Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients
| Autor: | Verena Voelter, Pedro Romero, Serge Leyvraz, Manuela Vicari, Cédric Touvrey, Anne Papaioannou, Victor Appay, Giorgia Canellini, Daniel E. Speiser, Nathalie Rufer, Julien Laurent, Donata Rimoldi |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research Skin Neoplasms medicine.medical_treatment CD8 Antigens T-Lymphocytes Immunology Freund's Adjuvant Lymphocyte proliferation Cancer Vaccines Immunotherapy Adoptive Lymphocyte Depletion Interleukin 21 MART-1 Antigen Antigen Immunology and Allergy Medicine Cytotoxic T cell Humans Busulfan Cyclophosphamide Melanoma Aged Cell Proliferation Pharmacology business.industry Immunotherapy Middle Aged Peptide Fragments Fludarabine Cytokines Female business Adjuvant CD8 Vidarabine medicine.drug |
| Zdroj: | Journal of immunotherapy (Hagerstown, Md. : 1997). 33(7) |
| ISSN: | 1537-4513 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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