Investigating under-reported human papillomavirus genotypes in Grenadian women through self-sampling for cervical cancer screening / Investigación de los genotipos de virus del papiloma humano infranotificados en mujeres de Granada mediante automuestreo para el tamizaje del cáncer cervicouterino / Investigação de genótipos subnotificados de papilomavírus humano em mulheres de Granada por meio de autoamostragem para rastreamento de câncer do colo do útero

[ABSTRACT]. Objective. To compare the adequacy, agreement, and acceptability of Papanicolaou testing (cytology) for cervical cancer screening using self-collected samples compared to physician-collected samples in Grenada in the Caribbean. Furthermore, the study identifies the human papillomavirus (HPV) genotypes present among asymptomatic women testing positive for HPV, the etiologic cause of cervical cancer. Methods. Participants were divided into two groups and two cervical samples were collected from the women in each group: a self-collected sample and a physician-collected sample. Cervical specimens were tested for cytology and HPV. HPV genotyping was performed on positive specimens. Results. Self-collected samples were adequate and in agreement with physician-collected samples, showing no difference between the two sampling methods. Oncogenic high-risk HPV genotypes were identified in cervical samples which were positive for atypical squamous cells and low-grade squamous intraepithelial lesions. The high-risk HPV genotypes found, notably HPV 45 and 53, differed from those most commonly reported. Although the commonly reported high-risk genotypes HPV 16 and 18 were found, so were 31, 33, 35, 52, 66, 68, and 82. Conclusions. Using self-collection facilitated the discovery of unexpected HPV genotypes among asymptomatic women in Grenada. These findings add new information to the literature regarding cervical cancer and neoplasia screening and HPV genotypes in the Caribbean. This genotype information may impact surveillance of women with low-grade lesions, HPV vaccine selection, and possibly further vaccine research. Research regarding HPV in Caribbean pathology samples of cervical neoplasia and cancer is needed.

[RESUMEN]. Objetivo. Comparar la idoneidad, concordancia y aceptabilidad de la prueba de Papanicolaou (citología) para el tamizaje del cáncer cervicouterino mediante la comparación de muestras obtenidas con automuestreo y muestras tomadas por personal médico en Granada, en el Caribe. Asimismo, en el estudio se identifican los genotipos del virus del papiloma humano (VPH) existentes en las mujeres asintomáticas con un resultado positivo en las pruebas del VPH, la causa etiológica del cáncer cervicouterino. Métodos. Las participantes se dividieron en dos grupos y se tomaron dos muestras cervicouterinas de las mujeres de cada grupo: una muestra tomada por la propia paciente y una muestra tomada por personal médico. Se realizó un examen citológico y una prueba de detección del VPH en las muestras. En las muestras positivas, se determinó el genotipo del VPH. Resultados. Las muestras tomadas por las propias pacientes fueron adecuadas y concordaron con las obtenidas por el personal médico, sin que se observaran diferencias entre ambos métodos de muestreo. Se identificaron genotipos de VPH de alto riesgo oncogénico en muestras cervicouterinas positivas para células escamosas atípicas y lesiones intraepiteliales escamosas de grado bajo. Los genotipos de VPH de alto riesgo encontrados, en especial VPH 45 y 53, diferían de los notificados con mayor frecuencia. Aunque se encontraron los genotipos de alto riesgo habituales 16 y 18 del VPH, también se encontraron los genotipos 31, 33, 35, 52, 66, 68 y 82. Conclusiones. El uso del automuestreo facilitó la detección de genotipos inesperados del VPH en mujeres asintomáticas de Granada. Estos resultados agregan nueva información a la bibliografía sobre el tamizaje de las neoplasias y el cáncer cervicouterino, así como sobre los genotipos del VPH, en el Caribe. Esta información sobre el genotipo puede repercutir en la vigilancia de las mujeres con lesiones de bajo grado, en la elección de la vacuna contra el VPH y, posiblemente, en las ulteriores investigaciones sobre vacunas. Es necesario investigar la presencia del VPH en muestras anatomopatológicas de neoplasias y cánceres cervicouterinos en el Caribe.

[RESUMO]. Objetivo. Comparar a adequação, o nível de concordância e a aceitabilidade do exame de Papanicolau (citologia) para o rastreamento do câncer do colo do útero usando amostras autocoletadas em comparação com amostras coletadas por médicos em Granada, no Caribe. Além disso, o estudo identifica os genótipos de papilomavírus humano (HPV) presentes entre as mulheres assintomáticas com resultado positivo para HPV, a causa etiológica do câncer do colo do útero. Métodos. As participantes foram divididas em dois grupos, e duas amostras cervicais foram coletadas das mulheres de cada grupo: uma amostra autocoletada e uma amostra coletada por um médico. As amostras cervicais foram submetidas a exames citológicos e de HPV. A genotipagem do HPV foi realizada nas amostras positivas. Resultados. As amostras autocoletadas eram adequadas e compatíveis com as amostras coletadas por médicos, não havendo diferença entre os dois métodos de amostragem. Foram identificados genótipos de HPV de alto risco oncogênico em amostras cervicais positivas para células escamosas atípicas e lesões intraepiteliais escamosas de baixo grau. Os genótipos de HPV de alto risco encontrados, principalmente HPV 45 e 53, não correspondiam aos genótipos registrados com mais frequência na literatura. Embora os genótipos de alto risco HPV 16 e 18, que são frequentemente registrados, tenham sido observados, também foram detectados os genótipos 31, 33, 35, 52, 66, 68 e 82. Conclusões. O uso da autocoleta facilitou a detecção de genótipos inesperados de HPV entre mulheres assintomáticas em Granada. Esses achados adicionaram novas informações à literatura sobre o rastreamento de neoplasias e câncer do colo do útero e sobre os genótipos de HPV no Caribe. Essas informações genotípicas podem afetar a vigilância de mulheres com lesões de baixo grau, a seleção da vacina contra o HPV e, possivelmente, futuras pesquisas sobre vacinas. É necessário pesquisar o HPV em amostras patológicas de neoplasias cervicais e câncer do colo do útero no Caribe.

COVID-19 point-of-care tests can identify low-antibody individuals: In-depth immunoanalysis of boosting benefits in a healthy cohort.

The recommended COVID-19 booster vaccine uptake is low. At-home lateral flow assay (LFA) antigen tests are widely accepted for detecting infection during the pandemic. Here, we present the feasibility and potential benefits of using LFA-based antibody tests as a means for individuals to detect inadequate immunity and make informed decisions about COVID-19 booster immunization. In a health care provider cohort, we investigated the changes in the breadth and depth of humoral and T cell immune responses following mRNA vaccination and boosting in LFA-positive and LFA-negative antibody groups. We show that negative LFA antibody tests closely reflect the lack of functional humoral immunity observed in a battery of sophisticated immune assays, while positive results do not necessarily reflect adequate immunity. After booster vaccination, both groups gain depth and breadth of systemic antibodies against evolving SARS-CoV-2 and related viruses. Our findings show that LFA-based antibody tests can alert individuals about inadequate immunity against COVID-19, thereby increasing booster shots and promoting herd immunity.

Guideline for the diagnosis and management of marginal zone lymphomas: a British Society of Haematology guideline

The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with marginal zone lymphoma (MZL).

Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.

PURPOSE: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen. PATIENTS AND METHODS: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7). RESULTS: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation. CONCLUSIONS: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.

Longitudinal Analysis of Humoral and Cellular Immune Response Following SARS-CoV-2 Vaccination Supports Utilizing Point-Of-Care Tests to Enhance COVID-19 Booster Uptake.

Individuals with weaker neutralizing responses show reduced protection with SARS-CoV-2 variants. Booster vaccines are recommended for vaccinated individuals, but the uptake is low. We present the feasibility of utilizing point-of-care tests (POCT) to support evidence-based decision-making around COVID-19 booster vaccinations. Using infectious virus neutralization, ACE2 blocking, spike binding, and TCR sequencing assays, we investigated the dynamics of changes in the breadth and depth of blood and salivary antibodies as well as T-cell clonal response following mRNA vaccination in a cohort of healthcare providers. We evaluated the accuracy of two POCTs utilizing either blood or saliva to identify those in whom humoral immunity was inadequate. >4 months after two doses of mRNA vaccine, SARS-CoV-2 binding and neutralizing Abs (nAbs) and T-cell clones declined 40-80%, and 2/3rd lacked Omicron nAbs. After the third mRNA booster, binding and neutralizing Abs increased overall in the systemic compartment; notably, individuals with previously weak nAbs gained sharply. The third dose failed to stimulate secretory IgA, but salivary IgG closely tracked systemic IgG levels. Vaccine boosting increased Ab breadth against a divergent bat sarbecovirus, SHC014, although the TCR-beta sequence breadth was unchanged. Post 3rd booster dose, Ab avidity increased for the Wuhan and Delta strains, while avidity against Omicron and SHC014 increased to levels seen for Wuhan after the second dose. Negative results on POCTs strongly correlated with a lack of functional humoral immunity. The third booster dose helps vaccinees gain depth and breadth of systemic Abs against evolving SARS-CoV-2 and related viruses. Our findings show that POCTs are useful and easy-to-access tools to inform inadequate humoral immunity accurately. POCTs designed to match the circulating variants can help individuals with booster vaccine decisions and could serve as a population-level screening platform to preserve herd immunity. One Sentence Summary: SARS-CoV-2 point-of-care antibody tests are valuable and easy-to-access tools to inform inadequate humoral immunity and to support informed decision-making regarding the current and future booster vaccination.

Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial.

B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA0 with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA0 rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.

Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.

Differential Efficacy From the Addition of Bortezomib to R-CHOP in Diffuse Large B-Cell Lymphoma According to the Molecular Subgroup in the REMoDL-B Study With a 5-Year Follow-Up.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression-based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.

Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation.

Vascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. The gene-regulatory mechanisms underpinning endothelial specialization are largely unknown, as are the roles of chromatin organization in regulating endothelial cell transcription. To investigate the relationships between chromatin organization and gene expression, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-sequencing assays at specific time points. Long-range intrachromosomal contacts increase over the course of differentiation, accompanied by widespread heteroeuchromatic compartment transitions that are tightly associated with transcription. Dynamic topologically associating domain boundaries strengthen and converge on an endothelial cell state, and function to regulate gene expression. Chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes essential to vascular biology. Chromatin dynamics guide transcription in endothelial cell development and promote the divergence of endothelial cells from cardiomyocytes.

Perturbations of the T-cell immune repertoire in kidney transplant rejection.

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.

Anti-spike T-cell and Antibody Responses to SARS-CoV-2 mRNA Vaccines in Patients with Hematologic Malignancies.

The anti-spike T-cell and antibody responses to SARS-CoV-2 mRNA vaccines in patients with B-cell malignancies were examined in a real-world setting. A next-generation sequencing (NGS)-based molecular assay was used to assess SARS-CoV-2-specific T-cell responses. After the second dose, 58% (166/284) of seropositive and 45% (99/221) of seronegative patients display anti-spike T cells. The percentage of patients who displayed T-cell response was higher among patients receiving mRNA-1273 vaccines compared with those receiving BNT162b2 vaccines. After the third vaccination, 40% (137/342) of patients seroconverted, although only 22% displayed sufficient antibody levels associated with the production of neutralizing antibodies. 97% (717/738) of patients who were seropositive before the third dose had markedly elevated anti-spike antibody levels. Anti-spike antibody levels, but not T-cell responses, were depressed by B cell-directed therapies. Vaccinated patients with B-cell malignancies with a poor response to SARS-CoV-2 vaccines may remain vulnerable to COVID-19 infections. SIGNIFICANCE: This study represents the first investigation of SARS-CoV-2-specific immune responses to vaccination in a patient registry using an NGS-based method for T-cell receptor repertoire-based analysis combined with anti-spike antibody assessments. Vaccinated patients with B cell-derived hematologic malignancies are likely at higher risk of infection or severe COVID-19. This article is highlighted in the In This Issue feature, p. 476.

Mathematical Modeling of Population Dynamics of Trogoderma granarium (Coleoptera: Dermistidae).

Khapra beetle, Trogoderma granarium Everts, is one of the economically important quarantine pests that mainly feeds on food grain and proteinaceous materials. Its total development time lasts approximately 40-45 d under favorable environmental conditions. Extreme temperatures, high relative humidity (RH), high larval densities, or low food quality can induce a larval diapause, where the insect can survive for up to a few years, occasionally feeding and molting. Ecological modeling is a helpful tool to study the population dynamics of biological systems. Physi-Biological age method is based on temperature-driven development rate, and factors such as RH and food quality were considered as multipliers. The objective of this study was to develop mathematical models to calculate the survival and development of adults, eggs, larvae, pupae, and oviposition and diapause under different environmental conditions such as temperature, RH, and food quality. Algorithms were developed to simulate the population dynamics for each day and coded in C++. The developed models were validated against the literature data and evaluated using linear regression, R2, and MSE. Population dynamics were simulated under Canadian grain storage conditions, and the developed models predicted that the diapausing larvae survived the extremely cold conditions found in Canadian grain. In contrast, other stages did not survive. The surviving larvae developed to pupae and adults, and females began laying eggs once the temperature became warmer in the grain bins.

Changes in T-cell subsets and clonal repertoire during chemoimmunotherapy with pembrolizumab and paclitaxel or capecitabine for metastatic triple-negative breast cancer.

