Ignite Creation Date:
2024-05-05 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00197522
Status:
COMPLETED
Last Update Posted:
2012-11-01
First Post:
2005-09-12
Brief Title:
Administration of Autologous Dendritic Cells DCs Infected With an Adenovirus Expressing Her-2
Sponsor:
Hamilton Health Sciences Corporation
Organization:
McMaster University
Study Overview
Official Title:
A Phase I Study Investigating Multiple Injections of Autologous CD34 Derived Dendritic Cells Transduced With an Adenovirus Vector Expressing Inactivated HER-2Neu in Patients With Metastatic Breast Cancer
Status:
COMPLETED
Status Verified Date:
2012-10
Last Known Status:
None
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:
None
Brief Summary:
We the researchers at Hamilton Health Sciences have developed a novel approach to cancer therapy using transfected dendritic cells DCs to generate enhanced immunity to defined tumor antigens Dendritic cells are highly specialized antigen presenting cells found in the bone marrow lymph nodes skin and thymus Infection of DCs with Adenovirus Ad vectors incorporating genes for defined tumor antigens enables intracellular expression and major histocompatability complex MHC-restricted presentation of tumor peptides by transfected DCs Given the potent immunostimulatory properties of DCs and ability to use gene transfer to load DCs with tumor antigen we hypothesize that administration of transduced autologous DCs may have potential therapeutic benefit as a cancer vaccine We have examined Ad-tumor antigen DC based vaccination in murine models of breast cancer and melanoma In both models injections of Ad-transduced DCs results in highly potent immune activation and antigen-specific anti-tumor responses In these models high levels of antigen-specific cytotoxic effector lymphocytes that recognize and kill cancer cells directly correlates with a therapeutic response tumor regression andor complete protection of animals subsequently re-challenged with tumor cells Animals demonstrating specific in vitro immunity are protected against subsequent injection of cancer cells Moreover we have observed complete resolution and significant long-term survival in animals with established metastatic disease with no demonstrable toxicity As opposed to vaccination protocols with tumor peptides or purified epitopes that are MHC-I restricted ie HLA-A2 we have found that injection of DCs transduced with a vector expressing the entire tumor antigen results in peptide presentation from both MHC-I and MHC-II complexes The subsequent immune response is comprised of both CD4 and CD8 T cell populations Thus Ad-based gene transfer of tumor antigens appears to be an efficient approach 1 enabling sustained endogenous peptide processing and 2 facilitating DC-specific presentation to the host immune system We have shown that using a replication deficient adenovirus vector expressing Her-2neu DNA under the control of a human mouse mammary tumor virus MMTV promoter that we can transfect bone marrow derived DCs AdHer2DC These cells are then used to immunize recipient mice against tumour challenge with Her2 transgenic tumour cells The protection is antigen specific anti Her2 On the basis of these pre-clinical studies we will initiate a pilot trial of the AdHer2DC vaccine in Her -2neu overexpressing patients with metastatic breast cancer Long-term goals and implications of possible results The goals of this initial pilot phase I study are to evaluate the safety and dosing schedule of the vaccine therapy The vaccine will be tested in subsequent phase II and III studies to determine efficacy in comparison to standard therapies The long-term goals are to eventually test this therapy in the adjuvant breast cancer setting in Her-2neu overexpressing patients
Detailed Description:
Following written informed consent consecutive cohorts of 3-6 patients up to a maximum of 18 patients will be treated at increasing dose levels based on a modified Fibonacci scheme Peripheral blood progenitor cells will be obtained from each patient following cytokine mobilization with GM-CSF and G-CSF Selected CD34 cells are then cultured with human GM-CSF human TNFα Flt-3 ligand and human interleukin-4 The CD34 derived dendritic cells are then transduced with an adenovirus expressing rat HER2neu These transduced DCs are then injected intradermally into the patient Patients will be injected with the AdHER2neu transduced DCs every 21 days for a total of three treatment cycles The starting dose of dendritic cells will be 10 X 106 DCs If none of the initial three patients treated at this dose experiences dose limiting toxicity DLT then a new cohort of three patients will be treated at a second dose level of 50 X 106 DCs If any patient experiences DLT then up to six patients will be treated at the current dose level if 26 or fewer patients experience DLT we will escalate to the to the second dose level If 3 or more patients experience DLT the maximum tolerated dose will be deemed as exceeded and a second cohort of 3 patients will be treated at a 10 fold dose reduction of the initial dose level The third dose level will consist of 100 x 106 DCs All treatments will occur in the out-patient setting and patients will be seen prior to each injection and then monthly for at least three months following the last injection of AdHER2neu DCs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| Award 2003HOO542 | None | None | None |
| CBCRA | None | None | None |