First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

被引：402

作者：

Liau, Linda M. ^{[1
,2
]}

Ashkan, Keyoumars ^{[3
]}

Tran, David D. ^{[4
]}

Campian, Jian L. ^{[5
]}

Trusheim, John E. ^{[6
]}

Cobbs, Charles S. ^{[7
]}

Heth, Jason A. ^{[8
]}

Salacz, Michael ^{[9
]}

Taylor, Sarah ^{[9
]}

D'andre, Stacy D. ^{[10
]}

Iwamoto, Fabio M. ^{[11
]}

Dropcho, Edward J. ^{[12
]}

Moshel, Yaron A. ^{[13
]}

Walter, Kevin A. ^{[14
]}

Pillainayagam, Clement P. ^{[15
]}

Aiken, Robert ^{[16
]}

Chaudhary, Rekha ^{[17
]}

Goldlust, Samuel A. ^{[18
]}

Bota, Daniela A. ^{[19
]}

Duic, Paul ^{[20
]}

Grewal, Jai ^{[60
]}

Elinzano, Heinrich ^{[21
]}

Toms, Steven A. ^{[21
]}

Lillehei, Kevin O. ^{[22
]}

Mikkelsen, Tom ^{[23
]}

Walpert, Tobias ^{[23
]}

Abram, Steven R. ^{[24
]}

Brenner, Andrew J. ^{[25
]}

Brem, Steven ^{[26
]}

Ewend, Matthew G. ^{[27
]}

Khagi, Simon ^{[27
]}

Portnow, Jana ^{[28
]}

Kim, Lyndon J. ^{[29
]}

Loudon, William G. ^{[30
]}

Thompson, Reid C. ^{[31
]}

Avigan, David E. ^{[32
]}

Fink, Karen L. ^{[33
]}

Geofroy, Francois J. ^{[34
]}

Lindhorst, Scott ^{[35
]}

Lutzky, Jose ^{[36
]}

Sloan, Andrew E. ^{[37
]}

Schackert, Gabriele ^{[38
]}

Krex, Dietmar ^{[38
]}

Meisel, Hans-Jorg ^{[39
]}

Wu, Julian ^{[40
]}

Davis, Raphael P. ^{[41
]}

Duma, Christopher ^{[42
]}

Etame, Arnold B. ^{[43
]}

Mathieu, David ^{[44
]}

Kesari, Santosh ^{[45
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA

[3] Kings Coll London, Sch Med Educ, London, England

[4] Univ Florida, Gainesville, FL USA

[5] Washington Univ, St Louis, MO USA

[6] Abbott NW Hosp, Minneapolis, MN 55407 USA

[7] Swedish Neurosci Inst, Swedish Med Ctr, Seattle, WA USA

[8] Univ Michigan, Med Sch, Ann Arbor, MI USA

[9] Univ Kansas, Canc Ctr, Kansas City, KS USA

[10] Sutter Inst Med Res, Sacramento, CA USA

[11] Columbia Univ, Med Ctr, New York, NY USA

[12] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA

[13] Overlook Med Ctr, Summit, NJ USA

[14] Univ Rochester, Med Ctr, Rochester, NY 14642 USA

[15] Rush Univ, Med Ctr, Rochester, NY USA

[16] Rutgers Canc Inst, New Brunswick, NJ USA

[17] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA

[18] Hackensack Univ, Med Ctr, Hackensack, NJ USA

[19] UC Irvine Med Ctr, Irvine, CA USA

[20] Winthrop Univ Hosp, Mineola, NY 11501 USA

[21] Rhode Isl Hosp, Providence, RI USA

[22] Univ Colorado Hosp, Aurora, CO USA

[23] Henry Ford Hlth Syst, Detroit, MI USA

[24] St Thomas Res Inst, Nashville, TN USA

[25] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA

[26] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[27] Univ N Carolina, Chapel Hill, NC USA

[28] City Hope Natl Med Ctr, Natl Med Ctr, Duarte, CA USA

[29] Thomas Jefferson Univ, Philadelphia, PA 19107 USA

[30] St Joseph Hosp, Newport Beach, CA USA

[31] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA

[32] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[33] Baylor Univ, Med Ctr, Dallas, TX USA

[34] Illinois CancerCare, Peoria, IL USA

[35] Med Univ South Carolina, Charleston, SC 29425 USA

[36] Mt Sinai Comprehens Canc Ctr, Miami, FL USA

[37] Univ Hosp Case Med Ctr, Cleveland, OH USA

[38] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dresden, Germany

[39] BG Klinikum Bergmannstrost, Halle, Germany

[40] Tufts Univ, Sch Med, Boston, MA 02111 USA

[41] SUNY Stony Brook, Stony Brook, NY 11794 USA

[42] Hoag Canc Ctr, Newport Beach, CA USA

[43] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA

[44] Sherbrooke Univ, CHUS Hop Fleurimont, Sherbrooke, PQ, Canada

[45] Univ Calif San Diego, UCSD Hlth Syst, San Diego, CA USA

[46] Univ Clin Hamburg Eppendorf, Neurochirurg Klin, Hamburg, Germany

[47] Houston Methodist, Houston, TX USA

[48] Geisinger Hlth Syst, Danville, PA USA

[49] Klinikum Chemnitz GGMBH, Chemnitz, Germany

[50] St Lukes Canc Inst, Kansas City, MO USA

来源：

JOURNAL OF TRANSLATIONAL MEDICINE | 2018年 / 16卷

关键词：

Glioblastoma; Immunotherapy; Dendritic cell; Vaccine; ADJUVANT TEMOZOLOMIDE; ANTITUMOR IMMUNITY; RANDOMIZED-TRIAL; TUMOR-ANTIGENS; OPEN-LABEL; IMMUNOTHERAPY; RADIOTHERAPY; BEVACIZUMAB; CONCOMITANT; RADIATION;

D O I：

10.1186/s12967-018-1507-6

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine - (DCVax (R)-L) to standard therapy for newly diagnosed glioblastoma. Methods: After surgery and chemoradiotherapy, patients were randomized (2: 1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are = 30 months past their surgery date; 67 of these (30.0%) have lived >= 30 months and have a Kaplan-Meier (KM)derived mOS of 46.5 months. 182 patients are >= 36 months past surgery; 44 of these (24.2%) have lived >= 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.

