Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients

J Immunother. 2010 Sep;33(7):723-34. doi: 10.1097/CJI.0b013e3181ea7e6e.


Recent immunotherapy trials have shown that lymphodepletion induced by short-term chemotherapy favors subsequent expansion of adoptively transferred T cells, by homeostatic mechanisms. To take advantage of this effect, novel regimens are being developed with the aim to enhance tumor immunity and reduce treatment toxicity. We have designed a clinical phase I trial combining chemotherapy, reinfusion of PBMC containing Melan-A(MART-1)-specific T cells, and vaccination with Melan-A peptide in Incomplete Freund's Adjuvant. Treatment with Busulfan plus Fludarabine depleted lymphocytes only weakly. Cyclophosphamide (CTX) plus Fludarabine depleted lymphocytes more profoundly, with a maximal effect using high doses of CTX. It is interesting to note that, the degree of homeostatic T-cell proliferation correlated tightly with the extent of lymphodepletion. As compared with CD4 T cells, CD8 T cells showed higher susceptibility to chemotherapy, followed by more rapid homeostatic proliferation and recovery, resulting in strong inversions of CD4/CD8 ratios. Despite efficient homeostatic proliferation of total CD4 and CD8 T cells, the frequency of CD8 T cells specific for Melan-A and cancer-testis antigens remained relatively low. In contrast, EBV-specific T cells expanded and reached high numbers. We conclude that short-term chemotherapy promoted homeostatic lymphocyte proliferation depending on the intensity of lymphocyte depletion, however without preferential expansion of tumor antigen-specific T cells.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Busulfan / administration & dosage
  • CD8 Antigens / biosynthesis
  • Cancer Vaccines*
  • Cell Proliferation / drug effects
  • Cyclophosphamide / administration & dosage
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Freund's Adjuvant / administration & dosage
  • Humans
  • Immunotherapy, Adoptive*
  • Lymphocyte Depletion
  • MART-1 Antigen / administration & dosage
  • MART-1 Antigen / immunology
  • Male
  • Melanoma / immunology
  • Melanoma / pathology
  • Melanoma / therapy*
  • Middle Aged
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / immunology
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Vidarabine / administration & dosage
  • Vidarabine / analogs & derivatives


  • CD8 Antigens
  • Cancer Vaccines
  • Cytokines
  • MART-1 Antigen
  • Peptide Fragments
  • Cyclophosphamide
  • Freund's Adjuvant
  • Vidarabine
  • Busulfan
  • fludarabine