Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete ...remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.
CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading ...cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.
Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment ...(TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells).
Using a suite of in vitro, in vivo, and ex vivo patient-derived models containing cancer cells and CAF, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAF within the TME. We developed and used patient-derived ex vivo models, including patient-derived organoids with patient-matched CAF and patient-derived organotypic tumor spheroids.
We demonstrated specific and significant binding of the TEAM to its respective antigens (CD3 and FAP) when released from mesothelin-targeting CAR T cells, leading to T-cell activation and cytotoxicity of the target cell. MesoFAP CAR-TEAM cells were superior in eliminating PDAC and CAF compared with T cells engineered to target either antigen alone in our ex vivo patient-derived models and in mouse models of PDAC with primary or metastatic liver tumors.
CAR-TEAM cells enable modification of tumor stroma, leading to increased elimination of PDAC tumors. This approach represents a promising treatment option for pancreatic cancer.
Purpose
The aim of the study was to compare the outcomes of patients with post‐COVID‐19 condition undergoing supervised therapeutic exercise intervention or following the self‐management WHO (World ...Health Organization) rehabilitation leaflet.
Methods
A randomized controlled trial was carried out that included 39 participants with post‐COVID‐19 condition who had a chronic symptomatic phase lasting >12 weeks. Comprehensive medical screening, patient‐reported symptoms, and cardiorespiratory fitness and muscular strength were assessed. Patients were randomly assigned to a tailored multicomponent exercise program based on concurrent training for 8 weeks (two supervised sessions per week comprised resistance training combined with aerobic training moderate intensity variable training, plus a third day of monitored light intensity continuous training), or to a control group which followed the WHO guidelines for rehabilitation after COVID‐19.
Results
After follow‐up, there were changes in physical outcomes in both groups, however, the magnitude of the change pre–post intervention favored the exercise group in cardiovascular and strength markers: VO2max +5.7%, sit‐to‐stand −22.7% and load‐velocity profiles in bench press +6.3%, and half squat +16.9%, (p < 0.05). In addition, exercise intervention resulted in a significantly better quality of life, less fatigue, less depression, and improved functional status, as well as in superior cardiovascular fitness and muscle strength compared to controls (p < 0.05). No adverse events were observed during the training sessions.
Conclusion
Compared to current WHO recommendations, a supervised, tailored concurrent training at low and moderate intensity for both resistance and endurance training is a more effective, safe, and well‐tolerated intervention in post‐COVID‐19 conditions.
Fractional killing is the main cause of tumour resistance to chemotherapy. This phenomenon is observed even in genetically identical cancer cells in homogeneous microenvironments. To understand this ...variable resistance, here we investigate the individual responses to TRAIL in a clonal population of HeLa cells using live-cell microscopy and computational modelling. We show that the cellular mitochondrial content determines the apoptotic fate and modulates the time to death, cells with higher mitochondrial content are more prone to die. We find that all apoptotic protein levels are modulated by the mitochondrial content. Modelling the apoptotic network, we demonstrate that these correlations, and especially the differential control of anti- and pro-apoptotic protein pairs, confer mitochondria a powerful discriminatory capacity of apoptotic fate. We find a similar correlation between the mitochondria and apoptotic proteins in colon cancer biopsies. Our results reveal a different role of mitochondria in apoptosis as the global regulator of apoptotic protein expression.
Serine incorporator protein 5 (SERINC5) is a key innate immunity factor that operates in the cell to restrict the infectivity of certain viruses. Different viruses have developed strategies to ...antagonize SERINC5 function but, how SERINC5 is controlled during viral infection is poorly understood. Here, we report that SERINC5 levels are reduced in COVID-19 patients during the infection by SARS-CoV-2 and, since no viral protein capable of repressing the expression of SERINC5 has been identified, we hypothesized that SARS-CoV-2 non-coding small viral RNAs (svRNAs) could be responsible for this repression. Two newly identified svRNAs with predicted binding sites in the 3'-untranslated region (3'-UTR) of the SERINC5 gene were characterized and we found that the expression of both svRNAs during the infection was not dependent on the miRNA pathway proteins Dicer and Argonaute-2. By using svRNAs mimic oligonucleotides, we demonstrated that both viral svRNAs can bind the 3'UTR of SERINC5 mRNA, reducing SERINC5 expression
. Moreover, we found that an anti-svRNA treatment to Vero E6 cells before SARS-CoV-2 infection recovered the levels of SERINC5 and reduced the levels of N and S viral proteins. Finally, we showed that SERINC5 positively controls the levels of Mitochondrial Antiviral Signalling (MAVS) protein in Vero E6. These results highlight the therapeutic potential of targeting svRNAs based on their action on key proteins of the innate immune response during SARS-CoV-2 viral infection.
The survival benefit of sentinel lymph node biopsy (SLNB) in immunocompetent and immunosuppressed patients with high-risk cutaneous squamous cell carcinoma (cSCC) has not been established.
