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

Julien Laurent*, Daniel E. Speiser, Victor Appay, Cedric Touvrey, Manuela Vicari, Anne Papaioannou, Giorgia Canellini, Donata Rimoldi, Nathalie Rufer, Pedro Romero, Serge Leyvraz, Verena Voelter

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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-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.

Original languageEnglish (US)
Pages (from-to)723-734
Number of pages12
JournalJournal of Immunotherapy
Volume33
Issue number7
DOIs
StatePublished - Sep 2010
Externally publishedYes

Keywords

  • antigen-specific CD8 T cells
  • chemotherapy
  • melanoma
  • vaccination

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Laurent, J., Speiser, D. E., Appay, V., Touvrey, C., Vicari, M., Papaioannou, A., Canellini, G., Rimoldi, D., Rufer, N., Romero, P., Leyvraz, S., & Voelter, V. (2010). Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. Journal of Immunotherapy, 33(7), 723-734. https://doi.org/10.1097/CJI.0b013e3181ea7e6e