Conditioning Patients to Increase DC-vaccine Potency

$100,931P01FY2006CANIH

Baylor Research Institute, Dallas TX

Investigators

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Abstract

Vaccination of HLA-A*201 patients with metastatic melanoma with dendritic cells (DCs) derived from CD34+[unreadable] hematopoietic cell progenitor cells (CD34+HPCs) loaded with melanoma peptide antigens, KLH and flu[unreadable] peptide resulted in the induction of CD8+ T cell immunity to melanoma peptides and some clinical benefit.[unreadable] Immunity was measured by the production of interferon-gamma in the presence of melanoma peptides and[unreadable] control antigens by CD8+ T cells obtained from blood. T cell immunity correlated with early clinical outcome[unreadable] and survival. Patients who progressed early had either no T cell immunity or transient T cell immunity to DC[unreadable] vaccination. There may be several reasons for the absence of DC-induced CD8+ T cell immunity in these[unreadable] patients including: the inability of DCs to prime T cells against tumor antigens, the presence of tumor[unreadable] specific tolerance induced by host suppressor lymphocytes, and an insufficient anti-melanoma T cell[unreadable] repertoire. AIM 1 will determine whether pre-treatment of patients with stage IV melanoma with CPA[unreadable] improves the immune and clinical response after DC vaccination. We will carry out a phase l/ll randomized[unreadable] clinical trial in patients with stage IV melanoma who will receive either placebo or CPA (500mg/m2) followed[unreadable] by vaccination with CD34-DCs pulsed with melanoma peptides and KLH. As a control, a separate aliquot of[unreadable] DCs will be pulsed with HIV peptides as neoantigens that will be mixed with the peptide-loaded DCs and[unreadable] administered at the same time. The primary outcome is the induction of melanoma-specific CD8+T cell[unreadable] immunity. The secondary outcome is the rate of objective clinical responses. Tertiary outcomes are:[unreadable] reduction of regulatory/suppressor CD4+T cells (AIM 2) and priming of HIV-specific CD8+T cells (AIM 3).

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