To ...determine whether SLNB improves disease-specific survival (DSS) in high-risk cSCC. Secondary objectives were to analyse disease-free survival, nodal recurrence-free survival and overall survival (OS).
Multicentre, retrospective, observational cohort study comparing survival outcomes in immunosuppressed and immunocompetent patients treated with SLNB or watchful waiting. Inverse probability of treatment weighting was used to adjust for possible confounding effects.
We studied 638 tumours in immunocompetent patients (SLNB n = 42, observation n = 596) and 173 tumours in immunosuppressed patients (SLNB n = 28, observation n = 145). Overall, SLNB was positive in 15.7% of tumours. SLNB was associated with a reduced risk of nodal recurrence (NR) (hazard ratio HR, 0.05 95% CI, 0.01-0.43; p = 0.006), disease specific mortality (HR, 0.17 95% CI, 0.04-0.72; p = 0.016) and all-cause mortality (HR, 0.33 95% CI, 0.15-0.71; p = 0.004) only in immunocompetent patients.
SLNB was associated with improvements in NR, DSS and OS in immunocompetent but not in immunosuppressed patients with high-risk cSCC.
The aim of this study was to compare tumour burden in patients who underwent surgery for melanoma and cutaneous squamous cell carcinoma during nationwide lockdown in Spain due to COVID-19 (for the ...period 14 March to 13 June 2020) and during the same dates in 2019 before the COVID-19 pandemic. In addition, associations between median tumour burden (Breslow thickness for melanoma and maximum clinical diameter for cutaneous squamous cell carcinoma) and demographic, clinical, and medical factors were analysed, building a multivariate linear regression model. During the 3 months of lockdown, there was a significant decrease in skin tumours operated on (41% decrease for melanoma (
n
= 352 vs
n
= 207) and 44% decrease for cutaneous squamous cell carcinoma (
n
= 770 vs
n
= 429)) compared with the previous year. The proportion of large skin tumours operated on increased. Fear of SARS-CoV-2 infection, with respect to family member/close contact, and detection of the lesion by the patient or doctor, were related to thicker melanomas; and fear of being diagnosed with cancer, and detection of the lesion by the patient or relatives, were related to larger size cutaneous squamous cell carcinoma. In conclusion, lockdown due to COVID-19 has resulted in a reduction in treatment of skin cancer.
This study aimed to evaluate the effects of a 12-week high-intensity interval exercise (HIIT) training program involving suspension exercises (TRX) on the muscle strength, body composition, gait ...speed, and quality of life of older adults. A total of 82 older adults were randomly assigned to 3 groups: a HIIT group (n=28), a continuous intensity training group (MIIT group, n=27), or a control group (CG, n=27). Compared to MIIT and CG, participants of the HIIT group showed significant post-intervention improvements in BMI (p=.002 and p<.001, respectively) and gait speed (p<.001 for both). Handgrip strength increase was also observed after HIIT (p=.002), but no differences were observed with MIIT and CG. Compared with MIIT and control groups, HIIT showed improvements in the SF-36 domains: general health (p<.001 for both) health changes (p<.001 for both), vitality (p=.002 and p=.001 respectively) and physical functioning (p=.036 and p<.001 respectively). Our results suggest that a HIIT training program with TRX have benefits in BMI, handgrip strength, gait speed, and quality of life in older adults.
Aim Montane Central America offers an ideal system for testing geographical hypotheses of species diversification. We examined how the complex geological history of Nuclear Central America has shaped ...the diversification of a genus of cloud‐forest‐inhabiting salamanders (Dendrotriton). We applied parametric models of geographical range evolution to determine the predominant mode of species formation within the genus and to test existing hypotheses of geographical species formation in the region. Location Montane cloud forests of Nuclear Central America. Methods We estimated a species tree for Dendrotriton using a multi‐locus DNA sequence data set and several coalescent methods, and performed molecular dating for divergence events within the genus. We then applied the species‐tree estimate to a likelihood‐based time‐stratified model of geographical range evolution, based on current species distributions and available geological information for Central America. Results Species trees from all methods contain two groups, one corresponding to species from the Sierra de los Cuchumatanes and the other containing all remaining species. In most cases, species formation within the genus involved an even division of the geographical range of the ancestral species between descendant species. The ancestor of extant Dendrotriton species was estimated to have occurred in either the Sierra de los Cuchumatanes or the Sierra Madre de Chiapas, and both of these areas appear to have been important for diversification within the genus. The single species found in the Quaternary‐age Guatemalan volcanic cordillera dispersed to the volcanoes from an older highland area. Main conclusions Models of geographical range evolution, when combined with robust species‐tree estimates, provide insight into the historical biogeography of taxa not available from phylogenies or distributional data alone. Vicariant species formation, rather than peripatric or gradient speciation, appears to have been the dominant process of diversification, with most divergence events occurring within or between ancient highland areas. The apparent dispersal of Dendrotriton to the Quaternary‐age volcanoes raises the possibility that the rich salamander community there is composed of species that dispersed from geologically older areas. The Motagua Valley appears not to have been as important in vicariant species formation within Dendrotriton as it is within other groups.
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