Exploiting antitumor immunity to overcome relapse and improve remission duration

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• 作者：Lei L. Chen (1) leileichen7@gmail.com
  Xinjian Chen (2)
  Haesun Choi (8)
  Hongxun Sang (14)
  Leo C. Chen (15)
  Hongbo Zhang (16)
  Launce Gouw (1)
  Robert H. Andtbacka (3)
  Benjamin K. Chan (4)
  Christopher K. Rodesch (4)
  Arnie Jimenez (17)
  Pedro Cano (9)
  Kimberly A. Jones (1)
  Caroline O. Oyedeji (11)
  Tom Martins (7)
  Harry R. Hill (7)
  Jonathan Schumacher (7)
  Carlynn Willmore (7)
  Courtney L. Scaife (3)
  John H. Ward (1)
  Kathryn Morton (5)
  R. Lor Randall (6)
  Alexander J. Lazar (10)
  Shreyaskumar Patel (11)
  Jonathan C. Trent (11)
  Marsha L. Frazier (13)
  Patrick Lin (12)
  Peter Jensen (2)
  Robert S. Benjamin (11)
• 关键词：IFN ; γ ; – ; IFN ; α ; – ; Peginterferon α ; 2b – ; GIST – ; Imatinib – ; Immunotherapy
• 刊名：Cancer Immunology, Immunotherapy
• 出版年：2012
• 出版时间：July 2012
• 年：2012
• 卷：61
• 期：7
• 页码：1113-1124
• 全文大小：1.3 MB
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• 作者单位：1. Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA2. Department of Pathology, University of Utah, Salt Lake City, UT, USA3. Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA4. Department of Core Facilities, University of Utah, Salt Lake City, UT, USA5. Department of Radiology, University of Utah, Salt Lake City, UT, USA6. Department of Orthopedic Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA7. ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, UT, USA8. Department of Radiology, University of Texas M D Anderson Cancer Center, Houston, TX, USA9. Laboratory Medicine, University of Texas M D Anderson Cancer Center, Houston, TX, USA10. Department of Pathology, University of Texas M D Anderson Cancer Center, Houston, TX, USA11. Department of Sarcoma, University of Texas M D Anderson Cancer Center, Houston, TX, USA12. Department of Orthopedic Surgery, University of Texas M D Anderson Cancer Center, Houston, TX, USA13. Department of Epidemiology, Graduate School of Biomedical Sciences, University of Texas M D Anderson Cancer Center, Houston, TX, USA14. Department of Orthopaedic Surgery, Institute of Orthopaedics, Xijing Hospital, Xi鈥檃n, People鈥檚 Republic of China15. School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA16. Department of Forensic Science, Xi鈥檃n Jiaotong University, Xi鈥檃n, People鈥檚 Republic of China17. Vel-Lab Research, Missouri City, TX, USA
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Immunology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0851

文摘

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient’s lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient’s own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib’s effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8+, -CD4+, -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types.