Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
OBJECTIVE
The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.


METHODS
We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.


RESULTS
Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.


CONCLUSIONS
Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
Dudley
Mark E
ME
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892-1201, USA. Mark_Dudley@nih.gov
Yang
James C
JC
Sherry
Richard
R
Hughes
Marybeth S
MS
Royal
Richard
R
Kammula
Udai
U
Robbins
Paul F
PF
Huang
JianPing
J
Citrin
Deborah E
DE
Leitman
Susan F
SF
Wunderlich
John
J
Restifo
Nicholas P
NP
Thomasian
Armen
A
Downey
Stephanie G
SG
Smith
Franz O
FO
Klapper
Jacob
J
Morton
Kathleen
K
Laurencot
Carolyn
C
White
Donald E
DE
Rosenberg
Steven A
SA
D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000097:blood; D007376:Interleukin-2 / Q000627:therapeutic use*; D015851:Interleukin-7 / Q000097:blood; D053208:Kaplan-Meier Estimate; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D013997:Time Factors; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; C508605:IL7 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine