Nat Med Research Articles

Manufacturing Bispecific LV20.19 CAR T-Cells with IL-7 & IL-15 for a Shorter Duration Improves CAR T-Cell Immunophenotype While Maintaining Target Cell Dose

Manufacturing Bispecific LV20.19 CAR T-Cells with IL-7 & IL-15 for a Shorter Duration Improves CAR T-Cell Immunophenotype While Maintaining Target Cell Dose

SHP1 Loss Augments DLBCL Cellular Response to Ibrutinib: A Candidate Predictive Biomarker

BackgroundB-cell receptor (BCR) signaling plays a key role in B-cell non-Hodgkin lymphoma (NHL). Protein tyrosine kinases such as LYN, SYK and BTK are essential in the activation of BCR leading to B-cell survival, proliferation and differentiation. SHP1 is a cytosolic protein tyrosine phosphatase functioning as a negative regulator of the BCR signaling cascade. It dephosphorylates and counteracts the activities of the tyrosine kinases, including CD79A/CD79B, SYK and BLNK (Curr. Opin. Immunol.12, 307).Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive NHL. DLBCL demonstrates heterogeneity in clinical presentation, genomic alterations and cell signaling. BCR signature has been identified in a subset of DLBCL (Monti Blood 105, 1851). Chronic active BCR plays a particular role in the subtype of activated B-cell like (ABC) DLBCL by cell-of-origin subclassification. Based on the success of ibrutinib in other B-cell NHL, clinical trials of ibrutinib in DLBCL was conducted and the initial results showed a 37% response rate in ABC-lymphomas vs 5% in GCB-DLBCL (Wilson Nat Med 21, 922). However, a large phase 3 clinical trial of ibrutinib-containing regimen in >800 non-GCB patients did not find any substantial difference in response between those received ibrutinib vs placebo. Thus, biomarker based on cell-of-origin did not seem to help stratify patients as expected (Younes JCO 27, 1285). New predictive biomarkers are needed to identify patients who likely benefit from ibrutinib or other BCR-directed therapeutic agents.We hypothesized that SHP1 may play a role in defining the level of the activity of the BCR pathway. Suppressed SHP1 expression in various types of NHL has been reported. We hypothesized that lack of SHP1 may contribute to the hyperactivity of BCR in DLBCL; and tumors with low SHP1 may respond better to ibrutinib. In this work, we set out to explore the relationship between SHP1 & ibrutinib sensitivity in DLBCL.Methods and ResultsWe first reviewed the published literature on SHP1 in NHL using a meta-analysis to provide a quantitative and thus unbiased analysis. Seventeen articles were selected based on criteria including inclusion of primary tumors with normal benign controls. The analysis of the SHP1 protein expression by immunohistochemistry (IHC) revealed that lack of SHP1 expression is found in 178 of 242 (73.6%) NHL tissues vs. 32 of 264 (12%) normal/benign controls. The odds ratio derived by the meta-analysis was 119.58 with a 95% confidence interval of 37.60-380.15, suggesting loss of SHP1 is strongly associated with NHL including DLBCL. Likewise, the analysis of the methylation studies revealed a strong association between SHP1 promoter hypermethylation and NHL (OR 69.46, 95% CI 12.32-391.74).To further understand the range of variability of SHP1 expression in subtypes of DLBCL tumors, we constructed a tissue microarray with 48 DLBCL tumors and 12 cell lines. By immunohistochemistry, we found a wide range of variability with regards to the expression levels and no substantial difference between the GCB and non-GCB subtypes.Using 12 cell lines together with resting B-cells from normal donors, we identified a strong reverse linear correlation between SHP1 protein expression and promoter methylation (r = 0.85, P=0.0002) suggesting that promoter hypermethylation may be responsible for reduced SHP1 expression in DLBCL cells.Using CRISPR, we knocked out SHP1 in both GCB and ABC cell lines. The phosphorylation of early BCR components, BTK, SYK and LYN, were increased in the SHP1 knockout clones compared to the wild type ones. The results demonstrate that SHP1 depletion results in increased proximal BCR signaling activity. Moreover, the knock out clones demonstrated increased sensitivity of ibrutinib. We further showed that re-introduction of SHP1 vector to the knockout clones via stable lentiviral transduction restored normal sensitivity of cells to ibrutinib.ConclusionsTogether, our results show that SHP1 expression is suppressed in a substantial fraction of DLBCL tumors regardless of cell-of-origin subclassifications. Using genetic approaches, we demonstrated that loss of SHP1 increases BCR signaling activity and sensitizes tumor cells to the inhibition by ibrutinib. Our results suggest that loss of SHP1 may be used as an alternative biomarker to cell-of-origin to identify patients who potentially benefit from ibrutinib treatment. DisclosuresWang: Incyte Research Institute: Ended employment in the past 24 months.

