PO.CL05.01 · 临床研究
Impact of number of IL-2 infusions and product out of specification status on outcomes of tumor infiltrating lymphocyte therapy for melanoma
作者与单位
摘要 Abstract
Background: High-dose interleukin-2 (IL-2) is administered after tumor-infiltrating lymphocyte (TIL) infusion to promote in-vivo expansion and persistence, yet optimal dosing and the clinical significance of out-of-specification (OOS) TIL products remain unclear. We investigated the impact of number of infused IL-2 doses and manufacturing OOS status on outcomes in metastatic melanoma treated with commercial TIL therapy.
Methods: We retrospectively analyzed 31 patients treated across three Mayo Clinic sites. Planned IL-2 was 600,000 IU/kg every 12 hours for ≤6 doses; actual dosing varied based on clinical tolerance. Patients were grouped as low (0-2) vs high (≥3) IL-2 doses. TIL products were classified as within-specification or OOS per commercial release criteria. Survival associations were evaluated using Kaplan-Meier and multivariable Cox regression.
Results: In our 31-patient cohort, the median age was 59 years (range 17-77), 58% were male, and 84% had ECOG 0. At TIL infusion, M-stage distribution was M1a 6%, M1b 10%, M1c 61%, and M1d 23%. LDH was elevated above the upper limit of normal in 42%. The median number of IL-2 infusions was 4 (range 0-6); 58% of patients received ≥3 doses, while 2 patients (6%) received none. Out-of-specification (OOS) TIL products occurred in 6 patients (19%). Best responses included complete response (26%) and partial response (23%), for an overall response rate of 48% and a disease-control rate of 61% (CR + PR + SD). Among responders, the median duration of response was 84 days (95% CI 73-95). At data cutoff, the median follow-up was 253 days (95% CI 137-370). The most common grade 3/4 toxicities occurring >14 days after TIL infusion were lymphopenia (39%), anemia (16%), and thrombocytopenia (10%). Median progression-free survival (PFS) was 99 days (95% CI 73-125) with 20 progression events, and median overall survival (OS) was 193 days (95% CI 32-354) with 13 deaths. Number of infused IL-2 doses was dependent on patients tolerability. Receiving ≥3 IL-2 doses was associated with improved overall survival (394 vs 101 days; p < 0.001) and a trend toward longer progression-free survival (110 vs 59 days; p = 0.055). OOS products predicted inferior PFS (30 vs 110 days; p = 0.003) and showed a trend toward worse OS (120 vs 394 days; p = 0.079). In multivariate analysis, ≥3 IL-2 doses independently improved PFS (HR 0.20, 95% CI 0.06-0.69; p = 0.011) and OS (HR 0.09, 0.02-0.36; p = 0.001), while OOS status increased risk of progression (HR 8.10, 2.24-29.25; p = 0.001) and death (HR 6.16, 1.35-28.20; p = 0.019).
Conclusions: Higher number of infused doses IL-2 and meeting commercial TIL release criteria were independently associated with improved outcomes.
利益披露 Disclosure
M. A. Aboelatta, None..
J. E. Johnson, None..
J. G. Zarka, None..
M. Benada, None..
J. W. Jakub, None..
R. S. Dronca, None.
R. Chen,
Immunocore ).
Replimune ).
Regeneron ).
Erasca ).
Elephas ).
Merck ).
Pierre Fabre ).
M. Seetharam,
Deciphera Other, Advisory Board.
Immunocore Other, Advisory Board.
Replimune Other, Advisory Board.
D. Behl,
Astra Zeneca Other, Participation in Advisory Board meetings.
Boehringer Ingelheim Participation in Advisory Board meetings.
Bristol Meyers Squibb Participation in Advisory Board meetings.
Novocure Participation in Advisory Board meetings.
Natera Participation in Advisory Board meetings.
S. N. Markovic, None..
L. A. Kottschade, None..
H. N. Montane, None..
M. S. Block, None.
A. Dimou,
TP therapeutics Other, Participation in Advisory Board.
Guardant Health Other, Participation in Advisory Board.
AnHeart Therapeutics Other, Participation in Advisory Board.
ChromaCode Other, Participation in Advisory Board.
Rigal Pharmaceuticals, Inc Other, Participation in Advisory Board.
Nuvation Bio Other, Participation in Advisory Board.
Syntrix Pharmaceuticals Other, Clinical Trial Support.
Novartis Other, Clinical Trial Support.
Merck Other, Clinical Trial Support.
AnHeart Therapeutics Other, Clinical Trial Support.
Astra Zeneca Other, Clinical Trial Support.
Sorrento Therapeutics Other, Clinical Trial Support.
Guardant Health Other, Clinical Trial Support.
Philogen Other, Clinical Trial Support.
Nuvation Bio Other, Clinical Trial Support.
Erasca Other, Clinical Trial Support.
R. R. McWilliams, None..
P. Gill, None.
Y. Lin,
Janssen Other, Participation in Advisory Board.
Sanofi Other, Participation in Advisory Board.
Bristol Meyers Squib Other, Participation in Advisory Board.
Regeneron Other, Participation in Advisory Board.
Genentech Other, Participation in Advisory Board.
Tessera Other, Participation in Advisory Board.
Legend Other, Participation in Advisory Board.
NexT Therapeutics Other, Participation in Advisory Board.
Janssen Other, Steering Committee.
Kite/Gilead Other, Steering Committee.
Janssen ).
Bristol Meyer Squibb ).
Neximmune Scientific Advisory Board.
Caribou Scientific Advisory Board.
Pfizer Other, Data Safety Monitoring Board.
A. Z. Dudek,
Iovance Other, Participation in Advisory Board.
TTC Oncology, LLC g., Board of Directors, non-salaried role), Stock.
IDEAYA Biosciences ).
Immunocore ).
Kumquat Biosciences, INC ).
Replimune ).
Pierre Fabre Medicament ).