title: Exploiting antitumor immunity to overcome relapse and improve remission duration.
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.
authors.affiliation: Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, USA. leileichen7@gmail.com
authors.forename: Lei L
authors.initials: LL
authors.lastname: Chen
authors.forename: Xinjian
authors.initials: X
authors.lastname: Chen
authors.forename: Haesun
authors.initials: H
authors.lastname: Choi
authors.forename: Hongxun
authors.initials: H
authors.lastname: Sang
authors.forename: Leo C
authors.initials: LC
authors.lastname: Chen
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.forename: Launce
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authors.lastname: Gouw
authors.forename: Robert H
authors.initials: RH
authors.lastname: Andtbacka
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chan
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Rodesch
authors.forename: Arnie
authors.initials: A
authors.lastname: Jimenez
authors.forename: Pedro
authors.initials: P
authors.lastname: Cano
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Jones
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Oyedeji
authors.forename: Tom
authors.initials: T
authors.lastname: Martins
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schumacher
authors.forename: Carlynn
authors.initials: C
authors.lastname: Willmore
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: John H
authors.initials: JH
authors.lastname: Ward
authors.forename: Kathryn
authors.initials: K
authors.lastname: Morton
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Shreyaskumar
authors.initials: S
authors.lastname: Patel
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Patrick
authors.initials: P
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Jensen
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D018572:Disease-Free Survival; D005770:Gastrointestinal Neoplasms / Q000276:immunology / Q000628:therapy*; D046152:Gastrointestinal Stromal Tumors / Q000276:immunology / Q000628:therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007167:Immunotherapy / Q000379:methods; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D001549:Benzamides; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D000068877:Imatinib Mesylate; C417083:peginterferon alfa-2b