Viewing Study NCT03747744



Ignite Creation Date: 2024-05-06 @ 12:23 PM
Last Modification Date: 2024-10-26 @ 12:58 PM
Study NCT ID: NCT03747744
Status: UNKNOWN
Last Update Posted: 2020-12-29
First Post: 2018-11-16

Brief Title: Intratumoral Injection of Autologous CD1c BDCA-1 Myeloid Dendritic Cells Plus Talimogene Laherparepvec T-VEC
Sponsor: Universitair Ziekenhuis Brussel
Organization: Universitair Ziekenhuis Brussel

Study Overview

Official Title: Phase I Clinical Trial on Intratumoral Injection of Autologous CD1c BDCA-1 Myeloid Dendritic Cells Plus Talimogene Laherparepvec T-VEC
Status: UNKNOWN
Status Verified Date: 2020-12
Last Known Status: ACTIVE_NOT_RECRUITING
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: myDCTV
Brief Summary: Over the past few years it has become evident that cancer cells can be recognized by the patients own immune system The immunological mechanisms at play are often referred to as the cancer immune cycle Chen and Mellman 2013 Mellman 2013 Chen and Mellman 2017In immune-evasive tumors a pivotal role has been attributed to myeloid dendritic cells myDC in regulating the activity of anti-tumor CTL activity within the TME Broz Binnewies et al 2014 In animal models myDC have been demonstrated to play an essential role in licensing anti-tumor CTLs to eradicate tumor cells These myDC also migrate to tumor-draining lymph nodes and present tumor antigens to T-cells in these secondary lymphoid organs Roberts Broz et al 2016 Human myDCs exist in two subsets that are differentiated by expression of either the BDCA-1 or BDCA-3 surface marker The CD1c BDCA-1 antigen is specifically expressed on human dendritic cells which are CD11chighCD123low and represent the major subset of myDCs in human blood about 06 of all peripheral blood mononuclear cells PBMCs CD1c BDCA-1 myDC play an important role in the cross-presentation of tumor antigens following immunogenic cell death Di Blasio Wortel et al 2016 Under conditions of tumor growth myDC will be poorly recruited to the tumor microenvironment do not get activated and thereby fail to efficiently coordinate anti-tumor immunity within the tumor micro-environment and present tumor associated antigens within tumor-draining lymph nodes Talimogene laherparepvec T-VEC is a first-in-class oncolytic virus based on a modified herpes simplex virus HSV type 1 designed to selectively replicate in and lyse tumor cells while promoting regional and systemic antitumor immunity In this phase I clinical trial we propose to investigate the safety of intratumoral injection of autologous CD1c BDCA-1 myDC in non-visceral metastases of melanoma plus intratumoral injection of T-VEC at its approved dose and regimen for the treatment of melanoma We hypothesize that CD1c BDCA-1 myDC in the T-VEC inflamed tumor microenvironment of the metastasis will capture tumor antigens in vivo and through cross-presentation of these antigens coordinate an effective anti-tumor T-cell response
Detailed Description: Over the past few years it has become evident that cancer cells can be recognized by the patients own immune system The immunological mechanisms at play are often referred to as the cancer immune cycle Chen and Mellman 2013 Mellman 2013 Chen and Mellman 2017 Remarkable anti-tumor activity has been achieved by blocking the inhibitory T-cell receptor CTLA-4 andor the PD-1-L1 axis Immune checkpoint inhibition by monoclonal antibody mAb therapy has become a standard of care in patients with advanced melanoma renal cell carcinoma non-small cell lung carcinoma Hodgkins lymphoma and bladder cancer Indications are still expanding Activity of PD-1 and CTLA-4 inhibition has been correlated with hallmarks of pre-existing anti-tumor T-cell response eg presence of cytotoxic T lymphocytes CTL in the tumor microenvironment TME PD-L1 expression in response to T-cell secreted IFN-gamma and transcriptional evidence for CTL-activity mutational load of the cancer cells and presence of highly immunogenic neo-epitopes in the cancer cell genome Tumeh Harview et al 2014 In immune-evasive tumors a pivotal role has been attributed to myeloid dendritic cells myDC in regulating the activity of anti-tumor CTL activity within the TME Broz Binnewies et al 2014 In animal models myDC have been demonstrated to play an essential role in licensing anti-tumor CTLs to eradicate tumor cells Activation of oncogenic signaling pathways such as the WNTbeta-Catenin pathway can lead to the exclusion of myeloid DCs from the TMZ Spranger Bao et al 2015 Spranger and Gajewski 2016 Absence of myDCs at the invasive margin and within metastases has been correlated with defective CTL activation allowing the metastasis to escape the anti-tumor immune response Salmon Idoyaga et al 2016 These myDC also migrate to tumor-draining lymph nodes and present tumor antigens to T-cells in these secondary lymphoid organs Roberts Broz et al 2016 Presence of myeloid DCs was more strongly correlated with T-cell infiltration into tumors as compared to neo-antigen load in 266 melanomas from The Cancer Genome AtlasSpranger Luke et al 2016 Human myDCs exist in two subsets that are differentiated by expression of either the BDCA-1 or BDCA-3 surface marker