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n3:pmcid
PMC0
bibo:doi
10.1186%2Fs12967-018-1507-6
n6:contains
_:vb78101393 _:vb78101404 _:vb78101379 _:vb78101389
Subject Item
_:vb78101379
rdf:type
n6:Section
dc:title
results
n6:contains
_:vb78101384 _:vb78101385 _:vb78101386 _:vb78101387 _:vb78101388 _:vb78101380 _:vb78101381 _:vb78101382 _:vb78101383
Subject Item
_:vb78101380
rdf:type
n3:Context
rdf:value
The ITT population (n = 331) (Table 1) is similar to other recent glioblastoma trials [>>4<<, 21, 24], with 61% males (n = 202) and 39% females (n = 129), with 75.2% of the patients ≥ 50 years of age (range 19–73 years), and median KPS of 90.
n3:mentions
n2:26670971
Subject Item
_:vb78101381
rdf:type
n3:Context
rdf:value
The ITT population (n = 331) (Table 1) is similar to other recent glioblastoma trials [4, 21, >>24<<], with 61% males (n = 202) and 39% females (n = 129), with 75.2% of the patients ≥ 50 years of age (range 19–73 years), and median KPS of 90.
n3:mentions
n2:29260225
Subject Item
_:vb78101382
rdf:type
n3:Context
rdf:value
Absolute lymphocyte count (ALC) was > 800 cells/mm3 in 48.6% of the patients (n = 161) and was < 800 cells/mm3 in 51.4% of patients (n = 170), a characteristic that has been associated with poor prognosis after radiation [>>23<<]. Patients with radiographic evidence of disease progression at baseline were excluded, as they have also been excluded in other recent trials for newly diagnosed glioblastoma [4, 21, 24].Table
n3:mentions
n2:26483062
Subject Item
_:vb78101383
rdf:type
n3:Context
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Patients with radiographic evidence of disease progression at baseline were excluded, as they have also been excluded in other recent trials for newly diagnosed glioblastoma [>>4<<, 21, 24].Table
n3:mentions
n2:26670971
Subject Item
_:vb78101384
rdf:type
n3:Context
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Patients with radiographic evidence of disease progression at baseline were excluded, as they have also been excluded in other recent trials for newly diagnosed glioblastoma [4, 21, >>24<<].Table
n3:mentions
n2:29260225
Subject Item
_:vb78101385
rdf:type
n3:Context
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In multiple reported studies, neither bevacizumab nor CCNU have been shown to extend survival [>>9<<, 25].
n3:mentions
n2:24552318
Subject Item
_:vb78101386
rdf:type
n3:Context
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In multiple reported studies, neither bevacizumab nor CCNU have been shown to extend survival [9, >>25<<].
n3:mentions
n2:19720927
Subject Item
_:vb78101387
rdf:type
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With immune-based therapies, a key focus is on the tail of the survival curve [>>26<<]. Among the ITT patients with a surgery date ≥ 30 months prior to the data collection (n = 223), 30% (n = 67) have lived ≥ 30 months, and their KM-derived mOS estimate is 46.5 months.
n3:mentions
n2:27458526
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Following SOC chemoradiotherapy, and before any DCVax-L treatment, lymphopenia was the most common adverse event, occurring in approximately 170 patients (51%) [>>23<<].
n3:mentions
n2:26483062
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methods
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Other eligibility criteria included Karnofsky Performance Score (KPS) of ≥ 70 [>>20<<], adequate bone marrow, liver, and renal function, life expectancy of ≥ 8 weeks, no other prior malignancy within the last 5 years, no active viral infections, and sufficient resected tumor material to produce the autologous vaccine.
n3:mentions
n2:8478956
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Patients were excluded if they already had apparent early disease progression/recurrence or pseudo-progression at the baseline visit, similar to the inclusion/exclusion criteria of other recent trials in glioblastoma [>>4<<, 21].
n3:mentions
n2:26670971
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The vaccine was aliquoted in individual doses and cryopreserved at < 150 °C [>>22<<]. The doses were stored centrally, and shipped individually to the clinical trial sites.
n3:mentions
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For example, Weller et al. reported mOS of 17.4 months from randomization in the ITT population [21], and Stupp et al. reported mOS of 16.0 months from randomization in the ITT population [>>24<<].
n3:mentions
n2:29260225
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For example, Stupp et al. reported for their control group an mOS of 21.2 months from randomization in a similar patient population [>>24<<]. The increase in survival in MGMT-methylated patients in the DCVax-L trial raises the possibility of a cooperative effect from the combination of temozolomide chemotherapy and the DCVax-L active immune therapy [17].
n3:mentions
n2:29260225
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The increase in survival in MGMT-methylated patients in the DCVax-L trial raises the possibility of a cooperative effect from the combination of temozolomide chemotherapy and the DCVax-L active immune therapy [>>17<<].
n3:mentions
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It will be collected and analyzed later, but is unlikely to explain the overall survival results, as the mutation associated with prolonged survival occurs in less than 10% of newly diagnosed glioblastoma patients [>>27<<].
