idiotopes (11). The allotypic markers on rabbit Ig have been used productively to obtain basic information on Ig structure, function, and regulation. Early work on the sharing of V- gene products by H-chains of several isotypes (12), on allelic exclusion (13), and on allotype suppression (14) has provided new insights and inspired continuing investi- gations.
    [Show full text]