Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients.
BACKGROUND
Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.


METHODS
This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.


RESULTS
Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.


CONCLUSIONS
Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.
CCIT, Center for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.
Eva
E
Ellebaek
Trine Zeeberg
TZ
Iversen
Niels
N
Junker
Marco
M
Donia
Lotte
L
Engell-Noerregaard
Özcan
Ö
Met
Lisbet Rosenkrantz
LR
Hölmich
Rikke Sick
RS
Andersen
Sine Reker
SR
Hadrup
Mads Hald
MH
Andersen
Per
P
thor Straten
Inge Marie
IM
Svane
D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D055815:Young Adult
D007376:Interleukin-2