This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biagi, E. Articles by Brenner, M. Search for Related Content PubMed PubMed Citation Articles by Biagi, E. Articles by Brenner, M.

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

Authors' Affiliations: ¹ Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital; ² Department of Pathology, The Methodist Hospital; and ³ Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Ettore Biagi, Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030. Phone: 832-824-4725; Fax: 832-825-4668; E-mail: ettore.biagi{at}pediatriamonza.it.

Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models.

Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/10⁶ cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations.

Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia–specific T-cell response was detected in seven patients. The mean frequencies of IFN-, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43- to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins. Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4⁺/CD25⁺/LAG-3⁺/FoxP-3⁺ immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity.

Conclusions: These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2–expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.

This article has been cited by other articles:

				S. A. Quezada, K. S. Peggs, T. R. Simpson, Y. Shen, D. R. Littman, and J. P. Allison Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma J. Exp. Med., September 1, 2008; 205(9): 2125 - 2138. [Abstract] [Full Text] [PDF]

				C. Quintarelli, G. Dotti, B. De Angelis, V. Hoyos, M. Mims, L. Luciano, H. E. Heslop, C. M. Rooney, F. Pane, and B. Savoldo Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia Blood, September 1, 2008; 112(5): 1876 - 1885. [Abstract] [Full Text] [PDF]

				A. P. Kater, M. H. J. van Oers, and T. J. Kipps Cellular immune therapy for chronic lymphocytic leukemia Blood, October 15, 2007; 110(8): 2811 - 2818. [Abstract] [Full Text] [PDF]

				C. Quintarelli, J. F. Vera, B. Savoldo, G. M. P. Giordano Attianese, M. Pule, A. E. Foster, H. E. Heslop, C. M. Rooney, M. K. Brenner, and G. Dotti Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes Blood, October 15, 2007; 110(8): 2793 - 2802. [Abstract] [Full Text] [PDF]

				C. Brignone, C. Grygar, M. Marcu, K. Schakel, and F. Triebel A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells J. Immunol., September 15, 2007; 179(6): 4202 - 4211. [Abstract] [Full Text] [PDF]

				J. Vera, B. Savoldo, S. Vigouroux, E. Biagi, M. Pule, C. Rossig, J. Wu, H. E. Heslop, C. M. Rooney, M. K. Brenner, et al. T lymphocytes redirected against the {kappa} light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells Blood, December 1, 2006; 108(12): 3890 - 3897. [Abstract] [Full Text] [PDF]