Kang Yubin, Armstrong Andrew J, Hsu David S
Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Divisions of Medical Oncology and Urology, Departments of Medicine, Surgery, and Pharmacology and Cancer Biology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University Medical Center, Durham, NC, USA.
Stem Cell Investig. 2022 Nov 8;9:8. doi: 10.21037/sci-2022-029. eCollection 2022.
There is an unmet need for developing faithful animal models for preclinical evaluation of immunotherapy. The current approach to generate preclinical models for immunotherapy evaluation has been to transplant CD34 cells from umbilical cord blood into immune-deficient mice followed by implantation of patient derived tumor cells. However, current models are associated with high tumor rejection rate secondary to the allograft tumor response from human leukocyte antigen (HLA) mismatches. We herein report the first development of a novel, humanized patient-derived xenograft (PDX) model using autologous CD34 cells from bone marrow aspirate obtained from a patient with metastatic clear cell renal cell carcinoma (mRCC) from whom a PDX had been developed.
This is a 68-year-old Caucasian man diagnosed with mRCC with metastasis to the liver in 2014. He was treated with sunitinib +/- AGS-003 and underwent a cytoreductive right nephrectomy, left adrenalectomy and partial liver resection. PDX was generated using resected nephrectomy specimen. After surgery, patient received multiple lines of standard of care therapy including sunitinib, axitinib, bevacizumab, everolimus and cabozantinib. While progressing on cabozantinib, he was treated with nivolumab. Seven years after initiation of nivolumab, and 4 years after stopping systemic therapy, he remains in complete remission. To generate autologous PDX model, bone marrow aspirate was performed and CD34 hematopoietic stem/progenitor cells (HSPCs) were isolated and injected into 150 rad irradiated non-obese diabetic scid gamma null (NSG) mice. At 11 weeks post-transplant, the matched patient PDX was injected subcutaneously into the humanized mice and the mice were treated with nivolumab.
Our case represents successful therapy of nivolumab in mRCC. Furthermore, HPSCs obtained from a single bone marrow aspirate were able to reconstitute an immune system in the mice that allowed nivolumab to inhibit the tumor growth of PDX and recapitulated the durable remission observed in the patient with nivolumab. We observed the reconstitution of human T cells, B cells and natural killer (NK) cells and unlike the humanized mouse model using cord blood, our model system eliminates the tumor rejection from mis-matched HLA. Our autologous humanized renal cell carcinoma (RCC) PDX model provides an effective tool to study immunotherapy in a preclinical setting.
开发用于免疫治疗临床前评估的可靠动物模型仍存在未满足的需求。目前用于生成免疫治疗评估临床前模型的方法是将脐带血中的CD34细胞移植到免疫缺陷小鼠中，然后植入患者来源的肿瘤细胞。然而，由于人类白细胞抗原（HLA）不匹配导致的同种异体肿瘤反应，当前模型的肿瘤排斥率较高。我们在此报告首次开发了一种新型的人源化患者来源异种移植（PDX）模型，该模型使用从一名已建立PDX的转移性透明细胞肾细胞癌（mRCC）患者获取的骨髓穿刺液中的自体CD34细胞。
这是一名68岁的白人男性，2014年被诊断为mRCC并伴有肝转移。他接受了舒尼替尼+/-AGS-003治疗，并接受了减瘤性右肾切除术、左肾上腺切除术和部分肝切除术。使用切除的肾切除标本生成PDX。手术后，患者接受了多线标准治疗，包括舒尼替尼、阿昔替尼、贝伐单抗、依维莫司和卡博替尼。在接受卡博替尼治疗进展期间，他接受了纳武单抗治疗。纳武单抗治疗7年后，在停止全身治疗4年后，他仍处于完全缓解状态。为了生成自体PDX模型，进行了骨髓穿刺，分离出CD34造血干/祖细胞（HSPCs）并注入150拉德照射的非肥胖糖尿病严重联合免疫缺陷γ0（NSG）小鼠体内。移植后11周，将匹配的患者PDX皮下注射到这些人源化小鼠中，并对小鼠进行纳武单抗治疗。
我们的病例代表了纳武单抗在mRCC治疗中的成功应用。此外，从单次骨髓穿刺中获得的HPSCs能够在小鼠体内重建免疫系统，使纳武单抗能够抑制PDX的肿瘤生长，并重现了该患者使用纳武单抗后观察到的持久缓解。我们观察到人类T细胞、B细胞和自然杀伤（NK）细胞的重建，与使用脐带血的人源化小鼠模型不同之处在于，我们的模型系统消除了因HLA不匹配导致的肿瘤排斥。我们的自体人源化肾细胞癌（RCC）PDX模型为临床前环境下研究免疫治疗提供了一个有效的工具。
Zotero 插件
