Dréno, Brigitte

2658 Background: Immune checkpoint inhibitors provide limited benefit in patients with immunologically cold tumors, characterized by a lack of T cells. This creates a niche for T cell-inducing agents such as TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFa-IRES-hIL2). While the 5/3 chimeric oncolytic adenovirus platform prompts potent immunogenic capacity per se, this virus has been armed with TNFa and IL-2 selected based on their ability to activate and attract T cells into tumors. TILT-123 capsid modification, and double selectivity devices for virus replication in cancer cells only, allow intravenous use of TILT-123. This is an important advantage over conventional oncolytic viruses whose widespread use has been hindered by the need for intratumoral injection. Methods: Here we report tumor transduction, pharmacokinetic and immune effects of a single intravenous administration of TILT-123 from three Phase 1 dose escalation clinical trials (TUNIMO-NCT04695327, TUNINTIL-NCT04217473, and PROTA-NCT05271318), with a total of 52 patients. Overall, the most common tumor types were melanoma (20), ovarian cancer (18) and sarcoma (7). In each of these trials, the first TILT-123 injection was performed intravenously, and a tumor biopsy collected 7 days later. Peripheral blood was collected before and after systemic TILT-123 treatment. No other therapy was administered concurrently. Presence of virus in blood was detected with qPCR, while presence of virus in tumor biopsies was measured with immunohistochemistry (IHC) for adenovirus proteins. Immune changes in tumors were evaluated by IHC. Results: TILT-123 was detected in the peripheral blood of all treated patients. Virus concentration was highest at 1 hour after administration, with lower levels seen 16 hours post-injection. Concurrently, IFN-γ levels increased in the patients´ serum. The lowest TILT-123 blood concentrations were observed with the lowest dose, with progressive increases in subsequent cohorts. At higher doses, TILT-123 was detected circulating in blood one week post-administration. Treatment was safe and no dose-limiting toxicity was encountered. Overall, signs of TILT-123 transduction in tumors were observed in 75% of patients evaluated in all three trials, 80% in TUNIMO patients, and 63.64% in TUNINTIL patients. Early results from PROTA suggest a positive effect of TILT-123 in tumors from all cohorts´ dosages studied. Conclusions: In summary, intravenous injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration. These data suggest that TILT-123 could be developed as an intravenous therapy. However, further increases in tumor transduction could be achieved by using multiple intravenous injections of TILT-123. Clinical trial information: NCT04695327 ; NCT04217473 ; NCT05271318 .

Importance Although isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice. Objective To establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne. Design, Setting, and Participants Using a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research. Main Outcomes and Measures The primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters. Results The 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%). Conclusions and Relevance This Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.

Abstract Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1–2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy.