Selective elimination of a chemoresistant side population of B-CLL cells by cytotoxic T lymphocytes in subjects receiving an autologous hCD40L/IL-2 tumor vaccine

A. E. Foster, F. V. Okur, E. Biagi, A. Lu, G. Dotti, E. Yvon, B. Savoldo, G. Carrum, M. A. Goodell, H. E. Heslop, M. K. Brenner

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Side-population (SP) analysis identifies precursor cells in normal and malignant tissues. Cells with this phenotype have increased resistance to many cytotoxic agents, and may represent a primary drug-resistant population in malignant diseases. To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing, we first established the presence of a malignant CD5+ CD19+ SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia (B-CLL). We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5+ CD19+ SP cells. T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells. Elimination of SP cells is likely triggered by their increased expression of target antigens, such as receptor for hyaluronan-mediated motility (RHAMM), after stimulation of the malignant cells by hCD40L, as CD8+ RHAMM-specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells. Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T-cell-mediated effector activity after immunization of human subjects.

Original languageEnglish (US)
Pages (from-to)563-572
Number of pages10
JournalLeukemia
Volume24
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • B-CLL
  • Chemoresistance
  • Cytotoxic T lymphocytes
  • Immunotherapy
  • Side population

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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