CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma.
OBJECTIVE
Tumor-infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunologic impact of unscreened, CD8+ enriched "young" TIL.


METHODS
Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following nonmyeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6 Gy of total body irradiation.


RESULTS
Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (Response Evaluation Criteria in Solid Tumors) including 3 complete responders. Eleven of 23 patients (48%) treated with TIL and 6 Gy total body irradiation had an objective response including 2 complete responders. At 1 month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response.


CONCLUSIONS
This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients.
Dudley
Mark E
ME
Surgery Branch and Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1201, USA. med@nih.gov
Gross
Colin A
CA
Langhan
Michelle M
MM
Garcia
Marcos R
MR
Sherry
Richard M
RM
Yang
James C
JC
Phan
Giao Q
GQ
Kammula
Udai S
US
Hughes
Marybeth S
MS
Citrin
Deborah E
DE
Restifo
Nicholas P
NP
Wunderlich
John R
JR
Prieto
Peter A
PA
Hong
Jenny J
JJ
Langan
Russell C
RC
Zlott
Daniel A
DA
Morton
Kathleen E
KE
White
Donald E
DE
Laurencot
Carolyn M
CM
Rosenberg
Steven A
SA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047368:Tumor Burden / Q000276:immunology