Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA ...damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC
models. CD8
T-cell depletion reversed the antitumor effect, demonstrating the role of CD8
T cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of
and
successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results define previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC. SIGNIFICANCE: Our results define previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment efficacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.
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The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact ...estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown.
RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model.
A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05–1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73–0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26–1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED.
ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.
•This meta-analysis quantifies excess of early mortality upon first-line immunotherapy in solid tumors.•Early mortality risk increases with immunotherapy alone versus other treatments.•Neither PD-L1 levels nor class of immune checkpoint inhibitors predict early mortality.•Gastric and urothelial carcinoma are at higher risk of early mortality upon immunotherapy.•Immunotherapy combination strategies can prevent early mortality.
Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an ...unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.
Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models.
AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor.
BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
AXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in ...non-small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of
and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in
-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. IMPLICATIONS: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.
We report the case of a 12-years-old patient who subacutely developed a positive and negative myoclonus of limbs and face, drowsiness and memory deficits after getting infected by SARS-CoV-2. On ...admission, nasopharyngeal swab for SARS-CoV-2, brain and spinal MRI with and without contrast, EEG, chest X-ray and abdominal ultrasound were negative. CSF physical-chemical examination, culture, PCR testing for SARS-CoV-2 and other pathogens, and oligoclonal IgG bands were negative as well. A full panel blood test, including clotting, autoimmunity and paraneoplastic blood studies, did not show any alteration. The neuropsychological examination showed an impairment in memory, visual-motor coordination, inductive reasoning skills, attention, and concentration. The patient was first treated with clonazepam and then with intravenous methylprednisolone for five days, with poor response. For this reason, he then received a cycle of IVIG, thus reaching a gradual and complete recovery. To date, this is the first case of a COVID-19 associated myoclonus affecting a paediatric patient.
•Covid-19 has many neurological complications in adults, including myoclonus.•No cases of Covid-19 related myoclonus have been reported in paediatric population.•We describe a case of myoclonus in a child with a previous SARS-CoV-2 infection.•We assumed myoclonus to be post-infectious with an immune-mediated mechanism.
To better understand the effects of short-term computer-based cognitive rehabilitation (cCR) on cognitive performances and default mode network (DMN) intrinsic functional connectivity (FC) in ...cognitively impaired relapsing remitting (RR) multiple sclerosis (MS) patients. Eighteen cognitively impaired RRMS patients underwent neuropsychological evaluation by the Rao’s brief repeatable battery and resting-state functional magnetic resonance imaging to evaluate FC of the DMN before and after a short-term (8 weeks, twice a week) cCR. A control group of 14 cognitively impaired RRMS patients was assigned to an aspecific cognitive training (aCT), and underwent the same study protocol. Correlations between DMN and cognitive performances were also tested. After cCR, there was a significant improvement of the following tests: SDMT (
p
< 0.01), PASAT 3″ (
p
< 0.00), PASAT 2″ (
p
< 0.03), SRT-D (
p
< 0.02), and 10/36 SPART-D (
p
< 0.04); as well as a significant increase of the FC of the DMN in the posterior cingulate cortex (PCC) and bilateral inferior parietal cortex (IPC). After cCR, a significant negative correlation between Stroop Color–Word Interference Test and FC in the PCC emerged. After aCT, the control group did not show any significant effect either on FC or neuropsychological tests. No significant differences were found in brain volumes and lesion load in both groups when comparing data acquired at baseline and after cCR or aCT. In cognitively impaired RRMS patients, cCR improves cognitive performances (i.e., processing speed and visual and verbal sustained memory), and increases FC in the PCC and IPC of the DMN. This exploratory study suggests that cCR may induce adaptive cortical reorganization favoring better cognitive performances, thus strengthening the value of cognitive exercise in the general perspective of building either cognitive or brain reserve.
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix ...factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
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•Differential expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes•An inflamed SCLC subtype (SCLC-I) has low expression of ASCL1, NEUROD1, and POU2F3•SCLC-I experiences greatest benefit from the addition of anti-PD-L1 to chemotherapy•Subtype switching accompanies acquired resistance to platinum chemotherapy
Gay et al. provide a classification for four subtypes of small cell lung cancer, each with unique molecular features and therapeutic vulnerabilities. An inflamed, mesenchymal subtype predicts benefit with the addition of immunotherapy to chemotherapy. Intratumoral switching between chemosensitive and chemoresistant subtypes accompanies therapeutic resistance.
