Ignite Creation Date:
2024-05-06 @ 3:16 PM
Last Modification Date:
2024-10-26 @ 1:46 PM
Study NCT ID:
NCT04571632
Status:
UNKNOWN
Last Update Posted:
2022-09-14
First Post:
2020-09-08
Brief Title:
Clinical Trial of SBRT and Systemic Pembrolizumab With or Without AvelumabIpilimumab Dendritic Cells in Solid Tumors
Sponsor:
Universitair Ziekenhuis Brussel
Organization:
Universitair Ziekenhuis Brussel
Study Overview
Official Title:
A Randomized Phase II Clinical Trial of SBRT and Systemic Pembrolizumab With or Without Intratumoral AvelumabIpilimumab Plus CD1c BDCA-1 CD141 BDCA-3 Myeloid Dendritic Cells in NSCLC Subtitle v30 A Randomized Phase II Clinical Trial of SBRT and Systemic Pembrolizumab With or Without Intratumoral AvelumabIpilimumab Plus CD1c BDCA-1CD141 BDCA-3 Myeloid Dendritic Cells in Solid Tumors
Status:
UNKNOWN
Status Verified Date:
2022-02
Last Known Status:
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:
Luscid
Brief Summary:
A randomized phase II clinical trial of SBRT and systemic pembrolizumab with or without intratumoral avelumabipilimumab plus CD1c BDCA-1CD141 BDCA-3 myeloid dendritic cells in solid tumors
Detailed Description:
Cancer cells can be recognized by the patients own immune system a process that is referred to as the cancer immunity cycle Chen Mellman 2013 Mellman 2013 Chen 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 continuously expanding Activity of PD-1-L1 and CTLA-4 inhibition has been correlated with hallmarks of pre-existing anti-tumor T-cell response presence of activated cytotoxic T lymphocytes CTL in the tumor microenvironment TME as evident from transcription profiles and PD-L1 expression by tumor cells in response to T-cell secreted IFN- Mutational load of the cancer cells and presence of highly immunogenic neo-epitopes in the cancer cell genome underlies the capacity for cancer cells to elicit an immune response Tumeh Harview et al 2014 Responsiveness to treatment with CTLA-4 has been correlated with the expression of HLA class I molecules by the cancer cells Tumeh Harview et al 2014
In immune-evasive tumors a pivotal role has been attributed to the elimination of myeloid dendritic cells myDC from the TME myDC play a pivotal role in the initiation and coordination of the activity of anti-tumor CTL activity within the TME Rodig Gusenleitner et al 2017 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 WNTCatenin pathway can lead to the exclusion of myeloid DC from the TME Broz et al 2014 Spranger 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 Salmon Idoyaga et al 2016 In mouse models tumor-residing Batf3 dendritic cells were shown to be required for effector T Cell trafficking and success of adoptive T-cell therapy Roberts et al 2016 Presence of myeloid DCs was more strongly correlated with a T-cell inflamed TME signature as compared to neo-antigen load in 266 melanomas from The Cancer Genome Atlas Spranger Luke et al 2016
Two important human myDCs subsets exist 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 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- 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 immune-stimulatory purposes Bakdash Buschow 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 Di Blasio Wortel et al 2016 In vitro IL-12 production by CD1c BDCA-1 myDC can be boosted by exogenous IFN-Nizzoli Krietsch et al 2013 CD1c BDCA-1 myDC spontaneously partially mature within 12 hours following their isolation Optimal maturation with secretion of IFN- as well as the orientation of stimulated T-lymphocytes towards a Th1 phenotype is only achieved following Toll-like receptor stimulation Nizzoli Krietsch et al 2013
Animal models have established the safety and efficacy of intra-tumoral administration of ipilimumab An intratumoral dose of CTLA-4 blocking mAb administered at a ratio of 1100 compared to intravenous dosing was found to result in equivalent anti-tumor effect and was associated with less systemic toxicity Skold van Beek et al 2015 Marabelle Kohrt et al 2013 In an ongoing clinical trial for patients with advanced melanoma conducted by our research group intratumoral injection of CD1c BDCA-1 myDC together with the CTLA-4 blocking mAb ipilimumab plus intravenous administration of the PD-1 blocking mAb nivolumab have been proven feasible and safe Intratumoral administration of an anti-PD-L1 IgG1 mAb may increase the potential for antibody dependent cellular cytotoxicity ADCC and complement dependent cytotoxicity CDC
Additionally the investigators have previously investigated the utility of SBRT to primary tumor and metastatic locations in oligometastatic non-small cell lung carcinoma NSCLC patients and found that this treatment was feasible safe and resulted in an overall metabolic response rate in 60 of the treated population with 30 of patients achieving a complete metabolic remission Collen Christian et al 2014 Radiation therapy RT has been recognized as potentially synergistic with immune checkpoint blockade Tumor cell killing by radiation results in release of tumor antigens reduces the immunosuppression within the TME and can reinvigorate the cancer-immunity cycle by upregulation of immunogenic cell surface markers and inducing immunogenic cell death Dewan Galloway et al 2009 Kulzer Rubner et al 2014 Frey Ruckert et al 2017 Moreover it has been shown that RT-induced immunogenic cell death can trigger DC maturation and activation in vitro Kulzer et al 2014 providing a clear rationale for combining DC-therapy together with RT
