TLR‐9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG‐28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3–6 patients with NM were treated for 5 weeks with escalating doses of CpG‐28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty‐nine patients were treated with CpG‐28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG‐28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Background and Objectives: Anti-CD19 CAR T-cell therapy is a promising treatment in relapsing B-cell lymphoma, but is frequently associated with acute neurotoxicity. Neurological long-term safety has not been thoroughly assessed. Methods: All consecutive refractory lymphoma patients admitted in our center for CAR T-cell therapy underwent neurological examination, extensive neuropsychological assessment, brain MRI (except one patient) and completed self-administrated questionnaires at baseline. The patients who remained disease-free at 2 years were re-evaluated similarly. All neurological assessments were conducted by senior neurologists. Results: None of the 19 disease-free patients developed new neurological deficits or MRI changes when compared to baseline. There was no difference in cognitive performances before and two years after, even for the 11 patients who had developed acute neurotoxicity after CAR T-cells. In self-questionnaire assessments, cognitive complaint was stable, reported by 32% of patients at 2 years. We observed a reduction in HADS anxiety scores two years after treatment when compared to baseline (median score: 7/21 vs 4/21, p=0.01). Discussion: In conclusion, no significant neurocognitive or neurological disorders were observed in this cohort of patients, two years after treatment with anti-CD19 CAR T-cells.