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.

Coexistence of Congenital Adrenal Hyperplasia and Autoimmune Addison's Disease.

Background: Underlying causes of adrenal insufficiency include congenital adrenal hyperplasia (CAH) and autoimmune adrenocortical destruction leading to autoimmune Addison's disease (AAD). Here, we report a patient with a homozygous stop-gain mutation in 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2), in addition to impaired steroidogenesis due to AAD. Case Report: Whole exome sequencing revealed an extremely rare homozygous nonsense mutation in exon 2 of the HSD3B2 gene, leading to a premature stop codon (NM_000198.3: c.15C>A, p.Cys5Ter) in a patient with AAD and premature ovarian insufficiency. Scrutiny of old medical records revealed that the patient was initially diagnosed with CAH with hyperandrogenism and severe salt-wasting shortly after birth. However, the current steroid profile show complete adrenal insufficiency including low production of pregnenolone, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), without signs of overtreatment with steroids. Conclusion: To the best of our knowledge, this is the first description of autoimmune adrenalitis in a patient with 3ßHSD2 deficiency and suggests a possible association between AAD and inborn errors of the steroidogenesis.

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.

Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking. Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS. Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy. Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%). Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Arteriovenous fistula of the groin in a drug abuser with endocarditis.

Intravenous drug abusers commonly develop endocarditis due to injection of particulate matter that can cause endothelial damage to the valves. The frequent need to access the venous system can result in vascular traumas with potential complications including arteriovenous (AV) fistulas. Here, we present the case of an intravenous drug abuser with endocarditis and an unusually large AV fistula in the groin. The patient was successfully operated for endocarditis. However, the AV fistula was at the time not acknowledged. The combination of ileofemoral vein thrombosis and a large AV fistula led to pulmonary septic embolism and life-threating, right-sided heart failure. Computed tomography scan did not reveal the AV fistula, but suspicion was raised. Ultrasound diagnosed and revealed the magnitude of the AV fistula, and the patient was treated with a minimally invasive percutaneous technique.

Efficacy of adrenal venous sampling is increased by point of care cortisol analysis.

Primary aldosteronism (PA) is a common cause of secondary hypertension and is caused by unilateral or bilateral adrenal disease. Treatment options depend on whether the disease is lateralized or not, which is preferably evaluated with selective adrenal venous sampling (AVS). This procedure is technically challenging, and obtaining representative samples from the adrenal veins can prove difficult. Unsuccessful AVS procedures often require reexamination. Analysis of cortisol during the procedure may enhance the success rate. We invited 21 consecutive patients to participate in a study with intra-procedural point of care cortisol analysis. When this assay showed nonrepresentative sampling, new samples were drawn after redirection of the catheter. The study patients were compared using the 21 previous procedures. The intra-procedural cortisol assay increased the success rate from 10/21 patients in the historical cohort to 17/21 patients in the study group. In four of the 17 successful procedures, repeated samples needed to be drawn. Successful sampling at first attempt improved from the first seven to the last seven study patients. Point of care cortisol analysis during AVS improves success rate and reduces the need for reexaminations, in accordance with previous studies. Successful AVS is crucial when deciding which patients with PA will benefit from surgical treatment.