PO.CL05.01 · 临床研究

IL-2输注次数和产品不合格状态对黑色素瘤肿瘤浸润淋巴细胞治疗结局的影响

Impact of number of IL-2 infusions and product out of specification status on outcomes of tumor infiltrating lymphocyte therapy for melanoma

编号 3706 展板 8 时间 4/20 02:00–05:00 区域 Section 40 主讲 Arkadiusz Dudek, MD;PhD

分会场 Adoptive Cell Therapy 1

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作者与单位 Authors & Affiliations

Mohamed A. Aboelatta¹, Jeffrey E. Johnson¹, Jabra G. Zarka¹, Matyáš Benada², James W. Jakub³, Roxana S. Dronca³, Ruqin Chen³, Mahesh Seetharam⁴, Deepti Behl¹, Svetomir N. Markovic¹, Lisa A. Kottschade¹, Heather N. Montane¹, Matthew S. Block¹, Anastasios Dimou¹, Robert R. McWilliams¹, Paula Gill¹, Yi Lin¹, Arkadiusz Z. Dudek¹

¹Mayo Clinic, Rochester, MN,²Charles University, Hradec Kralove, Czech Republic,³Mayo Clinic, Jacksonville, FL,⁴Mayo Clinic, Scottsdale, AZ

摘要 Abstract

中文摘要

背景：高剂量白细胞介素-2(IL-2)在肿瘤浸润淋巴细胞(TIL)输注后给药，以促进体内扩增和持久性，但最佳给药方案及不合格(OOS) TIL产品的临床意义仍不明确。我们研究了IL-2输注剂量次数和制造OOS状态对接受商业化TIL治疗的转移性黑色素瘤结局的影响。方法：我们回顾性分析了在三个Mayo Clinic中心接受治疗的31例患者。计划IL-2为每12小时600,000 IU/kg，最多≤6剂；实际给药根据临床耐受性而变化。患者分为低(0-2)剂与高(≥3)剂IL-2组。TIL产品根据商业化放行标准分类为合格或OOS。使用Kaplan-Meier法和多变量Cox回归评估生存相关性。结果：在我们的31例患者队列中，中位年龄为59岁(范围17-77)，58%为男性，84% ECOG 0。在TIL输注时，M分期分布为M1a 6%、M1b 10%、M1c 61%和M1d 23%。42%的患者LDH高于正常上限。IL-2输注的中位次数为4(范围0-6)；58%的患者接受了≥3剂，而2例患者(6%)未接受任何剂量。不合格(OOS) TIL产品发生于6例患者(19%)。最佳缓解包括完全缓解(26%)和部分缓解(23%)，总体缓解率为48%，疾病控制率为61%(CR + PR + SD)。在缓解者中，中位缓解持续时间为84天(95% CI 73-95)。在数据截止时，中位随访时间为253天(95% CI 137-370)。TIL输注后>14天发生的最常见3/4级毒性为淋巴细胞减少(39%)、贫血(16%)和血小板减少(10%)。中位无进展生存期(PFS)为99天(95% CI 73-125)，有20例进展事件，中位总生存期(OS)为193天(95% CI 32-354)，有13例死亡。IL-2输注剂量次数取决于患者的耐受性。接受≥3剂IL-2与总生存期改善相关(394天对101天；p < 0.001)，并有无进展生存期延长的趋势(110天对59天；p = 0.055)。OOS产品预示较差的PFS(30天对110天；p = 0.003)，并显示出较差OS的趋势(120天对394天；p = 0.079)。在多变量分析中，≥3剂IL-2独立改善PFS(HR 0.20, 95% CI 0.06-0.69; p = 0.011)和OS(HR 0.09, 0.02-0.36; p = 0.001)，而OOS状态增加了进展(HR 8.10, 2.24-29.25; p = 0.001)和死亡(HR 6.16, 1.35-28.20; p = 0.019)的风险。结论：更多的IL-2输注剂量次数和满足商业化TIL放行标准与改善的结局独立相关。

查看英文原文 English 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 ).

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