scholarly journals PDCT-18 (LTBK-03). PHASE I CLINICAL TRIAL WITH ONCOLYTIC VIRUS DNX-2401 FOR DIPGS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi283-vi284
Author(s):  
Ignacio Iñigo-Marco ◽  
Ricardo Díez-Valle ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González Huarriz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
Phase I ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Post Treatment ◽  
Phase I Clinical Trial ◽  
Tumor Biopsy

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.

scholarly journals CTIM-25. ONCOLYTIC VIRUS FOR DIPG: THE CLINICAL EXPERIENCE WITH DNX-2401

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Marta M Alonso ◽  
Ignacio Iñigo-Marco ◽  
Marc Garcia-Moure ◽  
Marisol González-Huarriz ◽  
Chris Jones ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Peripheral Blood Lymphocytes ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy

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.

scholarly journals OS5.1 Phase I clinical trial with oncolytic virus DNX-2401 for DIPGs

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii11-iii11
Author(s):  
M M Alonso ◽  
I Iñigo ◽  
M Gonzalez-Huarriz ◽  
P Dominguez ◽  
A Patiño ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Phase I ◽  
Brain Mri ◽  
Combined Treatment ◽  
High Grade Glioma ◽  
Phase I Clinical Trial ◽  
Close Monitoring ◽  
Newly Diagnosed ◽  
Tumor Biopsy

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.

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

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii473-iii473
Author(s):  
Ignacio Iñigo-Marco ◽  
Marisol Gonzalez-Huarriz ◽  
Marc García-Moure ◽  
Ibon Tamayo ◽  
Sandra Hervas ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy ◽  
Functional Studies ◽  
Cell Diversity

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.

Clinical scale facs-sorting and expansion of regulatory t cells (TREGS) for phase i clinical trial

Cytotherapy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. S196
Author(s):  
A. Ekwe ◽  
R. Au ◽  
B. McEnroe ◽  
M. Tan ◽  
A. Saldan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Regulatory T Cells ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Clinical Scale ◽  
Facs Sorting

scholarly journals Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

Gene Therapy ◽  
2008 ◽  
Vol 15 (12) ◽  
pp. 911-920 ◽  
Author(s):  
C L White ◽  
K R Twigger ◽  
L Vidal ◽  
J S De Bono ◽  
M Coffey ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Phase I ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Phase I Clinical Trial ◽  
Type 3

Preliminary effects on the innate immune system with the combination of cetuximab and durvalumab in metastatic/ relapsed head and neck squamous cell carcinoma in a phase II trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14273-e14273
Author(s):  
Shuchi Gulati ◽  
Rachel Vachon ◽  
Shireen Desai ◽  
Aubrey Steele ◽  
Sarah Palackdharry ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Innate Immune Response ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Post Treatment ◽  
Innate Immune ◽  
Adaptive Immune

e14273 Background: Cetuximab is a recombinant chimeric monoclonal IgG1 antibody which binds specifically to the epidermal growth factor receptor (EGFR) and stimulates an innate immune response by promoting natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab is approved as a single agent in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC). PD-1 check-point inhibitors which release the inhibition of the adaptive immune response, are also approved as single agents in this setting. However the response rates with these drugs, when used individually range from 10-20%. We hypothesized that adding a PD-L1 inhibitor, durvalumab to cetuximab would cause anti-tumor synergy by activating the innate as well as adaptive immune systems without compromising safety in this phase-2 trial in R/M HNSCC patients who have progressed on platinum based therapy. Methods: Blood samples were collected from the first six enrolled patients prior to starting treatment and 4 weeks after the first combined dose of cetuximab and durvalumab. PBMCs were isolated, stained with a live/dead stain as well as CD3, CD4, CD8, CD56, CD16 and NK2GD (natural killer group 2 member D activation receptor) antibodies and analyzed by flow cytometry. Cytokine levels in plasma were measured using standardized ELISA assay kits. Results: Compared to pre-treatment levels, post-treatment samples showed an increase in activated cytokine producing NK cells (CD56bright/CD16-) in all but one patient. Activated cytotoxic NK cell subpopulations (CD56dim/CD16+) showed variable results post-treatment. CD8+ T cells were similar pre and post-treatment in 5 patients. TGF-b levels increased in 5 patients and decreased in 1 patient post-treatment. Interestingly, the patient with decreased TGF-b levels post-treatment had an almost doubling of CD8+ T-cells and an increase in activated cytokine producing NK cells (CD56bright/CD16-). Conclusions: The clinical trial is ongoing and therefore, comparison to clinical response has not yet been analyzed. However, these findings support the combination of cetuximab and durvalumab in R/M HNSCC given the activation of an NK-cell mediated innate immune response in these patient samples. Clinical trial information: NCT03691714.

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