Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
OBJECTIVE
We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma.


METHODS
Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy.


RESULTS
Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation.


CONCLUSIONS
Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.
Dudley
Mark E
ME
Surgery Branch, National Cancer Institute, NIH, CRC 3-3940, 10 Center Dr MSC 1201, Bethesda MD 20892-1202, USA.
Wunderlich
John R
JR
Yang
James C
JC
Sherry
Richard M
RM
Topalian
Suzanne L
SL
Restifo
Nicholas P
NP
Royal
Richard E
RE
Kammula
Udai
U
White
Don E
DE
Mavroukakis
Sharon A
SA
Rogers
Linda J
LJ
Gracia
Gerald J
GJ
Jones
Stephanie A
SA
Mangiameli
David P
DP
Pelletier
Michelle M
MM
Gea-Banacloche
Juan
J
Robinson
Michael R
MR
Berman
David M
DM
Filie
Armando C
AC
Abati
Andrea
A
Rosenberg
Steven A
SA
D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D007376:Interleukin-2; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine