An autologous humanized patient-derived xenograft (PDX) model for evaluation of nivolumab immunotherapy in renal cell cancer: a case report.

Q1 Biochemistry, Genetics and Molecular Biology
Stem cell investigation Pub Date : 2022-11-08 eCollection Date: 2022-01-01 DOI:10.21037/sci-2022-029
Yubin Kang, Andrew J Armstrong, David S Hsu
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引用次数: 0

Abstract

Background: 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 vs. 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.

Case description: 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.

Conclusions: 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.

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用于评估肾细胞癌 nivolumab 免疫疗法的自体人源化患者异种移植 (PDX) 模型:病例报告。
背景:为免疫疗法的临床前评估开发可靠的动物模型的需求尚未得到满足。目前用于免疫疗法临床前评估的方法是将脐带血中的 CD34+ 细胞移植到免疫缺陷小鼠体内,然后再植入患者衍生的肿瘤细胞。然而,由于异体移植与人类白细胞抗原(HLA)不匹配引起的肿瘤反应,目前的模型存在较高的肿瘤排斥率。我们在此报告了首次开发的新型人源化患者异种移植(PDX)模型,该模型使用的是一名转移性透明细胞肾细胞癌(mRCC)患者骨髓抽吸物中的自体 CD34+ 细胞:这是一名 68 岁的白种男子,2014 年被诊断为 mRCC 并转移至肝脏。他接受了舒尼替尼+/-AGS-003治疗,并接受了囊肿切除性右肾切除术、左肾上腺切除术和肝脏部分切除术。利用切除的肾切除标本生成了 PDX。术后,患者接受了多线标准治疗,包括舒尼替尼、阿西替尼、贝伐单抗、依维莫司和卡博赞替尼。在卡博替尼治疗取得进展的同时,他又接受了 nivolumab 治疗。开始使用 nivolumab 治疗 7 年后,停止系统治疗 4 年后,他的病情仍然完全缓解。为了生成自体PDX模型,我们进行了骨髓抽吸,分离出CD34+造血干细胞/祖细胞(HSPCs),并将其注射到150rad照射的非肥胖糖尿病scid gamma null(NSG)小鼠体内。移植后11周,将匹配的患者PDX皮下注射到人源化小鼠体内,并用nivolumab治疗小鼠:我们的病例代表了尼夫单抗治疗mRCC的成功。此外,从单次骨髓抽吸中获得的 HPSCs 能够在小鼠体内重建免疫系统,从而使尼夫单抗能够抑制 PDX 的肿瘤生长,并再现了在使用尼夫单抗的患者身上观察到的持久缓解。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,我们的模型系统消除了HLA不匹配引起的肿瘤排斥反应。我们的自体人源化肾细胞癌(RCC)PDX模型为临床前研究免疫疗法提供了一种有效的工具。
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来源期刊
Stem cell investigation
Stem cell investigation Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
5.80
自引率
0.00%
发文量
9
期刊介绍: The Stem Cell Investigation (SCI; Stem Cell Investig; Online ISSN: 2313-0792) is a free access, peer-reviewed online journal covering basic, translational, and clinical research on all aspects of stem cells. It publishes original research articles and reviews on embryonic stem cells, induced pluripotent stem cells, adult tissue-specific stem/progenitor cells, cancer stem like cells, stem cell niche, stem cell technology, stem cell based drug discovery, and regenerative medicine. Stem Cell Investigation is indexed in PubMed/PMC since April, 2016.
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