Biomedical subjects

Adrian P Gee

Publications and source records attributed to Adrian P Gee.

10 recordsLinked to original sources

PubMed2005

Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation.

CD40L generates immune responses in leukemia-bearing mice, an effect that is potentiated by IL-2. We studied the feasibility, safety, and immunologic efficacy of an IL-2- and CD40L-expressing recipient-derived tumor vaccine consisting of leukemic blasts admixed with skin fibroblasts transduced with adenoviral vectors encoding human IL-2 (hIL-2) and hCD40L. Ten patients (including 7 children) with high-risk acute myeloid (n = 4) or lymphoblastic (n = 6) leukemia in cytologic remission (after allogeneic stem cell transplantation [n = 9] or chemotherapy alone [n = 1]) received up to 6 subcutaneous injections of the IL-2/CD40L vaccine. None of the patients were receiving immunosuppressive drugs. No severe adverse reactions were noted. Immunization produced a 10- to 890-fold increase in the frequencies of major histocompatibility complex (MHC)-restricted T cells reactive against recipient-derived blasts. These leukemia-reactive T cells included both T-cytotoxic/T-helper 1 (Th1) and Th2 subclasses, as determined from their production of granzyme B, interferon-gamma, and interleukin-5. Two patients produced systemic IgG antibodies that bound to their blasts. Eight patients remained disease free for 27 to 62 months after treatment (5-year overall survival, 90%). Thus, even in heavily treated patients, including recipients of allogeneic stem cell transplants, recipient-derived antileukemia vaccines can induce immune responses reactive against leukemic blasts. This approach may be worthy of further study, particularly in patients with a high risk of relapse.

CD40 Ligand↗

PubMed2005

Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients.

Epstein-Barr virus (EBV) is a common viral infection in pediatric liver transplant patients and can lead to development of post-transplant lymphoproliferative disorder (PTLD). Differing studies have used immunosuppression reduction, antiviral medications or i.v. CMV-immunogloublin for EBV prevention and treatment. The purpose of this study was to determine whether implementation of a protocol for frequent EBV monitoring and EBV viral load-driven immunosuppression reduction could decrease the incidence of PTLD in our patient population. All data were prospectively collected between 2001 and 2004 at a single institution. Seventy-three patients were entered into the study. Patients were divided into a historical control group (pre-2001, 30 patients) and a treatment group (post-2001, 43 patients). Approximately 1271 blood samples of 73 patients were collected between 2001 and 2004. Eleven out of 43 patients received immunosuppression tapering due to high EBV viral loads (>4000 copies/microg DNA). One patient developed allograft rejection after immunosuppression modulation. Prior to 2001, the incidence of PTLD at our institution was 16%. After instituting a protocol for EBV monitoring, the incidence of PTLD decreased to 2% (p-value<0.05). These findings illustrate that frequent EBV viral load monitoring and preemptive immunosuppression modulation have an integral role in preventing PTLD in the pediatric liver transplant population.

Adolescent↗

PubMed2004

Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes.

Conventional treatment for nasopharyngeal carcinoma (NPC) frequently fails and is accompanied by severe long-term side effects. Since virtually all undifferentiated NPCs are associated with Epstein-Barr virus (EBV), this tumor is an attractive candidate for cellular immunotherapy targeted against tumor-associated viral antigens. We now demonstrate that EBV-specific cytotoxic T-cell (CTL) lines can readily be generated from individuals with NPC, notwithstanding the patients' prior exposure to chemotherapy/radiation. A total of 10 patients diagnosed with advanced NPC were treated with autologous CTLs. All patients tolerated the CTLs, although one developed increased swelling at the site of pre-existing disease. At 19 to 27 months after infusion, 4 patients treated in remission from locally advanced disease remain disease free. Of 6 patients with refractory disease prior to treatment, 2 had complete responses, and remain in remission over 11 to 23 months after treatment; 1 had a partial remission that persisted for 12 months; 1 has had stable disease for more than 14 months; and 2 had no response. These results demonstrate that administration of EBV-specific CTLs to patients with advanced NPC is feasible, appears to be safe, and can be associated with significant antitumor activity.

Antigens, Viral↗

PubMed2004

Prompt versus preemptive intervention for EBV lymphoproliferative disease.

Posttransplantation lymphoproliferative disorders (PTLDs) caused by uncontrolled expansion of Epstein-Barr virus (EBV)-infected B cells after hematopoietic stem cell transplantation (HSCT) can be predicted by an increase in EBV DNA in peripheral blood mononuclear cells. We used real-time quantitative polymerase chain reaction (RQ-PCR) analysis to determine whether frequent monitoring of EBV DNA to allow preemptive treatment is truly of value in patients after HSCT. More than 1300 samples from 85 recipients were analyzed. No patient with consistently low EBV DNA levels developed PTLD. Nine patients had a single episode with a high EBV load (more than 4000 EBV copies/microg peripheral blood mononuclear cell [PBMC] DNA), and 16 patients had high EBV loads detected on 2 or more occasions. Only 8 of these developed symptoms consistent with PTLD, and all were promptly and successfully treated with EBV-specific cytotoxic T cells or CD20 monoclonal antibody. Hence, quantitative measurement of EBV DNA may best be used to enable the prompt rather than the preemptive treatment of PTLD.

Adoptive Transfer↗

PubMed2004

[Impact of regulations on translational research in cell and gene therapy: the American experience].

The increasing utilization of cell and gene therapy in the treatment of human diseases, particularly cancers, has led lawmakers to institute stringent rules to regulate this new area of medicine and optimally protect patients. Cell and gene therapy centers, often located within academic institutions, are becoming subject to rules previously applied only to pharmaceutical companies. Based on the US experience, we review here the regulations that currently regulate or are being proposed to cover cell and gene therapy centers. We describe the principles of good manufacturing practices, quality assurance and quality control and accreditation. Finally, we discuss the future of cell and gene therapy in the context of the increasingly rigorous regulatory environment implemented in the US.

