A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML

Development and characterization of CD22-targeted pegylated-liposomal doxorubicin (IL-PLD)

Non-Hodgkin’s lymphoma (NHL) is the sixth most common cause of cancer deaths in the U.S. Most NHLs initially respond well to chemotherapy, but relapse is common and treatment is often limited due to the toxicity of chemotherapeutic agents. Pegylated-liposomal doxorubicin (PLD, Ben Venue Laboratories, Inc), a produces less myelotoxicity than non-liposomal (NL) doxorubicin. To further enhance efficacy and NHL targeting and to decrease toxicity, we conjugated an anti-CD22 monoclonal antibody (HB22.7) to the surface of PLD, thereby creating CD22-targeted immunoliposomal PLD (IL-PLD). HB22.7 was successfully conjugated to PLD and the resulting IL-PLD exhibits specific binding to CD22-expressing cells as assessed by immunofluorescence staining. IL-PLD exhibits more cytotoxicity than PLD in CD22 positive cell lines but does not increase killing of CD22 negative cells. The IC50 of IL-PLD is 3.1 to 5.4 times lower than that of PLD in CD22+ cell lines while the IC50 of IL-PLD is equal to that of PLD in CD22- cells. Furthermore, IL-PLD remained bound to the CD22+ cells after washing and continued to exert cytotoxic effects, while PLD and NL- doxorubicin could easily be washed from these cells

Bright light therapy versus physical exercise to prevent co-morbid depression and obesity in adolescents and young adults with attention-deficit/hyperactivity disorder: study protocol for a randomized controlled trial

Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day– night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.The trial is funded by the EU Framework Programme for Research and Innovation, Horizon 2020 (Project no. 667302). Funding period: January 2016–December 2020. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Some local funds additionally contributed to carry out this study, especially for the preparation of the interventions: FBO research activity is by the Spanish Ministry of Economy and Competitiveness – MINECO (RYC-2011-09011) and by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Unit of Excellence on Exercise and Health (UCEES)

Efficacy and toxicity of a CD22-targeted antibody-saporin conjugate in a xenograft model of non-Hodgkin’s lymphoma

Antibody drug conjugates (ADCs) can deliver potent drugs to cancer cells by employing the specificity of monoclonal antibodies (mAbs). ADCs have demonstrated significant anticancer activity and, in 2011, brentuximab vedotin has been approved by the FDA for the treatment of Hodgkin's and anaplastic large cell lymphomas. CD22 is an ideal target for ADC against B-cell malignancies because of its lineage-specific expression and rapid internalization upon antibody binding. In this study, we evaluated the anti-CD22 mAb HB22.7 as a vehicle for the targeted delivery of the potent toxin saporin (SAP). In vitro, HB22.7-SAP was cytotoxic against a panel of non-Hodgkin's lymphoma (NHL) cell lines representing the most common types of the disease. Moreover, in a xenograft model of NHL, HB22.7-SAP significantly inhibited the growth of established lesions and completely prevented tumor development when treatment was initiated within 24 h from tumor-cell inoculation. HB22.7-SAP had no significant in vivo toxicity. In conclusion, HB22.7 constitutes a potential platform for CD22-targeted ADCs

Inhibition of B-cell death does not restore T-cell-dependent immune responses in CD40-deficient mice

Signalling through CD40 is essential for the development of immunoglobulin G (IgG) antibody responses, germinal centres and B-cell memory against T-dependent antigens. In addition, engagement of CD40 in B cells promotes cell survival by inducing the expression of anti-apoptotic members of the bcl-2 family of cell-death regulators. In the present study we analysed whether T-dependent immune responses can be developed in mice deficient in CD40 if the anti-apoptotic activity mediated by the engagement of CD40 in B cells is compensated by the constitutive over-expression of anti-apoptotic genes of the bcl-2 family. We showed that the over-expression of either hbcl-2 or hbcl-x L transgenes in B cells is not sufficient to restore IgG antibody responses and germinal centre formation in CD40-deficient mice. These results indicate that CD40 functions, other than those mediated through survival, are required for the establishment of T-dependent B-cell responses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75051/1/j.1365-2567.2003.01690.x.pd