Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients.
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.
Laurent
Julien
J
Multidisciplinary Oncology Center, University of Lausanne Hospitals, Ludwig Institute for Cancer Research Ltd., University of Lausanne, Switzerland. julien.laurent@chuv.ch
Speiser
Daniel E
DE
Appay
Victor
V
Touvrey
Cedric
C
Vicari
Manuela
M
Papaioannou
Anne
A
Canellini
Giorgia
G
Rimoldi
Donata
D
Rufer
Nathalie
N
Romero
Pedro
P
Leyvraz
Serge
S
Voelter
Verena
V
D000368:Aged; D002066:Busulfan / Q000008:administration & dosage; D016827:CD8 Antigens / Q000096:biosynthesis; D019496:Cancer Vaccines; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006801:Humans; D016219:Immunotherapy, Adoptive; D008212:Lymphocyte Depletion; D058965:MART-1 Antigen / Q000008:administration & dosage / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D016827:CD8 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D058965:MART-1 Antigen; D010446:Peptide Fragments; D003520:Cyclophosphamide; D005620:Freund's Adjuvant; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine