Yankelevich Maxim, Thakur Archana, Modak Shakeel, Chu Roland, Taub Jeffrey, Martin Alissa, Schalk Dana L, Schienshang Amy, Whitaker Sara, Rea Katie, Lee Daniel W, Liu Qin, Shields Anthony, Cheung Nai-Kong, Lum Lawrence G
St. Christopher's Hospital for Children, Drexel University.
University of Virginia.
Res Sq. 2023 Nov 9:rs.3.rs-3570311. doi: 10.21203/rs.3.rs-3570311/v1.
Since treatment of neuroblastoma (NB) with anti-GD2 monoclonal antibodies provides a survival benefit in children with minimal residual disease and our preclinical study shows that anti-CD3 x anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs) were highly cytotoxic to GD2+ cell lines, we conducted a phase I/II study in recurrent/refractory patients to establish safety and explore the clinical benefit of GD2BATs.
The 3+3 dose escalation study (NCT02173093) phase I involved 9 evaluable patients with NB (n=5), osteosarcoma (OST) (n=3), and desmoplastic small round cell tumors (DSRCT) (n=1) with twice weekly infusions of GD2BATs at 40, 80, or 160 x 10 GD2BATs/kg/infusion with daily interleukin 2 (300,000 IU/m) and twice weekly granulocyte-macrophage colony stimulating factor (250 μg/m). Phase II portion of the trial was conducted in patients with NB at the dose 3 level of 160 x 10 GD2BATs/kg/infusion but failed to enroll the planned number of patients.
Nine of 12 patients in the phase I completed therapy. There were no dose limiting toxicities (DLTs). All patients developed mild and manageable cytokine release syndrome (CRS) with grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody associated pain was not significant in this study. The median OS for patients in the Phase I and limited Phase II was 18.0 and 31.2 months, respectively, whereas the combined OS was 21.1 months. There was a complete bone marrow response with overall stable disease in one of the phase I patients with NB. Ten of 12 phase II patients were evaluable for response: 1 had partial response. Three additional patients were deemed to have clinical benefit with prolonged stable disease. More than 50% of evaluable patients showed augmented immune responses to GD2+ targets after GD2BATs as measured by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines.
Our study demonstrated safety of up to 160 x 10 cells/kg/infusion of GD2BATs. Combined with evidence for the development of post treatment endogenous immune responses, this data supports further investigation of GD2 BATs in larger Phase II clinical trials.
由于用抗GD2单克隆抗体治疗神经母细胞瘤（NB）可使微小残留病患儿的生存率提高，且我们的临床前研究表明，抗CD3×抗GD2双特异性抗体（GD2Bi）武装的T细胞（GD2BATs）对GD2+细胞系具有高度细胞毒性，因此我们在复发/难治性患者中进行了一项I/II期研究，以确定安全性并探索GD2BATs的临床益处。
3+3剂量递增研究（NCT02173093）的I期纳入了9例可评估的患者，其中NB患者5例、骨肉瘤（OST）患者3例、促结缔组织增生性小圆细胞肿瘤（DSRCT）患者1例，每周两次输注GD2BATs，剂量为40、80或160×10个GD2BATs/kg/次，同时每日注射白细胞介素2（300,000 IU/m²），每周两次注射粒细胞-巨噬细胞集落刺激因子（250 μg/m²）。试验的II期部分在NB患者中以160×10个GD2BATs/kg/次的3级剂量进行，但未能招募到计划数量的患者。
I期的12例患者中有9例完成了治疗。没有剂量限制毒性（DLT）。所有患者在输注GD2BATs后72小时内均出现了轻度且可控制的细胞因子释放综合征（CRS），伴有2-3级发热/寒战、头痛，偶尔出现低血压。本研究中GD2抗体相关疼痛不明显。I期和有限的II期患者的中位总生存期分别为18.0个月和31.2个月，而合并总生存期为21.1个月。I期的1例NB患者出现了完全骨髓反应且疾病总体稳定。II期的12例患者中有10例可评估疗效：1例有部分缓解。另外3例患者被认为有临床益处，疾病长期稳定。超过50%的可评估患者在输注GD2BATs后，通过干扰素-γ（IFN-γ）酶联免疫斑点试验、Th1细胞因子和/或趋化因子检测，显示对GD2+靶点的免疫反应增强。
我们的研究证明了输注高达160×10个细胞/kg的GD2BATs的安全性。结合治疗后内源性免疫反应发展的证据，这些数据支持在更大规模的II期临床试验中进一步研究GD2BATs。
