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Lymphoma Vaccines for Active Immunotherapy of T Cell Are More Tumor Cell Lysate-Pulsed Dendritic Cells Are More Effective Than TCR Id Protein Vaccines for Active Immunotherapy of T Cell Lymphoma This information is current as of October 3, 2021. Erin Gatza and Craig Y. Okada J Immunol 2002; 169:5227-5235; ; doi: 10.4049/jimmunol.169.9.5227 http://www.jimmunol.org/content/169/9/5227 Downloaded from References This article cites 42 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/169/9/5227.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 3, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/170/10/5333.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Tumor Cell Lysate-Pulsed Dendritic Cells Are More Effective Than TCR Id Protein Vaccines for Active Immunotherapy of T Cell Lymphoma1 Erin Gatza2* and Craig Y. Okada† TCR Id protein conjugated to keyhole limpet hemocyanin (KLH) (TCR Id:KLH) and injected with a chemical adjuvant (QS-21) induces a protective, Id-specific immune response against the murine T cell lymphoma, C6VL. However, Id-based immunotherapy of C6VL has not demonstrated therapeutic efficacy in tumor-bearing mice. We report here that C6VL lysate-pulsed dendritic cells (C6VL-DC) vaccines display enhanced efficacy in both the prevention and the therapy of T cell lymphoma compared with TCR Id:KLH with QS-21 vaccines. C6VL-DC vaccines stimulated potent tumor-specific immunity that protected mice against lethal challenge with C6VL and significantly enhanced the survival of tumor-bearing mice. Tumor-specific proliferation and secretion of IFN-␥ indicative of a Th1-type immune response were observed upon ex vivo stimulation of vaccine-primed lymph node cells. Downloaded from Adoptive transfer of immune T cell-enriched lymphocytes was sufficient to protect naive recipients from lethal tumor challenge. Furthermore, CD8؉ T cells were absolutely required for tumor protection. Although C6VL-DC and control vaccines stimulated low levels of tumor-specific Ab production in mice, Ab levels did not correlate with the protective ability of the vaccine. Thus, tumor cell lysate-pulsed DC vaccines appear to be an effective approach to generate potent T cell-mediated immune responses against T cell malignancies without requiring identification of tumor-specific Ags or patient-specific Id protein expression. The Journal of Immunology, 2002, 169: 5227–5235. http://www.jimmunol.org/ cell malignancies are diverse in their composition, aggres- response against a murine T cell lymphoma, C6VL. Vaccination siveness, and response to treatment. Despite modern ther- with recombinant TCR Id protein conjugated to keyhole limpet T apies, including radiation, chemotherapy, and bone mar- hemocyanin (KLH)3 and injected with a chemical adjuvant (TCR row transplants, most patients with T cell cancers remain incurable Id:KLHϩQS-21) stimulated both humoral and cellular anti-Id re- due to disease recurrence (1). Immunotherapeutic approaches to sponses in mice. Despite Id-specific Ab production in vaccine re- treat lymphoma patients once they attain a state of minimal resid- cipients, anti-tumor immunity was primarily mediated by CD8ϩ T ual disease may reduce or delay recurrence and enhance survival cells (10, 11). In subsequent experiments vaccination of mice with (2). To date, efforts to develop immunotherapy for B and T cell adenoviral vectors containing chimeric TCR Id also stimulated by guest on October 3, 2021 lymphomas have largely focused on the use of tumor-derived id- CD8ϩ-mediated anti-tumor responses in the C6VL model (12). iotype protein as a source of defined tumor-specific epitopes. Id This approach did not result in enhanced levels of survival com- proteins expressed on B cell lymphomas have been exploited in pared with vaccination with TCR Id:KLHϩQS-21, however. We numerous murine models (3–7) as tumor-specific targets for the hypothesized that combining the potent adjuvant potential of den- development of tumor immunotherapy and have also been associ- dritic cells (DC) in stimulating cell-mediated immunity against ated with enhanced clinical outcome (8, 9). For the development of tumors with the ability to target multiple tumor-specific Ags would immunotherapeutic approaches for T cell lymphoma, the studies allow increased efficacy in the immunotherapy of T cell lymphoma have been far fewer in number, but have also concentrated on compared with TCR Id:KLHϩQS-21 vaccines. using tumor-derived Id epitopes to generate anti-tumor immunity. The