n3:mentions
n2:18772396
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Beneficial effects of immune therapies are often observed at later time points, in the tail of the survival curve [>>26<<]. Although this Phase 3 trial requires further maturation, a picture is beginning to emerge from the blinded interim data which is consistent with an extended survival tail.
n3:mentions
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Thus, it appears that patients who survive past certain threshold time points may continue onwards to unusually long survival times, similar to the findings in our prior Phase I/II studies of this DC-based vaccine [>>17<<–19]. Further maturation of the trial data is needed to more fully reveal the extent of the long tail of the survival curve.
n3:mentions
n2:21135147 n2:18669440 n2:16061868
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DCVax-L has shown a benign safety profile in this Phase 3 study, as it has consistently done in prior early stage trials [>>17<<, 19], and in a large group of patients treated on a compassionate use basis [28].
n3:mentions
n2:16061868
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DCVax-L has shown a benign safety profile in this Phase 3 study, as it has consistently done in prior early stage trials [17, >>19<<], and in a large group of patients treated on a compassionate use basis [28].
n3:mentions
n2:21135147
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be combined with a wide range of other treatment agents, including immune checkpoint inhibitors and targeted therapies, without resulting in undue toxicities for patients such as have been seen with some other treatment combinations [>>29<<, 30]. Further studies to explore such combinations are warranted.
n3:mentions
n2:28495807
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combined with a wide range of other treatment agents, including immune checkpoint inhibitors and targeted therapies, without resulting in undue toxicities for patients such as have been seen with some other treatment combinations [29, >>30<<]. Further studies to explore such combinations are warranted.
n3:mentions
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Glioblastoma is the most aggressive primary malignant brain tumor in adults [>>1<<]. Standard of care (SOC) consists of surgical resection followed by 6 weeks of daily radiotherapy with concurrent temozolomide, then monthly temozolomide [2].
n3:mentions
n2:28475809
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Standard of care (SOC) consists of surgical resection followed by 6 weeks of daily radiotherapy with concurrent temozolomide, then monthly temozolomide [>>2<<]. Median overall survival (mOS) under this SOC is only 15–17 months [2, 3], and ≤ 5% of patients are alive at 5 years [3]. Loco-regional therapy with alternating electric fields has recently shown an increase in median PFS (mPFS) to 6.7
n3:mentions
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Median overall survival (mOS) under this SOC is only 15–17 months [>>2<<, 3], and ≤ 5% of patients are alive at 5 years [3].
n3:mentions
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Median overall survival (mOS) under this SOC is only 15–17 months [2, >>3<<], and ≤ 5% of patients are alive at 5 years [3].
n3:mentions
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Median overall survival (mOS) under this SOC is only 15–17 months [2, 3], and ≤ 5% of patients are alive at 5 years [>>3<<]. Loco-regional therapy with alternating electric fields has recently shown an increase in median PFS (mPFS) to 6.7 months and mOS to 20.9 months from randomization, respectively [4]. However, there has been no material advance in
n3:mentions
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Loco-regional therapy with alternating electric fields has recently shown an increase in median PFS (mPFS) to 6.7 months and mOS to 20.9 months from randomization, respectively [>>4<<]. However, there has been no material advance in survival with systemic therapies since the addition of temozolomide 12 years ago, despite investigations with many diverse agents [2, 5–10].
n3:mentions
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However, there has been no material advance in survival with systemic therapies since the addition of temozolomide 12 years ago, despite investigations with many diverse agents [>>2<<, 5–10].
n3:mentions
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However, there has been no material advance in survival with systemic therapies since the addition of temozolomide 12 years ago, despite investigations with many diverse agents [2, >>5<<–10].
n3:mentions
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Dendritic cells (DCs) are central to the immune system as key regulators of immune tolerance and immunity [>>11<<]. For more than a decade, our group and others have been testing active vaccination strategies, such as DCs pulsed with tumor lysates or synthetic peptides to induce antitumor immunity in glioblastoma patients [12, 13]. We have previously
n3:mentions
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For more than a decade, our group and others have been testing active vaccination strategies, such as DCs pulsed with tumor lysates or synthetic peptides to induce antitumor immunity in glioblastoma patients [>>12<<, 13]. We have previously demonstrated the effectiveness of DC vaccination in pre-clinical models [14–16], and early stage clinical trials have shown substantial promise [17–19].
n3:mentions
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For more than a decade, our group and others have been testing active vaccination strategies, such as DCs pulsed with tumor lysates or synthetic peptides to induce antitumor immunity in glioblastoma patients [12, >>13<<]. We have previously demonstrated the effectiveness of DC vaccination in pre-clinical models [14–16], and early stage clinical trials have shown substantial promise [17–19].
n3:mentions
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We have previously demonstrated the effectiveness of DC vaccination in pre-clinical models [>>14<<–16], and early stage clinical trials have shown substantial promise [17–19].
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We have previously demonstrated the effectiveness of DC vaccination in pre-clinical models [14–16], and early stage clinical trials have shown substantial promise [>>17<<–19].
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