509 A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer

BackgroundNL-201 is a selective and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors, which share beta and gamma signaling subunits. NL-201 is being developed as a potent activator of CD8+ T cells and NK cells for cancer immunotherapy. Binding to the beta and gamma subunits selectively stimulates dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and NK cells, thereby enhancing the immune response in the tumor. The absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. As such, NL-201 is designed to promote the desired immunomodulatory anti-tumor effects of IL-2 with an improved safety profile.MethodsNL201-101 is a Phase 1 first-in-human, open-label, dose-escalation, and cohort expansion study consisting of two parts. Part 1 is an adaptive monotherapy dose escalation study in up to 60 adult patients with advanced and/or refractory solid tumors to determine the safety profile and the recommended phase 2 dose (RP2D) and schedule of NL-201. During dose escalation, two different schedules will be evaluated: dosing every 21 days or on days 1 and 8 of each 21-day cycle. Tumor response to treatment will be assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and/or RECIST for use in cancer immunotherapy trials (iRECIST). In Part 2, patients with pathologically proven diagnosis of indication-specific cohorts (up to N=30/cohort), who have advanced and/or refractory measurable disease and have failed at least one line of treatment, which may include checkpoint inhibitors, will be enrolled. Key exclusion criteria include history of brain cancer, carcinomatous meningitis, neurologic autoimmune disease, or active central nervous system metastases; patients previously receiving CAR-T or IL-2-based therapies are not eligible. Recruitment of Part 1 began in April 2021, and the trial is actively enrolling. Clinicaltrials.gov identifier: NCT04659629.Trial RegistrationClinicaltrials.gov identifier: NCT04659629.Ethics ApprovalAll relevant documents have been or will be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC before the study is initiated. Site 1001: Belberry HREC, application number 2020–09–925 (Belberry does not provide an approval number); Site 1003: Austin Health HREC, approval number HREC/69340/Austin-2020; Site 2003: MDACC Office of Human Subjects Protection, approval number 2020–0383.

A meningitis carcinomatosa komplex megjelenése

Összefoglaló. Az emlőtumor miatt kezelt, majd gondozott beteget – több tünetmentes év után – fejfájás, szédülés, ataxia, megváltozott, furcsa viselkedés, emlékezetzavar és dezorientáció miatt neurológiai, majd belgyógyászati osztályokon vizsgálták. Az alapos kivizsgálás ellenére a tüneteit magyarázó organikus eltérést nem igazoltak, ugyanakkor már a kezdetektől felmerült a szomatizációs tünetképzés lehetősége, ezért pszichiátriai osztályos felvételére került sor. Az elvégzett vizsgálatok, illetve a klinikai kép regresszív állapotot valószínűsítettek. Terápiás próbálkozásaink ellenére a páciens állapota romlott, végül a megismételt neurológiai vizsgálatok meningitis carcinomatosát igazoltak. Az esettel szemléltetni kívánjuk, hogy a beteg premorbid működési nívója, személyiségstruktúrája hogyan képes befolyásolni az ellátószemélyzetet, milyen külső és belső konfliktusokat válthat ki. A diagnózishoz vezető folyamat bemutatásával fel kívánjuk hívni a figyelmet az interdiszciplináris együttműködés fontosságára. Orv Hetil. 2021; 162(43): 1744–1748. Summary. Our patient with known breast cancer in her past medical history was hospitalized – after several asymptomatic years – for headache, dizziness, ataxia, changed behaviour and disorientation. Thorough internal and neurologic investigations did not find any disease underlying her symptoms, therefore the possibility of somatization disorder was raised. Despite lege artis therapeutic interventions carried out on the psychiatry ward, the patient’s condition deteriorated and repeated neurological examinations eventually revealed carcinomatous meningitis. With this case, we would like to illustrate how the patient’s premorbid function level and personality features might influence the attitude and opinion of the health care personnel, and what kind of external and internal conflicts might be triggered. By presenting the complexity of the diagnostic work-up, we would like to emphasize the importance of interdisciplinary cooperation in the interest of our patients. Orv Hetil. 2021; 162(43): 1744–1748.

Cerebrospinal fluid tumor markers predict treatment response in a patient with carcinomatous meningitis

We report on a 56-year-old female patient diagnosed with carcinomatous meningitis caused by lung cancer. The diagnosis was confirmed by lung computed tomography, enhanced brain magnetic resonance imaging, histopathology, cerebrospinal fluid (CSF) cytology, and serum and CSF tumor markers. Genetic testing detected an epidermal growth factor receptor gene exon 19 deletion. The patient survived for 29 months after systemic treatment with gefitinib, radiotherapy, and chemotherapy. Dynamic monitoring of CSF and serum tumor markers was carried out during the treatment process. We considered that CSF tumor marker levels may have allowed the early diagnosis of meningeal carcinomatosis, and that systemic therapy in the early stage of the disease may prolong survival.

Two Cases of Cranial Nerve Metastasis Treated with Radiotherapy and Chemotherapy in Patients with Lung Adenocarcinoma

The incidence of central nervous system metastasis is known to be high among patients with lung cancer. The frequency of brain metastasis and carcinomatous meningitis during the entire clinical course of non-small cell lung cancer is reported to be about 40% and 5%, respectively. In contrast, the incidence of cranial nerve metastasis is extremely rare, and detailed reports of its clinical course remain limited. Herein, we report 2 patients diagnosed with cranial nerve metastasis of lung adenocarcinoma and treated with radiotherapy and systemic chemotherapy. Both patients had cranial nerve symptoms, and brain magnetic resonance imaging showed cranial nerve enhancement. However, no evidence of carcinomatous meningitis was noted on magnetic resonance imaging and cerebrospinal fluid cytology. Based on these observations, these patients were diagnosed with cranial nerve metastasis of lung adenocarcinoma. Radiotherapy and chemotherapy were performed in both cases. In both cases, neurological symptoms had not worsened and imaging findings did not indicate any deteriorations. Therefore, radiotherapy and systemic chemotherapy should be considered when treating cranial nerve metastasis of lung adenocarcinoma. Early therapeutic intervention may lead to attenuation of the cranial nerve dysfunction resulting from cranial nerve metastasis.