NKTR-255与安慰剂相比，可增强复发/难治性（R/R）大b细胞淋巴瘤（LBCL）患者cd19靶向CAR-T治疗后的完全缓解和持久性

IF 3.6 3区医学 Q2 HEMATOLOGY

Transplantation and Cellular Therapy Pub Date : 2025-02-01 DOI:10.1016/j.jtct.2025.01.021

Sairah Ahmed MD , John F. DiPersio MD, PhD , James Essell MD , Catherine Diefenbach MD , Miguel-Angel Perales MD , Christina Castilla Llorente MD , Saurabh Dahiya MD , Heng Xu PhD , Christie Fanton PhD , Sohail Chaudhry MD, PhD , Zachary Lee PharmD , Mario Q. Marcondes MD, PhD , Mary A. Tagliaferri MD , Jonathan Zalevsky PhD , David B. Miklos MD, PhD , Cameron J. Turtle MBBS, PhD , Joseph P McGuirk DO

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引用次数: 0

摘要

cd19靶向嵌合抗原受体（CAR）治疗难治性大b细胞淋巴瘤（LBCL）有很高的应答率。然而，超过一半的患者未能达到缓解和/或复发。因此，需要提高CAR-T细胞产品功效的策略。NKTR-255是一种正在研究的聚合物偶联IL-15激动剂，可激活、增殖和扩增CD8+T细胞和NK细胞，并促进记忆性CD8+T细胞的产生。NKTR-255的临床研究显示，CAR-T和CD8+T细胞在先前接受CAR-T治疗（NCT04136756）的R/R NHL患者中扩增，并且CAR-T转运到肿瘤微环境(Muffly, 2024；NCT03233854)。在这里，我们描述了评估NKTR-255联合CAR-T治疗（NCT05664217）的2期试验结果。这是一项随机、双盲、安慰剂对照的2期研究，在fda批准的两种CAR-T产品（axicabtagene-ciloleucel或lisocabtagene-maraleucel）之一之后，NKTR-255与安慰剂进行对比。符合条件的R/R LBCL患者在CAR-T输注后14天开始静脉注射研究药物，最长可达5个月。主要终点是CD19-CAR-T细胞治疗后第6个月的完全缓解率（CRR）。根据Lugano的说法，通过PET-CT评估疗效。关键的次要和探索性目标包括安全性/耐受性，NKTR-255 PK和CAR-T PD，通过流式细胞术定量。结果15例LBCL患者于2023年3月至12月随机分组。所有患者均接受CD19-CAR-T细胞治疗和≥1剂量的研究治疗；12/15（80%）接受axial -cel治疗，3/15（20%）接受liso-cel治疗。共有11人被随机分配到NKTR-255组(5人1.5µg/kg；3在3µg/kg；其中3名在3µg/kg组，然后6µg/kg组（周期2+），4名随机分配到安慰剂组。两组之间的LDH和组织学相似，除了肿瘤负荷（NKTR-255中位数为1408，安慰剂为940 mm2）。CAR-T后的NKTR-255耐受性良好。在接受NKTR-255治疗的11例患者中，分别有2/11（18%）和3/11（27%）患者报告了输液相关反应（IRR）和发热；均为1/2级，24小时内消退。在1例患者中，NKTR-255最常见的≥3级TRAEs为中性粒细胞计数减少5/11(46%)，血小板计数减少2/11(18%)，淋巴细胞计数减少2/11 (18%)；都解决了。根据意向治疗，NKTR-255第6个月的CRR为8/11(73%)，而安慰剂组为2/4（50%）。根据可评估反应的分析，NKTR-255第6个月的CRR为8/10(80%)，而安慰剂组为2/4（50%）。NKTR-255的CD8+CAR-T细胞再次扩增发生在8/11（73%）。额外的PD分析将被提出。结论初步数据显示，NKTR-255辅助CD19-CAR-T细胞治疗LBCL耐受良好，安全性好，6个月时的CR率优于单独CD19-CAR-T细胞治疗。NKTR-255辅助CAR-T治疗和其他细胞治疗的验证性研究是有必要的。

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NKTR-255 Vs Placebo to Enhance Complete Responses and Durability Following CD19-Directed CAR-T Therapy in Patients with Relapsed/ Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background

CD19-directed chimeric antigen receptor (CAR) have high response rates in refractory large B-cell lymphoma (LBCL). However, more than half of patients fail to achieve remission and/or relapse. Thus, strategies to improve efficacy of CAR-T cell products are needed. NKTR-255 is an investigational polymer-conjugated IL-15 agonist that activates, proliferates and expands CD8+T and NK cells, as well as promote creation of memory CD8+ T cells. Clinical studies with NKTR-255 have shown expansion of CAR-T and CD8+T cells in R/R NHL patients who previously received CAR-T therapy (NCT04136756), and CAR-T trafficking to the tumor microenvironment (Muffly, 2024; NCT03233854). Here, we describe results of a Phase 2 trial evaluating NKTR-255 in combination with CAR-T therapy (NCT05664217).

Methods

This is a phase 2 randomized, double-blind, placebo-controlled study of NKTR-255 vs placebo following one of two FDA-approved CAR-T products (axicabtagene-ciloleucel or lisocabtagene-maraleucel). Eligible patients with R/R LBCL received study drug intravenously starting +14 days following CAR-T infusion for up to 5 months. Primary endpoint was complete response rate (CRR) by blinded independent central review (BICR) at month 6 after CD19-CAR-T cells. Efficacy was assessed by PET-CT according to Lugano. Key secondary and exploratory objectives included safety/tolerability, NKTR-255 PK and CAR-T PD quantified by flow-cytometry.

Results

15 patients with LBCL were randomized between Mar and Dec 2023. All patients received CD19-CAR-T cell therapy and ≥1 dose of study treatment; 12/15 (80%) received axi-cel and 3/15 (20%) received liso-cel. In total, 11 were randomized to the NKTR-255 (5 at 1.5 µg/kg; 3 at 3 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 were randomized to placebo. LDH and histology were similar between both groups, except tumor burden (NKTR-255 median 1408 vs 940 mm² placebo). NKTR-255 following CAR-T was well-tolerated. Among 11 who received NKTR-255, infusion-related reaction (IRR) and fever were reported in 2/11 (18%) and 3/11 (27%) pts, respectively; all were grade 1/2 and resolved in 24 hrs. The most common grade ≥3 TRAEs with NKTR-255 in >1 patient was decreased neutrophil count 5/11 (46%), platelet count 2/11 (18%), and lymphocyte count 2/11 (18%); all resolved. Per intent-to-treat, the CRR at month 6 for NKTR-255 was 8/11 (73%) vs 2/4 (50%) with placebo. Per response-evaluable analysis, CRR at month 6 for NKTR-255 was 8/10 (80%) vs 2/4 (50%) with placebo. Re-expansion of CD8+CAR-T cells occurred in 8/11 (73%) for NKTR-255. Additional PD analyses will be presented.

Conclusions

Preliminary data of NKTR-255 adjuvant to CD19-CAR-T cell therapy in LBCL was well-tolerated, safe and demonstrated superior CR rate compared to CD19-CAR-T cell therapy alone at 6-months. Confirmatory studies with NKTR-255 adjuvant to CAR-T therapy and other cellular therapies are warranted.

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