Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial

被引：125

作者：

Nassiri, Farshad ^{[1
,2
]}

Patil, Vikas ^{[2
]}

Yefet, Leeor S. ^{[2
]}

Singh, Olivia ^{[2
]}

Liu, Jeff ^{[2
]}

Dang, Rachel M. A. ^{[3
]}

Yamaguchi, Takafumi N. ^{[3
]}

Daras, Mariza ^{[4
]}

Cloughesy, Timothy F. ^{[5
]}

Colman, Howard ^{[6
,7
]}

Kumthekar, Priya U. ^{[8
]}

Chen, Clark C. ^{[9
]}

Aiken, Robert ^{[10
]}

Groves, Morris D. ^{[11
]}

Ong, Shirley S. ^{[12
]}

Ramakrishna, Rohan ^{[13
]}

Vogelbaum, Michael A. ^{[14
]}

Khagi, Simon ^{[15
]}

Kaley, Thomas ^{[16
]}

Melear, Jason M. ^{[17
]}

Peereboom, David M. ^{[18
]}

Rodriguez, Analiz ^{[19
]}

Yankelevich, Maxim ^{[20
]}

Nair, Suresh G. ^{[21
]}

Puduvalli, Vinay K. ^{[22
]}

Aldape, Kenneth ^{[23
]}

Gao, Andrew ^{[24
]}

Lopez-Janeiro, Alvaro ^{[25
,26
]}

de Andrea, Carlos E. ^{[25
,26
]}

Alonso, Marta M. ^{[26
,27
,28
]}

Boutros, Paul ^{[3
]}

Robbins, Joan ^{[29
]}

Mason, Warren P. ^{[2
]}

Sonabend, Adam M. ^{[30
,31
]}

Stupp, Roger ^{[30
,31
,32
,33
]}

Fueyo, Juan ^{[22
]}

Gomez-Manzano, Candelaria ^{[22
]}

Lang, Frederick F. ^{[34
]}

Zadeh, Gelareh ^{[1
,2
,35
]}

机构：

[1] Univ Toronto, Div Neurosurg, Toronto, ON, Canada

[2] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[3] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[4] Univ Calif San Francisco, Div Neurooncol, San Francisco, CA USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Neurooncol Program, Los Angeles, CA USA

[6] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[7] Univ Utah, Dept Neurosurg, Salt Lake City, UT USA

[8] Northwestern Univ, Dept Neurol, Div Neurooncol, Feinberg Sch Med, Chicago, IL USA

[9] Univ Minnesota, Dept Neurosurg, Minneapolis, MI USA

[10] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ USA

[11] Texas Oncol, Dept Neurol, Austin, TX USA

[12] Ohio State Univ, Dept Neurol, Div Neurooncol, Wexner Med Ctr, Columbus, OH USA

[13] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Neurol Surg, New York, NY USA

[14] H Lee Moffitt Canc Ctr & Res Inst, Dept Neurooncol, Neurooncol Program, Tampa, FL USA

[15] Univ North Carolina Chapel Hill, Div Med Oncol, Chapel Hill, NC USA

[16] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY USA

[17] Baylor Univ, Dept Internal Med, Med Ctr, Dallas, TX USA

[18] Cleveland Clin, Rose Ella Burkhardt Brain Tumor & Neurooncol Ctr, Cleveland, OH USA

[19] Univ Arkansas Med Sci, Dept Neurosurg, Little Rock, AK USA

[20] Univ Michigan, Ann Arbor Beaumont Childrens Hosp, Dept Pediat, Royal Oak, MI USA

[21] Lehigh Valley Topper Canc Inst, Allentown, PA USA

[22] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX USA

[23] NCI, Lab Pathol, Bethesda, MD USA

[24] Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[25] Clin Univ Navarra, Dept Pathol, Pamplona, Spain

[26] Navarra Inst Hlth Res IdISNA, Pamplona, Spain

[27] Clin Univ Navarra, Dept Pediat, Pamplona, Spain

[28] Ctr Appl Med Res CIMA, Program Solid Tumors, Pamplona, Spain

[29] DNATrix Inc, Carlsbad, CA USA

[30] Northwestern Univ, Feinberg Sch Med, Dept Neurol Surg, Chicago, IL USA

[31] Northwestern Univ, Northwestern Med Malnati Brain Tumor Inst, Feinberg Sch Med, Lurie Comprehens Canc Ctr, Chicago, IL USA

[32] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Hematol Oncol, Chicago, IL USA

[33] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL USA

[34] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX USA

[35] Univ Toronto, Dept Surg, Toronto, ON, Canada

来源：

NATURE MEDICINE | 2023年 / 29卷 / 06期

关键词：

RESPONSE ASSESSMENT; COMBINED NIVOLUMAB; IPILIMUMAB; SURVIVAL; CRITERIA;

D O I：

10.1038/s41591-023-02347-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406). A safety and efficacy trial of a single intratumoral dose of the oncolytic adenovirus DNX-2401 followed by intravenous anti-PD-1 pembrolizumab in patients with recurrent glioblastoma shows an encouraging clinical benefit rate and 12 months overall survival.

引用

页码：1370 / +

页数：27

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