The CD1c BDCA-1 antigen is specifically expressed on human dendritic cells which are CD11chighCD123low and represent the major subset of myDCs in human blood about 06 of all peripheral blood mononuclear cells PBMC CD1c BDCA-1 myDC have a monocytoid morphology and express myeloid markers such as CD13 and CD33 as well as Fc receptors such as CD32 CD64 and FceRI Furthermore myDC are determined to be CD4 Lin CD3 CD16 CD19 CD20 CD56- CD2 CD45RO CD141 BDCA-3-low CD303 BDCA-2- and CD304 BDCA-4Neuropilin-1- A proportion of CD1c BDCA-1 myDC co-expresses CD14 and CD11b These dual positive cells for CD14 and CD1c BDCA-1 have immunosuppressive capacity and inhibit T-cell proliferation in vitro Depletion of this cell type is preferred prior to using CD1c BDCA-1 cells for immunostimulatory purposes Bakdash Buschow et al 2016 Schroder Melum et al 2016 CD1c BDCA-1 myDC play an important role in the cross-presentation of tumor antigens following immunogenic cell death Di Blasio Wortel et al 2016 Under conditions of tumor growth myDC will be poorly recruited to the tumor microenvironment do not get activated and thereby fail to efficiently coordinate anti-tumor immunity within the tumor micro-environment and present tumor associated antigens within tumor-draining lymph nodes When activated appropriately human CD1c BDCA-1 dendritic cells secrete high levels of IL-12 and potently prime CTL responses Nizzoli Krietsch et al 2013 In vitro IL-12 production by CD1c BDCA-1 myDC can be boosted by exogenous IFN-gamma Nizzoli Krietsch et al 2013 CD1c BDCA-1 myDC spontaneously partially mature within 12 hours following their isolation Optimal maturation with secretion of IFN-gamma as well as the orientation of stimulated T-lymphocytes towards a Th1 phenotype is only achieved following Toll-like receptor stimulationSkold van Beek et al 2015 Talimogene laherparepvec T-VEC Imlygic is a first-in-class oncolytic virus based on a modified herpes simplex virus HSV type 1 designed to selectively replicate in and lyse tumor cells while promoting regional and systemic antitumor immunity T-VEC is modified through the deletion of two nonessential viral genes Functional deletion of the herpes virus neurovirulence factor gene ICP345 attenuates viral pathogenicity and enhances tumor-selective replication T-VEC is further modified by deletion of the ICP47 gene to reduce virally mediated suppression of antigen presentation and increase the expression of the HSV US11 gene Insertion and expression of the gene encoding human granulocyte macrophage colony-stimulating factor GM-CSF results in local GM-CSF production to recruit and activate antigen presenting cells with subsequent induction of tumor-specific T cell responses T-VEC has been evaluated in early-phase studies which demonstrated intratumoral replication and expression of GM-CSF and an acceptable safety profile low-grade fever chills myalgias and injection site reactions after intralesional administration In a single arm phase II study an overall response rate ORR of 26 was reported in patients with stage IIIc to IV melanoma with responses observed in both injected and non-injected lesions including visceral lesions Biopsy of regressing lesions suggested an association between response and presence of IFN- producing MART-1-specific CD8 T cells and reduction in CD4 FoxP3 regulatory T cells consistent with induction of host antitumor immunity The efficacy and toxicity of T-VEC in advanced melanoma was evaluated in a randomized phase III trial comparing intratumoral T-VEC injections with subcutaneous GM-CSF injections With T-VEC the primary end point of durable response rate DRR continuous response lasting 6 months was significantly higher 16 vs 2 odds ratio 89 P001 ORR improved 26 vs 6 and the overall survival OS improved numerically but not statistically by 44 months hazard ratio 079 95 CI 062 to 100 P 051 Tumor regression was seen in tumors both injected and not injected with T-VEC The incidence of grade 34 T-VEC-related adverse events AEs was 11 Andtbacka Kaufman et al 2015 In an open-label multicenter phase Ib trial the combination of T-VEC with ipilimumab had a tolerable safety profile and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapyPuzanov Milhem et al 2016 The combination of T-VEC plus pembrolizumab an anti-PD1 monoclonal antibody was associated with clinical benefit in advanced melanoma as assessed by ORR and CR rate Ribas Dummer et al 2017 A randomized double-blind phase 3 trial of T-VEC plus pembrolizumab vs T-VEC placebo plus pembrolizumab is ongoing In this phase I clinical trial we propose to investigate the safety of intratumoral injection of autologous CD1c BDCA-1 myDC in non-visceral metastases of melanoma plus intratumoral injection of T-VEC at its approved dose and regimen for the treatment of melanoma

We hypothesize that CD1c BDCA-1 myDC in the T-VEC inflamed tumor microenvironment of the metastasis will capture tumor antigens in vivo and through cross-presentation of these antigens coordinate an effective anti-tumor T-cell response

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: False
Is a FDA Regulated Device?: False
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None