Exploiting antitumor immunity to overcome relapse and improve remission duration

Lei L. Chen, Xinjian Chen, Haesun Choi, Hongxun Sang, Leo C. Chen, Hongbo Zhang, Launce Gouw, Robert H. Andtbacka, Benjamin K. Chan, Christopher K. Rodesch, Arnie Jimenez, Pedro Cano, Kimberly A. Jones, Caroline O. Oyedeji, Tom Martins, Harry R. Hill, Jonathan Schumacher, Carlynn Willmore, Courtney L. Scaife, John H. WardKathryn Morton, R Randall, Alexander J. Lazar, Shreyaskumar Patel, Jonathan C. Trent, Marsha L. Frazier, Patrick Lin, Peter Jensen, Robert S. Benjamin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1113-1124
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume61
Issue number7
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

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Immunity
Recurrence
Natural Killer Cells
Neoplasms
Th1 Cells
Gastrointestinal Stromal Tumors
Neoplastic Stem Cells
Cytotoxic T-Lymphocytes
Clone Cells
Tumor-Infiltrating Lymphocytes
Leukopenia
Neoplasm Antigens
Pharmaceutical Preparations
Immunotherapy
Dendritic Cells
Disease-Free Survival
Survivors
Genotype
Clinical Trials
Lymphocytes

Keywords

  • GIST
  • IFN-α
  • IFN-γ
  • Imatinib
  • Immunotherapy
  • Peginterferon α-2b

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Chen, L. L., Chen, X., Choi, H., Sang, H., Chen, L. C., Zhang, H., ... Benjamin, R. S. (2012). Exploiting antitumor immunity to overcome relapse and improve remission duration. Cancer Immunology, Immunotherapy, 61(7), 1113-1124. https://doi.org/10.1007/s00262-011-1185-1

Exploiting antitumor immunity to overcome relapse and improve remission duration. / Chen, Lei L.; Chen, Xinjian; Choi, Haesun; Sang, Hongxun; Chen, Leo C.; Zhang, Hongbo; Gouw, Launce; Andtbacka, Robert H.; Chan, Benjamin K.; Rodesch, Christopher K.; Jimenez, Arnie; Cano, Pedro; Jones, Kimberly A.; Oyedeji, Caroline O.; Martins, Tom; Hill, Harry R.; Schumacher, Jonathan; Willmore, Carlynn; Scaife, Courtney L.; Ward, John H.; Morton, Kathryn; Randall, R; Lazar, Alexander J.; Patel, Shreyaskumar; Trent, Jonathan C.; Frazier, Marsha L.; Lin, Patrick; Jensen, Peter; Benjamin, Robert S.

In: Cancer Immunology, Immunotherapy, Vol. 61, No. 7, 01.07.2012, p. 1113-1124.

Research output: Contribution to journalArticle

Chen, LL, Chen, X, Choi, H, Sang, H, Chen, LC, Zhang, H, Gouw, L, Andtbacka, RH, Chan, BK, Rodesch, CK, Jimenez, A, Cano, P, Jones, KA, Oyedeji, CO, Martins, T, Hill, HR, Schumacher, J, Willmore, C, Scaife, CL, Ward, JH, Morton, K, Randall, R, Lazar, AJ, Patel, S, Trent, JC, Frazier, ML, Lin, P, Jensen, P & Benjamin, RS 2012, 'Exploiting antitumor immunity to overcome relapse and improve remission duration', Cancer Immunology, Immunotherapy, vol. 61, no. 7, pp. 1113-1124. https://doi.org/10.1007/s00262-011-1185-1
Chen, Lei L. ; Chen, Xinjian ; Choi, Haesun ; Sang, Hongxun ; Chen, Leo C. ; Zhang, Hongbo ; Gouw, Launce ; Andtbacka, Robert H. ; Chan, Benjamin K. ; Rodesch, Christopher K. ; Jimenez, Arnie ; Cano, Pedro ; Jones, Kimberly A. ; Oyedeji, Caroline O. ; Martins, Tom ; Hill, Harry R. ; Schumacher, Jonathan ; Willmore, Carlynn ; Scaife, Courtney L. ; Ward, John H. ; Morton, Kathryn ; Randall, R ; Lazar, Alexander J. ; Patel, Shreyaskumar ; Trent, Jonathan C. ; Frazier, Marsha L. ; Lin, Patrick ; Jensen, Peter ; Benjamin, Robert S. / Exploiting antitumor immunity to overcome relapse and improve remission duration. In: Cancer Immunology, Immunotherapy. 2012 ; Vol. 61, No. 7. pp. 1113-1124.
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AU - Zhang, Hongbo

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AU - Andtbacka, Robert H.

AU - Chan, Benjamin K.

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AU - Jones, Kimberly A.

AU - Oyedeji, Caroline O.

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