Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia

Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6916-23. doi: 10.1158/1078-0432.CCR-05-0484.

Abstract

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/10(6) 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-gamma, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Antigens, CD / biosynthesis
  • Antineoplastic Agents / metabolism
  • Area Under Curve
  • B7-2 Antigen / biosynthesis
  • CD3 Complex / biosynthesis
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Ligand / metabolism*
  • Cancer Vaccines / chemistry*
  • Cell Line, Tumor
  • Cell Proliferation
  • Coculture Techniques
  • Female
  • Forkhead Transcription Factors / biosynthesis
  • Humans
  • Immune System
  • Interleukin-2 / metabolism*
  • Leukemia, B-Cell / metabolism*
  • Leukemia, B-Cell / therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Male
  • Middle Aged
  • Receptors, Interleukin-2 / biosynthesis
  • T-Lymphocytes / metabolism
  • Time Factors
  • Treatment Outcome

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • B7-2 Antigen
  • CD223 antigen
  • CD3 Complex
  • Cancer Vaccines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Receptors, Interleukin-2
  • CD40 Ligand