Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy

被引:73
作者
Sterman, Daniel H. [1 ,13 ,14 ]
Alley, Evan [2 ]
Stevenson, James P. [2 ]
Friedberg, Joseph [3 ]
Metzger, Susan [1 ]
Recio, Adri [1 ]
Moon, Edmund K. [1 ]
Haas, Andrew R. [1 ]
Vachani, Anil [1 ]
Katz, Sharyn I. [4 ]
Sun, Jing [1 ]
Heitjan, Daniel F. [5 ,10 ,11 ]
Hwang, Wei-Ting [5 ]
Litzky, Leslie [6 ]
Yearley, Jennifer H. [7 ]
Tan, Kay See [5 ,12 ]
Papasavvas, Emmanouil [8 ]
Kennedy, Paul [1 ]
Montaner, Luis J. [8 ]
Cengel, Keith A. [9 ]
Simone, Charles B., II [9 ]
Culligan, Melissa [3 ]
Langer, Corey J. [2 ]
Albelda, Steven M. [1 ]
机构
[1] Univ Penn, Dept Med, Div Pulm Allergy & Crit Care Med, Perelman Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Med, Div Hematol Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA
[3] Univ Maryland, Sch Med, Div Thorac Surg, Baltimore, MD 21201 USA
[4] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA
[5] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA
[6] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
[7] Merck & Co Inc, Kenilworth, NJ USA
[8] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA
[9] Univ Penn, Dept Radiat Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA
[10] Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA
[11] Southern Methodist Univ, Dept Stat Sci, Dallas, TX USA
[12] Mem Sloan Kettering Canc Ctr, Div Biostat, Dept Epidemiol & Biostat, New York, NY 10021 USA
[13] NYU, Langone Med Ctr, Div Pulm Crit Care & Sleep Med, Dept Med, New York, NY USA
[14] NYU, Langone Med Ctr, Div Pulm Crit Care & Sleep Med, Dept Cardiothorac Surg, New York, NY USA
关键词
PHASE-I TRIAL; PLEURAL MESOTHELIOMA; INTERFERON-ALPHA; CANCER; IMMUNOTHERAPY; SURVIVAL; VACCINES; MECHANISMS; AUGMENTS; EFFICACY;
D O I
10.1158/1078-0432.CCR-15-2133
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. Experimental Design: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFN alpha 2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured. Results: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOSin the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFN alpha in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. Conclusions: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. (C) 2016 AACR.
引用
收藏
页码:3791 / 3800
页数:10
相关论文
共 34 条
[1]   Current Issues in Malignant Pleural Mesothelioma Evaluation and Management [J].
Ai, Jing ;
Stevenson, James P. .
ONCOLOGIST, 2014, 19 (09) :975-984
[2]   Interferon-α as Antiviral and Antitumor Vaccine Adjuvants: Mechanisms of Action and Response Signature [J].
Arico, Eleonora ;
Belardelli, Filippo .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2012, 32 (06) :235-247
[3]  
BOUTIN C, 1994, CANCER, V74, P2460, DOI 10.1002/1097-0142(19941101)74:9<2460::AID-CNCR2820740912>3.0.CO
[4]  
2-N
[5]   Modified RECIST criteria for assessment of response in malignant pleural mesothelioma [J].
Byrne, MJ ;
Nowak, AK .
ANNALS OF ONCOLOGY, 2004, 15 (02) :257-260
[6]   Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial [J].
Calabro, Luana ;
Morra, Aldo ;
Fonsatti, Ester ;
Cutaia, Ornella ;
Amato, Giovanni ;
Giannarelli, Diana ;
Di Giacomo, Anna Maria ;
Danielli, Riccardo ;
Altomonte, Maresa ;
Mutti, Luciano ;
Maio, Michele .
LANCET ONCOLOGY, 2013, 14 (11) :1104-1111
[7]   Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence [J].
de Biasi, Andreas R. ;
Villena-Vargas, Jonathan ;
Adusumilli, Prasad S. .
CLINICAL CANCER RESEARCH, 2014, 20 (21) :5384-5391
[8]   Phase I Trial of Intravesical Recombinant Adenovirus Mediated Interferon-α2b Formulated in Syn3 for Bacillus Calmette-Guerin Failures in Nonmuscle Invasive Bladder Cancer [J].
Dinney, Colin P. N. ;
Fisher, Mark B. ;
Navai, Neema ;
O'Donnell, Michael A. ;
Cutler, David ;
Abraham, Alice ;
Young, Sophia ;
Hutchins, Beth ;
Caceres, Maria ;
Kishnani, Narendra ;
Sode, George ;
Cullen, Constance ;
Zhang, Guangcheng ;
Grossman, H. Barton ;
Kamat, Ashish M. ;
Gonzales, Marshall ;
Kincaid, Michael ;
Ainslie, Nancy ;
Maneval, Daniel C. ;
Wszolek, Matthew F. ;
Benedict, William F. .
JOURNAL OF UROLOGY, 2013, 190 (03) :850-856
[9]   Interferon-α and cancer:: Mechanisms of action and new perspectives of clinical use [J].
Ferrantini, Maria ;
Capone, Imerio ;
Belardelli, Filippo .
BIOCHIMIE, 2007, 89 (6-7) :884-893
[10]   Chemotherapy Delivered After Viral Immunogene Therapy Augments Antitumor Efficacy Via Multiple Immune-mediated Mechanisms [J].
Fridlender, Zvi G. ;
Sun, Jing ;
Singhal, Sunil ;
Kapoor, Veena ;
Cheng, Guanjun ;
Suzuki, Eiji ;
Albelda, Steven M. .
MOLECULAR THERAPY, 2010, 18 (11) :1947-1959