Epstein-Barr virus, B cell lymphoproliferative disease, and SCID mice: modeling T cell immunotherapy in vivo.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) arises in up to 10% of organ transplant recipients and is fatal in ∼50% of cases. PTLD can be modeled in SCID mice using EBV+ve human B lymphoblastoid cell lines (BLCLs), and the current study investigated intraperitoneal (ip) inoculation of such animals in experiments which assessed the effect of EBV-specific cytotoxic T lymphocytes (CTLs) and cytokines on PTLD growth. Ip transfer of one dose of autologous CTLs, or CD8-enriched T cells, into ip BLCL-inoculated animals significantly delayed tumor development (P = 0.001) and prevented tumor formation in a significant proportion (40%) of mice (P = 0.001). A combination of interleukin (IL)2, 7, and 15 conditioning of CTLs prior to ip injection significantly delayed ip BLCL-derived tumor formation in vivo when compared to CTLs expanded in vitro using only IL2 (P = 0.04) and prevented tumor outgrowth in a significant proportion (60%) of mice (P = 0.02). Daily ip IL2 dosing of ip CTL-inoculated mice significantly delayed tumor development in vivo (P = 0.004) and prevented tumor outgrowth in a significant proportion (78%) of mice (P = 0.02) when compared to animals dosed with vehicle only. In SCID mice, autologous CTLs, and CD8-enriched T cells, have significant capacity to hinder development of PTLD-like tumors. Whilst studies are needed to delineate the role of cytokine conditioning and CD4-enriched T cells, the results suggest that IL2 plays a key role in supporting CTL funtion in vivo.

Regulatory T cell activity in primary and persistent Epstein-Barr virus infection.

Regulatory T cells (T(reg)) provide a balance to immune T cell activation thereby protecting the body from pathogen-induced immunopathology. Several persistent viruses induce T(reg) that subvert protective immune mechanisms and promote viral persistence. Epstein-Barr virus (EBV) generally infects children subclinically and persists thereafter, but primary infection in early adulthood may cause immunopathological damage manifest as infectious mononucleosis. In this study the role of T(reg) was investigated in acute infectious mononucleosis and healthy EBV seropositive donors. The proportion of CD4(+)CD25(high) T cells in blood from infectious mononucleosis patients was significantly lower than in seropositive donors (P = 0.05). Using the FOXP3 marker for T(reg) the same frequency and extra-follicular distribution of T(reg) was noted in infectious mononucleosis and control tonsils. Regulatory cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-beta, were significantly raised in infectious mononucleosis compared to seropositive donor plasma (P = 0.0001, P = 0.0004 respectively) although levels of IL-10 peaked earlier in infectious mononucleosis than TGF-beta. Previous studies identified EBV latent membrane protein (LMP)-1-induced T(reg) activity [Marshall et al. (2003): J Immunol 170:6183-6189; Marshall et al. (2007): Brit J Haematol 139:81-89], and in this study a significant reduction in interferon-gamma production was found from infectious mononucleosis but not seropositive donor lymphocytes after stimulation with a recall antigen when LMP-1 peptide PRG was added (P = 0.03). It is possible that T(reg) are important in controlling primary EBV infection to a subclinical level in most cases and that infectious mononucleosis represents a failure of this protective mechanism.

Phase I trial of weekly paclitaxel in advanced lung cancer.

PURPOSE: We conducted a phase I study in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose (MTD) of paclitaxel using an extended weekly schedule. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were treated with paclitaxel administered weekly over 3 hours for 6 weeks of an 8-week cycle. Doses were modified for granulocyte counts less than 1,800/microL or neurotoxicity greater than grade I. Groups of three patients were entered at each dose level. The dose was escalated to the next level if less than 50% of patients developed unacceptable toxicity and received more than 80% of the intended first-cycle dose. RESULTS: Twenty-six patients were entered through six dose levels (100, 125, 135, 150, 175, and 200 mg/m2/wk). Four of six patients at the 175-mg/m2 dose level and only one of six patients at the 200-mg/m2 level received all scheduled doses of paclitaxel during cycle 1. Neutropenia was dose-limiting. Fourteen patients were treated with subsequent cycles of paclitaxel. Grade II to III neuropathy developed in five of 24 patients. It occurred more commonly with greater duration of therapy, but improved following dose reduction. Nine of 26 (35% +/- 10%) patients demonstrated an objective response. CONCLUSION: The MTD of paclitaxel using a weekly schedule is 175 mg/m2/wk for 6 of 8 weeks. Neutropenia limits dosing acutely, but neuropathy is limiting with sustained therapy. This schedule of paclitaxel results in a twofold to threefold increase in dose-intensity with less toxicity than anticipated from conventional dosing. Further evaluation of this schedule is warranted to assess efficacy and toxicity of prolonged administration.

Computer generated mandibular model: surgical role.

A life-size nylon model of a traumatized mandible was produced from CT scan data by the process of laser sintering. The model was used for pre-operative planning and for production of surgical aids in order to facilitate the restoration of a large bony defect. Vascularized iliac crest bone was harvested, titanium implants placed and the bone then grafted to the mandible.

Recruiting cancer patients to participate in motivating their relatives to quit smoking. A cancer control study of the Cancer and Leukemia Group B (CALGB 9072).

BACKGROUND: A diagnosis of cancer provides a teachable moment in which a physician can counsel or teach the patient. The Cancer and Leukemia Group B hypothesized that this teachable moment could also be used to encourage counseling of the patients' relatives who smoke. The authors' first study sought to determine the feasibility of such an intervention, the cooperation of the patients, and the compliance of relatives who were smokers. The long-range goal is to recruit by mail a large population of adult smokers into an intervention program and to assist them in quitting cigarette smoking. METHODS: Oncologists and their clinical research associates asked recently diagnosed cancer patients to identify their relatives who were smokers and assist in persuading them to quit. Consenting patients spoke to relatives and mailed them a personalized motivational leaflet along with a list of the benefits of quitting smoking. Intervention was continued only with relatives who were contacted in this manner. The participating physicians then wrote to the smokers, advising them to quit; enclosed with each physician's letter were the National Cancer Institute booklet "Clearing the Air," which is about quitting smoking, and a questionnaire determining "stage of change" (the stage of the smoker's inaction or action regarding quitting smoking). After 6 months, a postintervention questionnaire was mailed to the relatives. RESULTS: Written consent was obtained from 89% of 144 eligible patients solicited. Eighty percent of patients involved in the study contacted relatives. Sixty-three percent of contacted relatives returned the first questionnaire and 40% answered the second. Nine percent of all contacted relatives reported having quit smoking after the intervention. CONCLUSIONS: The intervention proved to be feasible and will lead to the next study, which will randomize relatives who smoke within a more intensive intervention over 12 months and compare the results with nonintervention controls.