Abstract Objective Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic course. Dysphagia represents one of the current challenges in clinical ...practice for the management of MS patients. Dysphagia starts to appear in mildly impaired MS subjects (EDSS 2–3) and becomes increasingly common in the most severely disabled subjects (EDSS 8–9). The aim of the present study was to evaluate the frequency and characteristics of patient-reported dysphagia in MS patients with a multicenter study using the recently developed DYMUS (DYsphagia in MUltiple Sclerosis) questionnaire. Design Data were collected in a multi-centre, cross-sectional study using a face-to-face structured questionnaire for clinical characteristics and the DYMUS questionnaire. Results 1875 patients were interviewed. The current study has shown a correlation between patient-reported dysphagia and EDSS and disease course but not with age, gender and disease duration. Questionnaires were divided into “patient-reported dysphagia–yes” (587, 31.3%) and “patient-reported dysphagia–no” (1288, 68.7%). Compared with the patient-reported dysphagia–no group, patients in patient-reported dysphagia–yes group had higher EDSS score (mean EDSS 4.6 vs. 2.8; p < 0.001) and had a longer disease duration (mean duration 13 years vs. 11 years; p < 0.001), while there was no significant difference in gender (32.7% vs. 30.5% male and 67.3% vs. 69.5% female) and in age composition (46.18 vs. 42.05). Conclusions This study represents the largest, multi-centre sample of MS patients evaluated for patient-reported dysphagia utilizing an ad-hoc questionnaire for this condition.
Background and purpose
In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting‐state ...(RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D‐MS) patients and in appropriately matched control groups.
Methods
Sixteen D‐MS patients, 17 non‐depressed MS (ND‐MS) patients, 17 non‐depressed healthy controls and 15 depressed subjects (D‐S), age, sex and education matched, cognitively preserved and non‐fatigued, were enrolled. All participants underwent a neuropsychological evaluation and RS functional magnetic resonance imaging study.
Results
Comparing D‐MS patients with D‐S, within the DMN, a significant RS‐FC suppression was found in the posterior cingulate cortex (PCC); comparing D‐MS with ND‐MS, FC was significantly increased in the anterior cingulate cortex and significantly reduced in the PCC. Within the SN increased FC in the right supramarginal gyrus and right middle frontal gyrus was found in D‐MS patients compared to D‐S and to ND‐MS; within the ECN increased FC in the right inferior parietal cortex was found in D‐MS patients compared to ND‐MS patients.
Conclusions
In cognitively preserved D‐MS patients, FC derangement occurs in the SN, ECN and DMN. In the latter, changes occurring both in the anterior cingulate cortex and PCC suggest that depression in MS may be linked to MS itself and, in particular, to a peculiar pattern of network abnormalities favored by MS pathology through disconnection mechanisms. Reduced FC in the PCC, similar to MS patients with cognitive impairment, suggests a functional link between depression and cognitive impairment in MS.
Cognitive disorders occur in up to 65 % of multiple sclerosis (MS) patients; they have been correlated with different MRI measures of brain tissue damage, whole and regional brain atrophy. The ...hippocampal involvement has been poorly investigated in cognitively impaired (CI) MS patients. The objective of this study is to analyze and compare brain tissue abnormalities, including hippocampal atrophy, in relapsing–remitting MS (RRMS) patients with and without cognitive deficits, and to investigate their role in determining cognitive impairment in MS. Forty-six RRMS patients 20 CI and 26 cognitively preserved (CP) and 25 age, sex and education-matched healthy controls (HCs) underwent neuropsychological evaluation and 3-Tesla anatomical MRI. T2 lesion load (T2-LL) was computed with a semiautomatic method, gray matter volume and white matter volume were estimated using SIENAX. Hippocampal volume (HV) was obtained by manual segmentation. Brain tissues volumes were compared among groups and correlated with cognitive performances. Compared to HCs, RRMS patients had significant atrophy of WM, GM, left and right Hippocampus (
p
< 0.001). Compared to CP, CI RRMS patients showed higher T2-LL (
p
= 0.02) and WM atrophy (
p
= 0.01). In the whole RRMS group, several cognitive tests correlated with brain tissue abnormalities (T2-LL, WM and GM atrophy); only verbal memory performances correlated with left hippocampal atrophy. Our results emphasize the role of T2-LL and WM atrophy in determining clinically evident cognitive impairment in MS patients and provide evidence that GM and hippocampal atrophy occur in MS patients regardless of cognitive status.
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