Administration of Autologous Dendritic Cells (DCs) Infected With an Adenovirus Expressing Her-2
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1

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,
      injection(s) 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 and/or 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 (i.e. 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-2/neu DNA under the
      control of a human mouse mammary tumor virus (MMTV) promoter that we can transfect bone
      marrow derived DCs (AdHer2/DC). 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
      AdHer2/DC vaccine in Her -2/neu 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-2/neu 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 HER2/neu. These transduced DCs are then
      injected intradermally into the patient. Patients will be injected with the AdHER2/neu
      transduced DCs every 21 days for a total of three treatment cycles. The starting dose of
      dendritic cells will be 10 X 10^6 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 10^6 DCs. If any patient experiences DLT then up to
      six patients will be treated at the current dose level; if 2/6 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 10^6 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 AdHER2/neu DCs.
    

Intervention name(s): CD34+ derived DCs
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: breast cancer; vaccination; dendritic cells; HER-2; CD34+ stem cells