Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections.

BACKGROUND: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

Extracorporeal photopheresis vs. systemic immunosuppression for immune-related adverse events: Interim analysis of a prospective two-arm study.

BACKGROUND: Checkpoint inhibitor-induced steroid-refractory (sr) and steroid-dependent (sd) immune-related adverse events (irAE) account for about 11 % of irAE. Although these patients face worse outcomes due to irAE mortality and/or sustained immunosuppression, which impairs anti-tumor response, there is no established second-line treatment based on prospective trial data. METHODS: This prospective comparative study investigates outcomes of extracorporeal photopheresis (ECP), an immunomodulating therapy, versus second-line immunosuppressants (SLI) in sr/sd-irAE. The primary endpoint was longitudinal change in immunophenotype; secondary endpoints were outcome of irAE and tumor response. Patient demographics, quality of life (EORTC QLQ-C30; global health status (GHS/QoL)) and longitudinal blood samples were analyzed at baseline; in weeks 1, 4, 8, and 12. RESULTS: At interim analysis, 21 patients (11 ECP, 10 SLI) with 7 different sr/sd-irAE were included. Compared with the SLI group, the ECP group demonstrated a higher clinical response rate of irAE (93 % vs. 80 %; 95 % CI 0.83-1.92; P = 0.54) and a better GHS/QoL score throughout all follow-up visits. ECP patients showed a numerically higher overall survival (23 vs. 12 months; 95 % CI 0.02-3.02; P = 0.27) and lower cancer progression rates (33 % vs. 67 %; 95 % CI 0.09-1.60; P = 0.52). Immunophenotyping revealed changes in immune cell populations and the regulation of immune checkpoints. There were no significant safety issues in either treatment group. CONCLUSION: This prospective comparative study supports the clinical efficacy of ECP in the treatment of sr/sd-irAE in comparison to the SLI cohort. Thus, ECP represents a potential treatment option for this indication, given its good safety profile while maintaining anti-tumor response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05700565, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05700565.

In vitro investigation of the effects of high-intensity therapeutic ultrasound (HITU) in glial tumor cell culture.

OBJECTIVE: Amidst the evident challenges posed by brain tumors and the evident limitations of conventional treatment methodologies like surgery, radiotherapy, and chemotherapy, our primary objective was to probe the therapeutic potential of high-intensity therapeutic ultrasound (HITU). The aim was to introduce a safer, cost-effective, and efficient alternative to existing treatments, especially beneficial for inaccessible brain tumor sites and resource-constrained medical facilities. MATERIALS AND METHODS: Leveraging post-1990s MR technology advancements, we employed the non-invasive HITU technique, akin to high-intensity focused ultrasound. This method directs acoustic energy to tissues, primarily inducing coagulation necrosis by absorbing energy and elevating tissue temperatures. Glial tumor cells were subjected to HITU to assess its effects. RESULTS: Upon applying HITU to glial tumor cells, significant alterations in cellular structural integrity were evident. The main action of HITU was the absorption of acoustic energy, leading to a notable temperature rise and coagulation necrosis. Flow cytometry indicated significant cellular changes post-HITU. ANOVA and t-test analyses showed a significant relationship between HITU application and time (p<0.05). The Shapiro-Wilk test revealed non-normal data distribution (p<0.05), leading to the use of nonparametric methods. The t-test results after HITU displayed significant differences (p<0.05) in cell counts and fluorescence intensity between control and treated groups. This result was consistent across multiple tests, indicating the reliability of the method in causing cellular damage to the tumor cells. CONCLUSIONS: Our laboratory analyses offer compelling evidence that HITU is not merely feasible but is also a promising non-invasive approach in the treatment paradigm of brain tumors. Standing distinctively apart from radiotherapy, HITU averts early, or late complications commonly associated with the former. While the path ahead mandates comprehensive research to ascertain its clinical utility, preliminary indications firmly posit HITU as a groundbreaking prospect in the management of brain tumors.