CD20-targeting immunotherapy promotes cellular senescence in B-cell lymphoma

The CD20-targeting monoclonal antibody Rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its co-administration with conventional anti-cancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which Rituximab exerts its anti-lymphoma activity are only partially understood. We show here that Rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biological properties, in established B-cell lymphoma cell lines as well as primary transformed B-cells. In addition, Rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound Adriamycin (a.k.a. Doxorubicin), and, to a lesser extent, by the antimicrotubule agent Vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response (DDR) signaling cascade triggered by Adriamycin. As the underlying pro-senescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to Rituximab, and, in turn, the ROS scavenger N-acetylcysteine (NAC) to largely abrogate Rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a Rituximab-containing treatment regimen, provide important mechanistic insights into the biological complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy

Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematological malignancy often curable only by using intensive chemotherapy. Nonetheless, resistance/early relapses are frequent, underscoring the need to investigate the molecular events occurring shortly after chemotherapy. Therapy-induced senescence (TIS) is a fail-safe tumor suppressive mechanism that may elicit immune-mediated responses contributing to senescent cell clearance. Yet, TIS functional role in AML eradication and immune surveillance early post-chemotherapy remains ill-defined. By combining transcriptional and cellular-based evaluation of senescence markers in AML patient samples, we found upregulation of senescence-associated genes and interferon gene categories with concomitant induction of HLA class I and class II molecules, pointing to a causal link between TIS and leukemia immunogenicity. Consistently, senescence-competent AML samples activated autologous CD4+ and CD8+ T cells and improved leukemia recognition by both T-cell subsets. Lastly, the anti-leukemic activity of Immune Checkpoint Blockades (ICBs) was enhanced upon senescence engagement in AML. Altogether, our results identify senescence as a potent immune-related anti-leukemic mechanism that may rapidly translate into innovative senescence-based strategies to prevent AML relapse

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies:a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).</p