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Bispecific LV20.19 CAR T-Cells Expanded in IL-7 and IL-15 Have Greater Polyfunctionality and Polyfunctional Strength Than CAR T-Cells Expanded in IL-2

Bispecific LV20.19 CAR T-Cells Expanded in IL-7 and IL-15 Have Greater Polyfunctionality and Polyfunctional Strength Than CAR T-Cells Expanded in IL-2

Subsequent Anti-Myeloma Therapy after Idecabtagene Vicleucel (ide-cel, bb2121) Treatment in Patients with Relapsed/Refractory Multiple Myeloma from the KarMMa Study

Subsequent Anti-Myeloma Therapy after Idecabtagene Vicleucel (ide-cel, bb2121) Treatment in Patients with Relapsed/Refractory Multiple Myeloma from the KarMMa Study

Therapeutic and Immunologic Responses Elicited By in Situ Vaccination with CpG, Ibrutinib, and Low-Dose Radiation

Introduction: In situ vaccination aims to induce an immune response locally at one tumor site that propagates systemically to all tumor sites. This approach can be effective in indolent lymphoma (Brody et al., JCO 2010, Frank et al., Cancer Discov 2018, Hammerich et al., Nat Med 2019). We designed a novel clinical strategy combining in situ vaccination with systemic ibrutinib, a kinase inhibitor that modulates B and T cells. Our preclinical work had shown that combined intratumoral CpG injection and systemic ibrutinib administration was curative of systemic disease in a mouse lymphoma model, an effect that was T cell dependent (Sagiv-Barfi, Blood, 2015). Here we report the results and correlative data from the Phase I/II clinical trial testing this combination along with local low-dose radiation in adults with recurrent low-grade B cell lymphoma (NCT02927964).Methods: Enrolled patients received intratumoral injections of CpG (SD-101, 3 mg) weekly for 5 doses and local radiation (4Gy in two fractions) to the same site. Daily oral ibrutinib (560mg) began after the second intratumoral injection. Revised Lugano criteria (Cheson et al., JCO, 2014) were used to assess overall radiographic responses to therapy. Distal responses were assessed by excluding the injected site and measuring only non-injected sites. Fine needle aspirates (FNAs) were obtained from CpG-injected and non-injected nodal tumor sites pre- and post-treatment and analyzed by flow cytometry and droplet-based single-cell RNA sequencing (scRNAseq).Results: Among the twenty patients treated on study, median age was 64, 55% were male, and all but one had a diagnosis of follicular lymphoma. All patients were previously treated with an average of 2 lines of therapy, and half had previously received chemotherapy. Adverse events (AEs) were consistent with known effects of ibrutinib (including diarrhea and rash) and of CpG (including fever and flu-like reactions). No drug-related grade 4, serious, or unexpected AEs were observed. As anticipated, all patients experienced tumor reduction at the locally treated site (median 84% reduction). Remarkably, all patients experienced some tumor reduction at non-injected non-irradiated index lesions (median 45%, range 13-100%), suggesting the generation of systemic immune responses (Figure 1A). By Cheson criteria, ten patients achieved an objective response, including one complete response (ORR 50%). Despite an overall improvement in tumor burden, three patients had new or progressing non-index lesions and scored as progressive disease. Treatment induced an expansion of naïve and effector memory T cells and reductions in T follicular helper (Tfh) and activated regulatory T cells (Tregs) at the injected site. T cells with high expression of transcripts related to oxidative phosphorylation (Toxphos) increased preferentially in patients with subsequent clinical tumor reduction (Figure 1B), implicating T cell metabolism in successful generation of immune responses. Analysis of single cell T cell receptor (TCR) sequencing data revealed>300 clones that were comprised of at least 2 cells at each timepoint and which expanded or contracted at least two-fold during treatment. Expanding clones were more likely than contracting clones to be activated or memory T cells and less likely than contracting clones to be Tfh or Tregs (Figure 1C-D). Clone dynamics were often similar at the two sampled tumor sites, reflecting systemic immune responses. Finally, in vitro assays showed treatment-induced expansion of tumor-specific T cells in the peripheral blood of all 6 evaluable patients.Conclusion: The combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is safe and can generate systemic antitumor immune responses and systemic tumor shrinkage in low-grade B cell lymphoma. [Display omitted] DisclosuresShree: Gilead: Other: Spouse's employment. Khodadoust: CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Beygi: Kite/Gilead: Current Employment. Levy: GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Kira: Membership on an entity's Board of Directors or advisory committees; Abintus Bio: Membership on an entity's Board of Directors or advisory committees; Khloris: Membership on an entity's Board of Directors or advisory committees; Virsti: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees.

