Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence.We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 10(10)/m(2); the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m(2)/dayx5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8-11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0-38+) to 13.0 days (range 2-63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3.Lymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy.ClinicalTrials.gov NCT00317759

Invasive fungal infections in neutropenic enterocolitis: A systematic analysis of pathogens, incidence, treatment and mortality in adult patients

BACKGROUND: Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis. METHODS: Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature. RESULTS: Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy. CONCLUSION: In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis

Limited usefulness of CA125 measurement in the management of Hodgkin's and non-Hodgkin's lymphoma.

BACKGROUND: Several papers have reported an association of high CA125 serum levels with advanced non-Hodgkin's lymphoma (NHL) as well as a relationship between high CA125 values and poor outcome. PATIENTS AND METHODS: Ninety-nine patients with NHL or Hodgkin's disease (HD) underwent serum CA125 assessment at diagnosis. Gender, age, presence of B symptoms, performance status (PS), histology, sites of tumor involvement, presence of effusion, clinical stage, age-adjusted International Prognostic Index, C-reactive protein (CRP), Hb, lactate deshydrogenase (LDH) and beta2-microglobulin were evaluated for their association with serum CA125 levels. The impact of CA125 levels and other features on overall (OS) and progression-free (PFS) survival was also assessed. RESULTS: CA125 serum levels were elevated in 34% of the patients, including 19% of patients with aggressive NHL, 45% of patients with indolent NHL, and 29% of patients with HD. Univariate analyses showed that CA125 levels correlated with poor PS, the presence of B symptoms, advanced clinical stage, abdominal, bone marrow or mediastinal involvement, presence of effusions, high aaIPI, low Hb levels and high CRP, LDH or beta2-microglobulin levels. In multivariate analysis, bone marrow involvement, the presence of effusions, and high aaIPI were all associated with high CA125 serum levels. In univariate analyses, OS and PFS were affected by age (PFS only), poor PS, B symptoms, advanced clinical stage, bone marrow or abdominal involvement (PFS only), high aaIPI, low Hb, high CRP or beta2-microglobulin levels. OS and PFS were not different in patients with normal or elevated CA125 levels. Multivariate analyses showed significantly inferior OS and PFS in patients with high beta2-microglobulin but no influence of CA125. CONCLUSION: While CA125 serum level correlates significantly with a number of features associated with more aggressive disease, it does not enhance the performance of standard prognostic markers in the management of patients with NHL or HD