use of DC in the development of effective prophylactic and Okada and colleagues (10, 11) demonstrated that vaccination with therapeutic vaccines for a variety of cancers has been the focus of tumor-derived TCR Id protein generated an effective anti-tumor intense investigation by many groups. DC have been targeted in this effort largely due to their unique ability to initiate potent pri- mary and secondary immune responses (13) and to control the type *Graduate Program in Immunology, University of Michigan Medical School, Ann of immune response that is induced (14). DC loaded with tumor- Arbor, MI 48101; and †Division of Hematology and Oncology, University of Mich- derived DNA, RNA, protein(s), or peptides have been used as an igan and Veterans Administration Ann Arbor Health Care Systems, Ann Arbor, MI 48105 efficacious vaccine in multiple murine tumor models (15–26). DC have also been effective as cellular adjuvants for B cell Id protein Received for publication June 24, 2002. Accepted for publication September 3, 2002. vaccines. Loading DC with B cell Id:KLH stimulated levels of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance anti-tumor immunity superior to Id:KLH injected with a chemical with 18 U.S.C. Section 1734 solely to indicate this fact. adjuvant (27). In patients, loading DC with B cell Id protein with 1 This work was supported in part by the Office of Research and Development, Med- ical Research Service, Department of Veterans Affairs, and a G&P Medical Research Award. E.G. was supported by National Institute of Allergy and Infectious Diseases Training Grant T32AI07413 and National Cancer Institute Training Grant 3 Abbreviations used in this paper: KLH, keyhole limpet hemocyanin; CM, complete T32CA88784. medium; DC, dendritic cells; C6VL-DC, C6VL lysate-pulsed DC; MAC, metal af- 2 Address correspondence and reprint requests to Erin Gatza, Graduate Program in finity column; MBL-2-DC, MBL-2 lysate-pulsed DC; MLF, mean log fluorescence; Immunology, University of Michigan, Veterans Administration Ann Arbor Health SI, stimulation index; S:R ratio, stimulator:responder ratio; TCR Id:KLHϩQS-21, Care Systems Research Service 11R, Ann Arbor, MI 48185. E-mail address: TCR Id conjugated to keyhole limpet hemocyanin and mixed with QS-21; VPLN, [email protected] vaccine-primed lymph nodes. Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 5228 DC-BASED IMMUNOTHERAPY OF T CELL LYMPHOMA or without carrier protein (KLH) resulted in the generation of Id- CD3, CD4, and H-2Db surface proteins (37). C6VL does not express MHC specific cellular immune responses (9, 28, 29) in addition to the class II or Fas (10). MBL-2 (H-2b) is a T cell lymphoma cell line of largely humoral immune response observed in patients receiving B C57BL/6 origin (provided by I. L. Weissman, Stanford, CA) that was used as a control T cell lymphoma lysate and a control tumor challenge. B16/ cell Id vaccines without DC. F10 (American Type Culture Collection, Manassas, VA) is a melanoma The ability to target multiple tumor Ags may increase the mag- derived from C57BL/6 mice and was used as a non-lymphoid tumor lysate nitude and diversity of anti-tumor responses, thus preventing tu- control. mor from escaping responses limited in repertoire (30). Loading Antibodies DC with proteins from tumor cell lysates may result in the pre- sentation of a broader array of tumor-specific Ags than what may mAb 124-40 (mouse IgG1␬) recognizes a determinant on the C6VL TCR ␣ be presented using Id protein (31), including multiple epitopes for -chain V region (36). mAb 2.43 (Rat IgG2b) recognizes mouse CD8.2. ϩ ϩ mAb SFR8-B6 (rat IgG2b) recognizes human HLA-Bw6. The 2.43 hy- both CD4 and CD8 T cells (32). In addition, tumor cell lysates bridoma was purchased from American Type Culture Collection. The contain agents known to induce maturation of DC (32). Mature DC SFR8-B6 hybridoma was provided by J. Parnes (Stanford, CA). mAb have an enhanced capacity to prime potent Ag-specific CTL ac- 124-40 was purified from culture supernatant over a protein A-Sepharose tivity and stimulate IFN-␥ release by CD4ϩ Th cells. column. 2.43 and SFR8-B6 were purified from serum-free hybridoma cul- ture supernatants by ammonium sulfate precipitation, followed by strong Recently, two groups have demonstrated that tumor lysate-spe- anion exchange chromatography. Ab concentrations were determined by cific cytotoxic T lymphocytes can be generated ex vivo against bicinchoninic acid assay (Pierce, Rockford, IL).
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