In this randomized phase II clinical trial the investigators propose to conduct hypofractionated SBRT in combination with systemic PD-1 immune checkpoint blockade pembrolizumab with or without intratumoral PD-L1CTLA-4 inhibition plus intratumoral administration of CD1c BDCA-1 CD141 BDCA-3 myDC
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 continuously expanding Activity of PD-1-L1 and CTLA-4 inhibition has been correlated with hallmarks of pre-existing anti-tumor T-cell response presence of activated cytotoxic T lymphocytes CTL in the tumor microenvironment TME as evident from transcription profiles and PD-L1 expression by tumor cells in response to T-cell secreted IFN- Mutational load of the cancer cells and presence of highly immunogenic neo-epitopes in the cancer cell genome underlies the capacity for cancer cells to elicit an immune response Tumeh Harview et al 2014 Responsiveness to treatment with CTLA-4 has been correlated with the expression of HLA class I molecules by the cancer cells Tumeh Harview et al 2014
In immune-evasive tumors a pivotal role has been attributed to the elimination of myeloid dendritic cells myDC from the TME myDC play a pivotal role in the initiation and coordination of the activity of anti-tumor CTL activity within the TME Rodig Gusenleitner et al 2017 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 WNTCatenin pathway can lead to the exclusion of myeloid DC from the TME Broz et al 2014 Spranger 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 Salmon Idoyaga et al 2016 In mouse models tumor-residing Batf3 dendritic cells were shown to be required for effector T Cell trafficking and success of adoptive T-cell therapy Roberts et al 2016 Presence of myeloid DCs was more strongly correlated with a T-cell inflamed TME signature as compared to neo-antigen load in 266 melanomas from The Cancer Genome Atlas Spranger Luke et al 2016
Two important human myDCs subsets exist 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 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- 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 immune-stimulatory purposes Bakdash Buschow 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 Di Blasio Wortel et al 2016 In vitro IL-12 production by CD1c BDCA-1 myDC can be boosted by exogenous IFN-Nizzoli Krietsch et al 2013 CD1c BDCA-1 myDC spontaneously partially mature within 12 hours following their isolation Optimal maturation with secretion of IFN- as well as the orientation of stimulated T-lymphocytes towards a Th1 phenotype is only achieved following Toll-like receptor stimulation Nizzoli Krietsch et al 2013
Animal models have established the safety and efficacy of intra-tumoral administration of ipilimumab An intratumoral dose of CTLA-4 blocking mAb administered at a ratio of 1100 compared to intravenous dosing was found to result in equivalent anti-tumor effect and was associated with less systemic toxicity Skold van Beek et al 2015 Marabelle Kohrt et al 2013 In an ongoing clinical trial for patients with advanced melanoma conducted by our research group intratumoral injection of CD1c BDCA-1 myDC together with the CTLA-4 blocking mAb ipilimumab plus intravenous administration of the PD-1 blocking mAb nivolumab have been proven feasible and safe Intratumoral administration of an anti-PD-L1 IgG1 mAb may increase the potential for antibody dependent cellular cytotoxicity ADCC and complement dependent cytotoxicity CDC
Additionally the investigators have previously investigated the utility of SBRT to primary tumor and metastatic locations in oligometastatic non-small cell lung carcinoma NSCLC patients and found that this treatment was feasible safe and resulted in an overall metabolic response rate in 60 of the treated population with 30 of patients achieving a complete metabolic remission Collen Christian et al 2014 Radiation therapy RT has been recognized as potentially synergistic with immune checkpoint blockade Tumor cell killing by radiation results in release of tumor antigens reduces the immunosuppression within the TME and can reinvigorate the cancer-immunity cycle by upregulation of immunogenic cell surface markers and inducing immunogenic cell death Dewan Galloway et al 2009 Kulzer Rubner et al 2014 Frey Ruckert et al 2017 Moreover it has been shown that RT-induced immunogenic cell death can trigger DC maturation and activation in vitro Kulzer et al 2014 providing a clear rationale for combining DC-therapy together with RT
In this randomized phase II clinical trial the investigators propose to conduct hypofractionated SBRT in combination with systemic PD-1 immune checkpoint blockade pembrolizumab with or without intratumoral PD-L1CTLA-4 inhibition plus intratumoral administration of CD1c BDCA-1 CD141 BDCA-3 myDC
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?:
False
Is an FDA AA801 Violation?:
None