A Phase I Study of Immunization Using Particle-Mediated Epidermal Delivery of Genes for gp100 and GM-CSF into Uninvolved Skin of Melanoma Patients

Abstract

Purpose: We examined in vivo particle-mediated epidermal delivery (PMED) of cDNAs for gp100 and granulocyte macrophage colony-stimulating factor (GM-CSF) into uninvolved skin of melanoma patients. The aims of this phase I study were to assess the safety and immunologic effects of PMED of these genes in melanoma patients. Experimental Design: Two treatment groups of six patients each were evaluated. Group I received PMED with cDNA for gp100, and group II received PMED with cDNA for GM-CSF followed by PMED for gp100 at the same site. One vaccine site per treatment cycle was biopsied and divided for protein extraction and sectioning to assess transgene expression, gold-bead penetration, and dendritic cell infiltration. Exploratory immunologic monitoring of HLA-A2+ patients included flow cytometric analyses of peripheral blood lymphocytes and evaluation of delayed-type hypersensitivity to gp100 peptide. Results: Local toxicity in both groups was mild and resolved within 2 weeks. No systemic toxicity could be attributed to the vaccines. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. GM-CSF transgene expression in vaccinated skin sites was detected. GM-CSF and gp100 PMED yielded a greater infiltration of dendritic cells into vaccine sites than did gp100 PMED only. Exploratory immunologic monitoring suggested modest activation of an antimelanoma response. Conclusions: PMED with cDNAs for gp100 alone or in combination with GM-CSF is well tolerated by patients with melanoma. Moreover, pathologic autoimmunity was not shown. This technique yields biologically active transgene expression in normal human skin. Although modest immune responses were observed, additional investigation is needed to determine how to best utilize PMED to induce antimelanoma immune responses.

Increased interstitial pressure improves nucleic acid delivery to skin enabling a comparative analysis of constitutive promoters

“…Although skin represents a promising target (due to large unmet clinical needs, easy access to tissue and relative ease of monitoring 1 ), only a few clinical trials have been carried out in the last decade, with the majority related to the treatment of melanoma. 2,3 A large number of genetic skin disorders, that have few if any treatment options, are amenable to gene therapy [4][5][6][7] but efforts to translate such approaches to the clinic are hampered by the difficulty of delivering nucleic acids across tissue and cellular barriers.…”

Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen

“…Entities with a wide variety of biologic effects have been used as chemically defined adjuvants for DNA vaccines, including biologic response modifiers such as cytokines (eg, granulocytemacrophage colony-stimulating factor [GM-CSF] 9 ) and costimulatory molecules 10,11 as well as monoclonal antibodies (mAbs) that block undesired or trigger desired pathways, such as anti-CD40 12 or anti-CD137. 13 An alternative strategy involves codelivery of "helper antigens" (ie, foreign antigens that induce strong T-cell responses) with weak antigens of interest.…”

“…8 Adjuvants include conventional adjuvants, such as Freund adjuvant, and the more recently developed chemically defined ("molecular") adjuvants. The latter are intended to enhance immune responses while avoiding, or at least significantly reducing, adverse effects associated with conventional adjuvants.Entities with a wide variety of biologic effects have been used as chemically defined adjuvants for DNA vaccines, including biologic response modifiers such as cytokines (eg, granulocytemacrophage colony-stimulating factor [GM-CSF] 9 ) and costimulatory molecules 10,11 as well as monoclonal antibodies (mAbs) that block undesired or trigger desired pathways, such as anti-CD40 12 or anti-CD137. 13 An alternative strategy involves codelivery of "helper antigens" (ie, foreign antigens that induce strong T-cell responses) with weak antigens of interest.…”

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

“…40,45 Another interesting approach has been to target antigens toward dendritic cells in vivo, by linking antigens to nanoparticles known to be captured by dendritic cells. 46 Our group has focused on a whole cell vaccine approach whereby patient derived tumor cells are fused to autologous, ex-vivo generated dendritic cells by co-culture in the presence of polyethylene glycol.…”