引用

页数：9

共 30 条

[1] Phase III Randomized Trial Comparing the Efficacy of Cediranib As Monotherapy, and in Combination With Lomustine, Versus Lomustine Alone in Patients With Recurrent Glioblastoma [J].

Batchelor, Tracy T. ;

Mulholland, Paul ;

Neyns, Bart ;

Nabors, L. Burt ;

Campone, Mario ;

Wick, Antje ;

Mason, Warren ;

Mikkelsen, Tom ;

Phuphanich, Surasak ;

Ashby, Lynn S. ;

DeGroot, John ;

Gattamaneni, Rao ;

Cher, Lawrence ;

Rosenthal, Mark ;

Payer, Franz ;

Juergensmeier, Juliane M. ;

Jain, Rakesh K. ;

Sorensen, A. Gregory ;

Xu, John ;

Liu, Qi ;

van den Bent, Martin .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (26) :3212-3218

[2]

Chinot OL, 2014, NEW ENGL J MED, V370, P709, DOI 10.1056/NEJMoa1308345

[3] RECURSIVE PARTITIONING ANALYSIS OF PROGNOSTIC FACTORS IN 3 RADIATION-THERAPY ONCOLOGY GROUP MALIGNANT GLIOMA TRIALS [J].

CURRAN, WJ ;

SCOTT, CB ;

HORTON, J ;

NELSON, JS ;

WEINSTEIN, AS ;

FISCHBACH, AJ ;

CHANG, CH ;

ROTMAN, M ;

ASBELL, SO ;

KRISCH, RE ;

NELSON, DF .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1993, 85 (09) :704-710

[4] Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma [J].

Friedman, Henry S. ;

Prados, Michael D. ;

Wen, Patrick Y. ;

Mikkelsen, Tom ;

Schiff, David ;

Abrey, Lauren E. ;

Yung, W. K. Alfred ;

Paleologos, Nina ;

Nicholas, Martin K. ;

Jensen, Randy ;

Vredenburgh, James ;

Huang, Jane ;

Zheng, Maoxia ;

Cloughesy, Timothy .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (28) :4733-4740

[5] A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma [J].

Gilbert, Mark R. ;

Dignam, James J. ;

Armstrong, Terri S. ;

Wefel, Jeffrey S. ;

Blumenthal, Deborah T. ;

Vogelbaum, Michael A. ;

Colman, Howard ;

Chakravarti, Arnab ;

Pugh, Stephanie ;

Won, Minhee ;

Jeraj, Robert ;

Brown, Paul D. ;

Jaeckle, Kurt A. ;

Schiff, David ;

Stieber, Volker W. ;

Brachman, David G. ;

Werner-Wasik, Maria ;

Tremont-Lukats, Ivo W. ;

Sulman, Erik P. ;

Aldape, Kenneth D. ;

Curran, Walter J., Jr. ;

Mehta, Minesh P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (08) :699-708

[6] Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors [J].

Grossman, Stuart A. ;

Ellsworth, Susannah ;

Campian, Jian ;

Wild, Aaron T. ;

Herman, Joseph M. ;

Laheru, Dan ;

Brock, Malcolm ;

Balmanoukian, Ani ;

Ye, Xiaobu .

JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2015, 13 (10) :1225-1231

[7] Immuno-oncology combinations: raising the tail of the survival curve [J].

Harris, Sarnuel J. ;

Brown, Jessica ;

Lopez, Juanita ;

Yap, Timothy A. .

CANCER BIOLOGY & MEDICINE, 2016, 13 (02) :171-193

[8] Cellular and vaccine therapeutic approaches for gliomas [J].

Hickey, Michelle J. ;

Malone, Colin C. ;

Erickson, Kate L. ;

Jadus, Martin R. ;

Prins, Robert M. ;

Liau, Linda M. ;

Kruse, Carol A. .

JOURNAL OF TRANSLATIONAL MEDICINE, 2010, 8

[9] Optimizing dendritic cell vaccine for immunotherapy in multiple myeloma: tumour lysates are more potent tumour antigens than idiotype protein to promote anti-tumour immunity [J].

Hong, S. ;

Li, H. ;

Qian, J. ;

Yang, J. ;

Lu, Y. ;

Yi, Q. .

CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2012, 170 (02) :167-177

[10] Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis [J].

Larkin, James ;

Chmielowski, Bartosz ;

Lao, Christopher D. ;

Hodi, F. Stephen ;

Sharfman, William ;

Weber, Jeffrey ;

Suijkerbuijk, Karijn P. M. ;

Azevedo, Sergio ;

Li, Hewei ;

Reshef, Daniel ;

Avila, Alexandre ;

Reardon, David A. .

ONCOLOGIST, 2017, 22 (06) :709-718

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