PURPOSE: TP53-mutated ( TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

Background: Chimeric antigen receptor-modified T (CAR T) cells are profoundly changing the standard of care in B-cell malignancies. This new therapeutic class induces a significant number of acute neurotoxicity, but data regarding mid- and long-term neurological safety are scarce. We evaluated mid-term neurological safety, with special emphasis on cognitive functions, in a series of adults treated with CAR T cells.Methods: Patients treated in a single center with CD19-targeted CAR T cells for a relapsing B-cell lymphoma were prospectively followed up by neurologists. Before CAR T-cell infusion, all patients underwent neurological examinations with neuropsychological testing and filled out questionnaires assessing anxiety, depression, and cognitive complaints. Patients surviving without tumor progression were re-evaluated similarly, 6-12 months later.Results: In this prospective cohort of 56 consecutive adult patients treated with CAR T cells, 27 were eligible for mid-term evaluation (median time 7.6 months). Twelve patients developed an acute and reversible neurotoxicity with median duration time of 5.5 days. In all patients, neurological examination on mid-term evaluation was similar to baseline. In self-assessment questionnaires, 63% of patients reported clinically meaningful anxiety, depression, or cognitive difficulties at baseline, a number reduced to 44% at the time of mid-term evaluation. On cognitive assessments, no significant deterioration was found when compared to baseline, in any cognitive functions assessed (verbal and visual memory, executive functions, language, and praxis), even in patients who developed acute neurotoxicity.Conclusion: In this cohort of patients treated with CD19-targeted CAR T cells, we found no evidence for neurological or cognitive toxicity, 6-12 months after treatment.

Thanks to the growing knowledge about cancers and their interactions with the immune system, a huge number of therapeutic cancer vaccines have been developed in the past two decades. Despite encouraging results in pre-clinical models, cancer vaccines have not yet achieved significant clinical efficacy. Several factors may contribute to such poor results, including the difficulty of triggering a strong immune response and the immunosuppressive tumor microenvironment. Many strategies are currently being explored. Different types of adjuvants have been incorporated into vaccine formulations to improve their efficacy, as cancer antigens are usually poorly immunogenic. Nanoparticle systems are promising tools as they act as carriers for antigens and can be surface-modified so that they specifically target antigen-presenting cells in lymph nodes. Bioinspired nanomaterials are ideal candidates thanks to their biocompatibility. Recently, melanin-based nanoparticles were reported to efficiently localize into draining lymphoid tissues and trigger immune responses against loaded antigens. In addition, by virtue of their photochemical properties, melanin-based nanoparticles can also play an immunomodulatory role to promote anti-cancer responses in the context of photothermal therapy. In this review, we discuss the above-mentioned properties of melanin, and summarize the promising results of the melanin-based cancer vaccines recently reported in preclinical models.

PURPOSE: The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention. METHODS: Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period. RESULTS: Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group. CONCLUSION: Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.

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.