IL-2 Adenovector-Transduced Autologous Tumor Cells Induce Antitumor Immune Responses in Patients With Neuroblastoma

Abstract

In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4+ T lymphocytes, and a systemic response, with a rise in circulating CD25+and DR+ CD3+ T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children. © 1998 by The American Society of Hematology.

Targeting of GD2-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes

“…Recent experience with immunotherapy for neuroblastoma has shown that this tumor is indeed amenable to immune‐mediated cytotoxicity. Treatment of neuroblastoma with an IL‐2 gene‐transduced autologous tumor cell vaccine has produced clinically effective antitumor immune responses in children with advanced neuroblastoma 1. However, the clinical use of this highly individualized strategy is limited by the requirements for in vitro culture and transduction of each patient's tumor cells.…”

Chronic neuroblastoma

“…Such regimens include oral etoposide19, 20 and topotecan with/without cyclophosphamide,18, 25, 26 and are compatible with many normal childhood activities. Second, emerging biologic therapeutic agents such as cis ‐retinoic acid,4 fenretinide,42 anti‐G D2 MoAbs,33, 34, 43 and antiidiotype vaccines44‐46 may prove effective in achieving or consolidating remissions. In addition, these agents are generally accepted as being nontoxic to children.…”

Selection of human antitumor single‐chain Fv antibodies from the B‐cell repertoire of patients immunized against autologous neuroblastoma

“…To determine whether antibodies with distinct specificity or at higher frequency can be found after tumor vaccination, we also screened a library based on neuroblastoma patients who had received an autologous IL2gene-modified tumor cell vaccine, resulting in the gen- eration of a systemic antitumor response, including cytotoxic, T helper, and specific antibody responses [5].…”

“…For the immunized patients library, peripheral blood samples were obtained at monthly intervals from three pediatric patients with relapsed neuroblastoma, 3-10 months after the first injection of an IL-2 gene-modified autologous tumor cell vaccine (Table Ia). All three patients had shown a significant tumor response to the vaccine [5]. For the naive neuroblastoma patients library, peripheral blood and bone marrow lymphocytes were collected from 13 neuroblastoma patients at diagnosis prior to treatment ( Table Ib).…”