Biomedical subjects
Publications and source records attributed to Kenneth G Lucas.
Adoptive immunotherapy with antigen specific cytotoxic T lymphocytes can favorably impact the outcome of serious herpesvirus infections in organ transplant recipients. Current challenges in this field include the determination of which patients are at highest risk, and the development of protocols that permit more rapid expansion of virus specific effector cells.
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BACKGROUND: It has been shown that adoptive immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (CTL) is effective for the treatment of EBV-induced lymphoproliferative disease in stem cell transplantation recipients and organ transplantation recipients. The role of EBV CTL in other tumors for which this virus has been implicated in pathogenesis, such as EBV-positive Hodgkin disease (HD), has not been demonstrated clearly. METHODS: To investigate the antitumor effects and toxicity of allogeneic EBV CTL in EBV-positive HD, the authors initiated a pilot trial in which EBV CTL were cultured from allogeneic, partially human leukocyte antigen-matched donors and were infused into patients who had therapy-refractory disease. The first cohort of 3 patients (Cohort I) received 3 separate infusions of EBV CTL (5.0 x 10(6) EBV CTL/kg per dose), and the second cohort (Cohort II) received 30 mg/m(2) per day of fludarabine for 3 days followed by a single CTL infusion (1.5 x 10(7) EBV CTL/kg). RESULTS: All three patients in Cohort I had decreases in measurable disease after EBV CTL infusions, and one of those patients was without evidence of disease 22 months after infusion. Two of 3 patients in Cohort II had decreases in measurable disease, although it was not determined whether those decreases were related to fludarabine or to CTL, and 1 patient in Cohort II had 7 months without disease progression. Unlike the patients in Cohort I, fludarabine recipients did not have increases in antidonor CTL responses. Donor cells could not be detected in any of the CTL recipients. CONCLUSIONS: Adoptive immunotherapy with allogeneic EBV CTL was safe for patients with recurrent, refractory, EBV-positive HD; and clinical responses may be observed without the establishment of detectable donor lymphoid chimerism.
Epstein-Barr Virus (EBV) is associated with a number of tumors, including lymphomas in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, patients with the acquired immunodeficiency syndrome (AIDS), Burkitt's lymphoma, as well as a subset of patients with nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD). The types of latent EBV infections vary in these tumors, which influences the EBV antigens expressed and ultimately the immunogenicity of tumor cells. Not all EBV associated malignancies are directly related to altered cellular immunity, as is the case with EBV induced lymphoproliferations in immunocompromised patients. Treatment strategies have ranged from restoration of normal cellular immunity, which is generally successful in SOT and HSCT patients, anti-B cell monoclonal antibodies, and conventional chemotherapy and radiation. The fact that these tumors express EBV antigens for which many individuals have high circulating levels of protective cytotoxic T lymphocytes (CTL) has lead to investigation into the applicability of adoptive transfer of EBV specific T cells. Initial success with adoptive immunotherapy for HSCT and SOT patients has lead to current studies examining the feasibility and efficacy of this strategy for other EBV associated tumors, such as NPC and HD. We will review the pathogenesis of these disorders, current therapies, and future investigations aimed at targeting EBV antigen expression on these tumors.
Ex vivo expanded Epstein-Barr virus (EBV)-specific T cells have been successfully applied clinically for adoptive immunotherapy. However, the role of CD4(+) T cells in the therapeutic T-cell culture has not been established for the reconstitution of EBV-specific immunity. We isolated and characterized CD4(+) T-cell lines from the ex vivo T-cell cultures. Monoclonal line PD-F4 and oligoclonal lines ND-R4 and TD-B4 were CD3(+)CD4(+)CD8(-). Cytolytic tests with targets of mismatched major histocompatibility complex (MHC) and anti-MHC antibodies confirmed that the cytotoxicity of these CD4(+) cells was restricted by MHC class II. Single cells of ND-R4 expressed interferon-gamma (IFN-gamma, or interleukin 4 (IL-4), but rarely coexpressed these 2 cytokines. In contrast, PD-F4 coexpressed IFN-gamma, IL-2, and IL-4. Kinetic studies with PD-F4 showed that expression of the 3 cytokines plateaued 5 hours upon stimulation and was then drastically reduced, with a pattern consistent with independent modulation and differential off-cycle signal requirements. The cytotoxicity of these CD4(+) cells was largely resistant to brefeldin A, an inhibitor for cytolytic pathways by Fas-ligand family molecules. Although sensitive to concanamycin A and ethyleneglycotetraacetic acid, which inhibit cytotoxicity by granule exocytosis, the CD4(+) cytotoxic T lymphocytes (CTLs) did not express perforin, suggesting a cytotoxic mechanism independent of perforin although involving exocytosis. Flow cytometric analysis showed that the CD4(+) CTLs expressed granulysin, a recently identified cytolytic molecule associated with exocytotic cytolytic granules. These data suggested that CD4(+) T cells in the therapeutic B-lymphoblastoid cell lines-primed T-cell culture are diverse in producing T(H)1 and T(H)2 cytokines, and may exert specific cytotoxicity via exocytosis of granulysin.
Epstein-Barr virus (EBV) causes lymphomas in immunocompromised individuals such as recipients of stem cell or organ transplants and patients with acquired immunodeficiency syndrome (AIDS). EBV has also been detected in the Reed-Sternberg cells of approximately 50% of all cases of Hodgkin's disease (HD). The purpose of this study was to examine the safety, and the clinical and immunological effects of infusing allogeneic EBV-specific cytotoxic T lymphocytes (CTL) for patients with refractory EBV-positive malignancies. In this pilot study, we have treated four patients with EBV-related lymphoma using allogeneic EBV-specific CTL. Two patients received EBV-specific CTL derived from partially human leucocyte antigen (HLA)-matched donors and the other two from HLA-matched siblings. No complications were observed as a result of the CTL infusions and all patients showed increased levels of EBV-specific CTL precursors (CTLp) post infusion. Of the two organ transplant patients, one had refractory disease and has sustained a complete remission following the T-cell infusions. The second has also been disease free since T-cell infusions, although the efficacy cannot be definitively attributed to CTL therapy because this patient received local radiation therapy prior to immunotherapy. A patient with AIDS-related, EBV-positive lymphoma had disease progression following CTL infusions. One HD patient received HLA 4/6 matched T cells from an unrelated donor and showed a decrease in the size of affected lymph nodes and resolution of B-symptoms post infusion. In conclusion, adoptive immunotherapy with allogeneic EBV-specific CTL is safe and may have efficacy in patients with high-risk or refractory EBV-related tumours.