PMID- 36393918
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230610
IS  - 2306-9759 (Print)
IS  - 2313-0792 (Electronic)
IS  - 2306-9759 (Linking)
VI  - 9
DP  - 2022
TI  - An autologous humanized patient-derived xenograft (PDX) model for evaluation of 
      nivolumab immunotherapy in renal cell cancer: a case report.
PG  - 8
LID - 10.21037/sci-2022-029 [doi]
LID - 8
AB  - 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.
CI  - 2022 Stem Cell Investigation. All rights reserved.
FAU - Kang, Yubin
AU  - Kang Y
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, Duke University Medical Center, Durham, NC, USA.
FAU - Armstrong, Andrew J
AU  - Armstrong AJ
AD  - 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.
FAU - Hsu, David S
AU  - Hsu DS
AD  - 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.
AD  - Center for Genomics and Computational Biology, Duke University, Durham, NC, USA.
LA  - eng
GR  - R01 CA233585/CA/NCI NIH HHS/United States
PT  - Case Reports
DEP - 20221108
PL  - China
TA  - Stem Cell Investig
JT  - Stem cell investigation
JID - 101672113
PMC - PMC9659479
OTO - NOTNLM
OT  - Metastatic clear cell renal cell carcinoma (mRCC)
OT  - case report
OT  - immunotherapy
OT  - nivolumab
OT  - patient-derived xenografts (PDXs)
COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure 
      form (available at 
      https://sci.amegroups.com/article/view/10.21037/sci-2022-029/coif). DSH and YK 
      were funded by NIH U01 CA217514. AJA was funded by NIH R01 (5R01CA233585-04). 
      Besides, he was supported by Astellas, Pfizer, Bayer, Janssen, Dendreon, 
      Genentech/Roche, BMS, AstraZeneca, Merck, Constellation, Beigene, Forma, Celgene 
      and Amgen, irrelevant to current manuscript; he received consulting fees from 
      Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, 
      Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant and Exelixis, irrelevant 
      to current manuscript.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/18 06:01
PMCR- 2022/11/08
CRDT- 2022/11/17 13:11
PHST- 2022/09/16 00:00 [received]
PHST- 2022/10/19 00:00 [accepted]
PHST- 2022/11/17 13:11 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/18 06:01 [medline]
PHST- 2022/11/08 00:00 [pmc-release]
AID - sci-09-2022-029 [pii]
AID - 10.21037/sci-2022-029 [doi]
PST - epublish
SO  - Stem Cell Investig. 2022 Nov 8;9:8. doi: 10.21037/sci-2022-029. eCollection 2022.