Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors.

PURPOSE: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. RESULTS: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (≥30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8+ T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. CONCLUSIONS: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.

Enhanced T-lymphocyte infiltration in a desmoid tumor of the thoracic wall in a young woman treated with intratumoral injections of the oncolytic peptide LTX-315: a case report.

BACKGROUND: Desmoid tumors are intermediary malignant, fibrous lesions occurring in various soft tissues. Surgical treatment is relentlessly challenging because of the propensity for local aggressive behavior and high risk of recurrence. Consequently, a wide range of oncological drugs and radiation therapy are being used; however, outcomes are unpredictable. We investigated whether local treatment with an oncolytic peptide could be beneficial in a patient with an unresectable desmoid tumor. CASE PRESENTATION: In a young 29-year-old Caucasian woman who was diagnosed with a retromammary desmoid tumor infiltrating deeply into the anterior thoracic wall, surgery was considered excessively mutilating, and observation was recommended. The lesion progressed, however, and caused debilitating pain, despite nonsteroidal anti-inflammatory medication. Subcutaneous injections of human interferon-α (Multiferon®) resulted in reduced growth kinetics but had to be terminated because of development of symptomatic pneumonitis. Frequently used oncological treatment was withheld because of the toxicity profile, and the patient was instead included in a phase I study investigating transdermal intratumoral injection of LTX-315, an oncolytic peptide that induces anticancer immune responses ( ClinicalTrials.gov , NCT01986426 ). A marked increase of CD8+ tumor-infiltrating T cells in the lesion was complemented by upregulation of immune gene signature (including effector T-cell, T-helper type 1 cell, chemokine, and cytokine genes). These changes were followed by gradual symptom relief and long-term disease stabilization, indicating clinical benefit. LTX-315 was well tolerated until termination in week 16 after a serious allergic reaction. CONCLUSIONS: Our patient was treated with repeated intratumoral injections of LTX-315, resulting in tumor regression accompanied by upregulation of immune genes and T-cell infiltration. Local application of immunotherapy, minimizing systemic side effects, represents a novel treatment modality in desmoid tumors that should be tested in further clinical trials.

Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. PATIENTS AND METHODS: Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. RESULTS: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. CONCLUSIONS: In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers.

Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to alterations in the plasma Trp:LNAA ratio and brain 5-HT. In the present study, we tested whether whisky consumption as part of a meal may alter the plasma Trp:LNAA ratio and influence mood and performance in healthy volunteers. Twenty-four healthy male subjects participated in a within-subjects cross-over study. Subjects consumed whisky (125 ml; 40 g alcohol) or water (125 ml) as part of a standard evening meal. Effects of whisky consumption were tested on mood and choice reaction time and blood samples were taken to measure changes in plasma amino acids, glucose and insulin. The plasma Trp:LNAA ratio showed a significant decline 2 h after whisky consumption of alcohol (P<0.001). No effects were found on choice reaction time or mood as compared with the control condition. The present findings reveal that whisky consumption alters available plasma Trp for uptake into the brain, whereas there were no effects on mood and performance.

Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity.

OBJECTIVE: Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sensitivity. Moderate alcohol consumption may increase adiponectin, which in turn causes a decrease of tumor necrosis factor (TNF)-alpha. A decreased TNF-alpha level may consequently increase insulin sensitivity. RESEARCH DESIGN AND METHODS: To test this hypothesis, we performed a randomized crossover partially diet-controlled study. A total of 23 healthy middle-aged male subjects consumed daily four glasses of whisky (40 g ethanol) or tap water with dinner during two successive periods of 17 days. RESULTS: Moderate alcohol consumption increased plasma adiponectin level (11%; P = 0.0002) but did not affect plasma TNF-alpha level. An increase in insulin sensitivity index was observed in an insulin-resistant subgroup (21%; P = 0.11), which positively correlated with the relative alcohol-induced increase in plasma adiponectin level (r = 0.73, P = 0.02). CONCLUSIONS: The experimental results are in agreement with observational data. Moderate alcohol consumption improved insulin sensitivity in relatively insulin-resistant middle-aged men, an effect that may be mediated through alcohol-induced increases in adiponectin.