BACKGROUND: Chemoimmunotherapy is a standard treatment for triple-negative breast cancer (TNBC), however, the impacts of different chemotherapies on T-cell populations, which could correlate with clinical activity, are not known. Quantifying T-cell populations with flow cytometry and T-cell receptor (TCR) immunosequencing may improve our understanding of how chemoimmunotherapy affects T-cell subsets, and to what extent clonal shifts occur during treatment. TCR immunosequencing of intratumoral T cells may facilitate the identification and monitoring of putatively tumor-reactive T-cell clones within the blood. METHODS: Blood and tumor biopsies were collected from patients with metastatic TNBC enrolled in a phase Ib clinical trial of first or second-line pembrolizumab with paclitaxel or capecitabine. Using identical biospecimen processing protocols, blood samples from a cohort of patients treated for early-stage breast cancer were obtained for comparison. Treatment-related immunological changes in peripheral blood and intratumoral T cells were characterized using flow cytometry and TCR immunosequencing. Clonal proliferation rates of T cells were compared based on intratumoral enrichment. RESULTS: When combined with pembrolizumab, paclitaxel and capecitabine resulted in similar time-dependent lymphodepletions across measured peripheral T-cell subsets. Their effects were more modest than that observed following curative-intent dose-dense anthracycline and cyclophosphamide (ddAC) (average fold-change in CD3+ cells, capecitabine: -0.42, paclitaxel: -0.56, ddAC: -1.21). No differences in T-cell clonality or richness were observed following capecitabine or paclitaxel-based treatments. Regression modeling identified differences in the emergence of novel T-cell clones that were not detected at baseline (odds compared with ddAC, capecitabine: 0.292, paclitaxel: 0.652). Pembrolizumab with paclitaxel or capecitabine expanded T-cell clones within tumors; however, these clones did not always expand within the blood. Proliferation rates within the blood were similar between clones that were enriched and those that were not enriched within tumors. CONCLUSION: Chemoimmunotherapy for metastatic TNBC with pembrolizumab and capecitabine or paclitaxel resulted in similar peripheral T-cell subset lymphodepletion without altering T-cell clonal diversity. Regression modeling methods are applicable in immune monitoring studies, such as this to identify the odds of novel T-cell clones emerging during treatment, and proliferation rates of tumor-enriched T-cell clones.

The epidemiology and control of Toxocara canis in puppies.

Toxocara canis is a helminth zoonosis that is estimated to infect more than 100 million dogs and 1 billion people, mostly in the tropics. Humans can be infected by accidentally ingesting embryonated T. canis eggs from the environment or occasionally after ingesting L3 larvae from paratenic hosts. This study investigated the importance of vertical transmission and the role of puppies in the epidemiology of T. canis through the examination of fecal samples from dogs less than one year of age in Grenada, West Indies, a small island tropical developing country. Samples were stored at 4 °C or in 10% formalin until microscopic examination for helminth eggs or using a rapid antigen test for the presence of protozoan species. A knowledge, attitudes and practices study was completed among dog owners, physicians and veterinary students. Of 306 dogs less than one year of age, 147 (48%) were found to have T. canis eggs. Vertical transmission was indicated by the proportion of infected dogs increasing from 50% at two weeks of age (from in utero transmission) to 70% by 12 weeks (in utero and lactogenic transmission). After 12 weeks the positivity rate dropped rapidly with no dogs over 40 weeks of age being infected. As T. canis eggs were found in puppy feces at two weeks of age, initial treatment of puppies should begin earlier, at twelve days post-partum, than currently recommended to prevent shedding of eggs. Perhaps even more importantly, treatment of pregnant dogs, preventing vertical transmission, would have a major impact on the control of T. canis infection. Knowledge of T. canis and other zoonotic helminths such as Ancylostoma caninum was found to be low among dog owners, physicians and veterinary students. None of the dog owners treated their dogs for helminths, all were unaware of the risk of zoonoses, and only 9% picked up dog feces. Efforts to prevent vertical transmission and to increase awareness and knowledge of these zoonoses could result in reducing their public health impact.

A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma.

Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma.

AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific TH1 response with a diverse TCR repertoire.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus­vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein­specific CD4+ T cell helper type 1 (TH1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages after two doses of AZD1222. CD4+ TH2 responses after AZD1222 vaccination were not detected. Furthermore, AZD1222-specific TH1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor ß (TCRß) sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional TH1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein.

Impact of HLA type, age and chronic viral infection on peripheral T-cell receptor sharing between unrelated individuals.

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, factors such as thymic selection and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCRß variable region of 426 healthy individuals, we find that, on average, fewer than 1% of TCRß clones are shared between individuals, consistent with largely private TCRß repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCRß clones, with each additional shared HLA allele contributing to an increase in ~0.01% of the total shared TCRß clones, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCRß clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCRß clone sharing, indicating that the pattern of private TCRß clonal expansion is a general feature of the T-cell response to other infectious antigens as well. However, increased age also correlates with increased sharing among the lowest frequency clones, consistent with decreased repertoire diversity in older individuals. Together, all of these factors contribute to shaping the TCRß repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.