Biomedical Research↗

PubMed2003

Regulatory issues in cellular therapies.

An improved understanding of cellular activation, plasticity, interactions, targeting, differentiation and maturation, combined with the availability of recombinant growth factors, improved cell culture, separation and analytical systems have together brought new life to cellular therapies. Targeted T lymphocytes are being used, post-haematopoietic cell transplant, for prophylaxis and treatment of relapsed cancer, lymphoproliferative disease and viral infections. Pancreatic islet preparations have produced promising results in patients with refractory Type 1 diabetes, and stem cell plasticity is being exploited to repair disease-induced damage in a variety of tissues and organs. In the US, the rapid emergence of these therapies and reported adverse events have excited the interest of the Food and Drug Administration (FDA). The evolving regulatory strategy is likely to have profound effects on the future of this area of medicine.

Biological Products↗

PubMed2002

Autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection.

Chronic active Epstein-Barr virus (CAEBV) infection syndrome is a heterogeneous EBV-related disorder characterized by chronic fatigue, fever, lymphadenopathy, and/or hepatosplenomegaly, associated with abnormal patterns of antibody to EBV. CAEBV can range from disabling mild/moderate forms to rapidly lethal disorders. Even patients with mild/moderate disease frequently suffer adverse effects from long-term anti-inflammatory agents and have a quality of life that progressively deteriorates. It is still unknown why these individuals are unable to produce an effective immune response to control EBV, and no effective treatment is currently available. Since ex vivo-expanded EBV-specific cytotoxic T lymphocytes (EBV-CTLs) can safely restore EBV-specific cellular immune responses in immunodeficient patients, we assessed the possibility that adoptive immunotherapy might also effectively treat CAEBV infection. Following stimulation with irradiated EBV-transformed lymphoblastoid cell lines (LCLs), EBV-CTLs were successfully generated from 8 of 8 patients with the mild/moderate form of CAEBV infection. These CTLs were predominantly CD3(+) CD8(+) cells and produced specific killing of the autologous LCLs. There were 5 patients with 1- to 12-year histories of disease who were treated with 1 to 4 injections of EBV-CTLs. Following infusion, there was resolution of fatigue and malaise, disappearance of fever, and regression of lymphadenopathy and splenomegaly. The pattern and titers of anti-EBV antibodies also normalized. No toxicity was observed. There were 4 patients who did not show any relapse of disease within 6 to 36 months follow-up; one patient had recurrence of fatigue and myalgia one year after CTL infusion. We suggest that adoptive immunotherapy with autologous EBV-CTLs may represent a safe and feasible alternative treatment for patients affected with mild/moderate CAEBV infection and that this approach should be evaluated in the more severe forms of the disease.

Adolescent↗

PubMed2002

Generation of EBV-specific CD4+ cytotoxic T cells from virus naive individuals.

Adoptive immunotherapy with EBV-specific CTL (EBV-CTL) effectively prevents and treats EBV-driven lymphoproliferation in immunocompromised hosts. EBV-seronegative solid organ transplant recipients are at high risk of EBV-driven lymphoproliferation because they lack EBV-specific memory T cells. For the same reason, standard techniques for generating EBV-CTL in vitro from EBV-naive individuals are unsuccessful. To overcome this problem, we compared several methods of expanding EBV-CTL from seronegative adults and children. First, the standard protocol, using EBV-transformed lymphoblastoid B cell lines (LCL) as the source of APC, was compared with protocols using EBV-Ag-loaded dendritic cells as APC. Surprisingly, the standard protocol effectively generated CTL from all seronegative adults. The additional finding of EBV-DNA in the peripheral blood of three of these four adults suggested that some individuals may develop cellular, but not humoral, immune responses to EBV. By contrast, LCL failed to reactivate EBV-CTL from any of the six EBV-seronegative children. EBV-Ag-loaded dendritic cells could expand EBV-CTL, but only in a minority of children. However, the selective expansion of CD25-expressing T cells, 9-11 days after activation with LCL alone, proved to be a simple and reliable method for generating EBV-CTL from all seronegative children. The majority of these CTL were CD4(+) (71 +/- 26%) and demonstrated HLA class II-restricted, EBV-specific killing. Our results suggest that a negative EBV serology does not accurately identify EBV-negative individuals. In addition, our method for selecting EBV-specific CTL from naive individuals by precursor cell enrichment may be applicable to the immunotherapy of cancer patients with a low frequency of tumor- or virus-specific CTL.

Adult↗

PubMed2002

Regulatory issues in cellular therapies.

Cellular and gene therapies offer considerable promise as new treatment modalities. The Food and Drug Administration has been developing strategies to regulate these rapidly evolving fields in a manner that sustains progress and also ensures minimization of potential risks. The death of a patient on a gene therapy study highlighted a number of potential problems that have galvanized the agency to examine their strategy and to review current regulations for gene therapy. Meanwhile, a unified regulatory approach is emerging for cell-based therapies. This stratifies the level of regulation based upon the potential risk to the donor of the cells and the recipient. In this article the history and status of regulation of cellular therapy is briefly reviewed.

Cell- and Tissue-Based Therapy↗

PubMed2002

The impact of regulatory policy on the development of somatic cell therapies in the United States.

Cellular therapies offer new promise for the treatment of a variety of diseases. In order to protect patients and donors, the Food and Drug Administration in the USA has been developing specific regulations. These have undergone several iterations, however, a broad-based strategy has recently emerged. These proposals are reviewed and their impact on academic institutions is assessed.

Accreditation↗