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Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients.
- Source :
-
Journal of immunotherapy (Hagerstown, Md. : 1997) [J Immunother] 2010 Sep; Vol. 33 (7), pp. 723-34. - Publication Year :
- 2010
-
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(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.
- Subjects :
- Aged
Busulfan administration & dosage
CD8 Antigens biosynthesis
Cell Proliferation drug effects
Cyclophosphamide administration & dosage
Cytokines genetics
Cytokines metabolism
Female
Freund's Adjuvant administration & dosage
Humans
Lymphocyte Depletion
MART-1 Antigen administration & dosage
MART-1 Antigen immunology
Male
Melanoma immunology
Melanoma pathology
Middle Aged
Peptide Fragments administration & dosage
Peptide Fragments immunology
Skin Neoplasms immunology
Skin Neoplasms pathology
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes pathology
Vidarabine administration & dosage
Vidarabine analogs & derivatives
Cancer Vaccines
Immunotherapy, Adoptive
Melanoma therapy
Skin Neoplasms therapy
T-Lymphocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1537-4513
- Volume :
- 33
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of immunotherapy (Hagerstown, Md. : 1997)
- Publication Type :
- Academic Journal
- Accession number :
- 20664354
- Full Text :
- https://doi.org/10.1097/CJI.0b013e3181ea7e6e