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THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL

ABSTRACT: Abstract The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.

SUBMITTER: Inigo-Marco I

PROVIDER: S-EPMC7715674 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Project description:Abstract Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. The objective of this study was to evaluate the suitability of DNX-2401 as treatment for pHGG/DIPGs. Our results showed that DNX-2401 exerts a potent antitumor effect in pHGG (n=5) and DIPG (n=6) cell lines in vitro and in vivo. Our clinical trial experience with DNX-2401 in adult glioblastoma underscored the importance of the immune system in durable responses observed in patients. DNX-2401 administration in two DIPG immunocompent models was safe and without toxicity. DNX-2401 prolonged the overall survival, leading 20% to 80% of long-term survivors. Histologic examination showed that DNX-2401 stimulated T-cell infiltration (CD3+, CD4+ and CD8+; p<0.001) within the tumor. Esplenocytes from DNX-2401 treated-mice co-cultured with tumor cells significantly increase the IFNg production (p<0.0001). These outstanding preclinical results allowed us to open a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. Up to date 7 patients have been treated within the trial (3x1010viral particles in 1mL). The procedure was well tolerated and safe. Patients were home 3–4 days after the procedure. All the patients displayed a reduced tumor volume after combined treatment. In the next weeks, we will have information regarding the median survival. We are currently conducting molecular and functional studies to assess the response of the patients to the virus. Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumor patients.

Project description:Abstract Despite our increased understanding of Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains dismal. Recently we showed that the virus Delta-24-RGD (DNX-2401 in the clinic) was effective in preclinical models of DIPG and had the ability to trigger an antitumor immune response. These data allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. The main objective is to determine the safety, tolerability, and toxicity of DNX-2401. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 9 out of the 12 patients. The immune cell composition of the biopsies was assessed using multiplexed quantitative immunofluorescence. T cells were hardly noticeable in these tumors while macrophages were abundant. We detected increased clonal T cell diversity following treatment with virus in peripheral blood lymphocytes when compared paired pre- and post-treatment samples from the trial. In addition, we measure pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). Overall, the administration of DNX2401 was safe, feasible and therapeutically beneficial in a subgroup of patients. This trial constitutes a proof of principle that aids to understand the response of DIPGs to viral therapies allowing to set the bases to improve this strategy for DIPG.

Project description:Abstract BACKGROUND Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Recently our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These outstanding preclinical results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. MATERIALS AND METHODS A phase I clinical trial with DNX-2401 for patients with newly diagnosed DIPG to assess the MTD is taking place in our hospital (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection. The virus is injected using a cannula, MEMS cannula (Alcyone Lifesciences) that prevents the reflux. Virus will be injected starting with 1010 pv. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG and to collect tumor samples of this type of tumor. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. The follow up includes close monitoring of neurological status, blood tests and brain MRI. If this trial shows evidence of safety and efficacy will propel a multicenter clinical trial. RESULTS All the clinical data from the trial available until September 2019 will be presented during the congress, to date 8 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 6 out of the 8 patients. We are currently assessing the immune responses to the virus. CONCLUSIONS Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumors.

Project description:Abstract Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral injection of DNX-2401 (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection using a cannula that prevents the reflux. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. To date 9 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 8 out of the 9 patients (RNAseq and a thermofisher pediatric panel). Subsequently we evaluated the immune cell composition in the tumor using multiplexed quantitative immunofluorescence on the biopsies pre-virus injection. T cells were hardly noticeable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with virus. In addition, we are assessing the existence of pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we have performed functional studies using 2 cell lines isolated from patients included in this trials and confronting them with T-cells isolated from peripheral blood of the same patients before and after the treatment with the virus. Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival of pediatric brain tumors.

Project description:Abstract As part of a phase 1, dose-escalation, biological-endpoint clinical study (NCT00805376) of DNX-2401 (Delta-24-RGD), a Rb-targeted, tumor-selective, replication-competent oncolytic adenovirus, conducted in 37 patients with recurrent malignant glioma, 12 patients received an intratumoral injection through an implanted catheter, followed 14-days later by en bloc resection and DNX-2401 injections into the post-resection tumor bed. 10 surgical post-treatment specimens and 5 pre-treated tumors were examined for markers of immune response. From all selected cases, formalin fixed, paraffin embedded tissue blocks were selected. IHC was performed using a Leica Bond Max automated stainer as previously described. The slides were scanned in an Aperio AT2 scanner (Leica Biosystems). The IHC scores for CD3, CD4, CD8, CD45Ro, FOXP3, TIM3, LAG-3, VISTA, CD20, CD57, CD68, and OX40 were expressed as cell density in the inflammatory cell population (number of positive cells per mm square of tumor area), except PD-L1, PD-L2, B7-H3, B7-H4, IDO-1, which were expressed using percentage of positive tumor cells, and also as H-Score of the tumor cells. Correlations between immunostaining marker values and survival and dose level were assessed using Spearman rank correlation analysis. Differences in immunostaining marker values before and after treatment were assessed. These analyses demonstrated that all the target proteins are expressed in gliomas in different patterns and tumor regions. Although, we did not observe significant treatment-related changes in the expression of PD-1 in lymphocytes and PD-L1 in glioma cells, TIM3, a marker for T cell exhaustion, was downregulated after DNX-2401 treatment. In addition, expression of B7-H3, a marker of poor prognosis in other tumors, correlated with poorer survival. Because PD-1 and TIM3 cooperate to maintain T-cell exhaustion our data provide a rationale for the combination of DNX-2401 and anti-PD-1 antibodies for the treatment of malignant gliomas. A multicenter clinical trial (NCT02798406) to test this strategy is ongoing.

Dataset Information

THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL

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