In Situ Vaccination Induces Changes in Follicular Lymphoma Tumor Cells That Correlate with Abscopal Clinical Regressions

In Situ Vaccination Induces Changes in Follicular Lymphoma Tumor Cells That Correlate with Abscopal Clinical Regressions

Luspatercept Redistributes Body Iron to the Liver in Transfusion-Dependent-Thalassemia (TDT) during Erythropoietic Response

Luspatercept Redistributes Body Iron to the Liver in Transfusion-Dependent-Thalassemia (TDT) during Erythropoietic Response

Neuronal cell-based medicines from pluripotent stem cells: Development, production, and preclinical assessment.

Brain degeneration and damage is difficult to cure due to the limited endogenous repair capability of the central nervous system. Furthermore, drug development for treatment of diseases of the central nervous system remains a major challenge. However, it now appears that using human pluripotent stem cell‐derived neural cells to replace degenerating cells provides a promising cell‐based medicine for rejuvenation of brain function. Accordingly, a large number of studies have carried out preclinical assessments, which have involved different neural cell types in several neurological diseases. Recent advances in animal models identify the transplantation of neural derivatives from pluripotent stem cells as a promising path toward the clinical application of cell therapies [Stem Cells Transl Med 2019;8:681‐693; Drug Discov Today 2019;24:992‐999; Nat Med 2019;25:1045‐1053]. Some groups are moving toward clinical testing in humans. However, the difficulty in selection of valuable critical quality criteria for cell products and the lack of functional assays that could indicate suitability for clinical effect continue to hinder neural cell‐based medicine development [Biologicals 2019;59:68‐71]. In this review, we summarize the current status of preclinical studies progress in this area and outline the biological characteristics of neural cells that have been used in new developing clinical studies. We also discuss the requirements for translation of stem cell‐derived neural cells in examples of stem cell‐based clinical therapy.

Nowcasting towards sustainable SARS-CoV-2 endemicity

Nowcasting towards sustainable SARS-CoV-2 endemicity

Cheminformatics modeling of the correlation between Bupleurum Root-formula medicines and Excess and Deficiency pattern in the diagnostic criteria of Sho in Kampo (traditional Japanese medicine) by non-targeted direct infusion mass spectrometry with machine learning.

Kampo is a form of traditional Japanese medicine, and its therapeutic strategy has been validated empirically over millennia, mainly in Asia. Kampo therapy aims to holistically prevent and treat disease based on the specific diagnosis Sho (in Japanese), in contrast with modern medical treatment which focuses on a patient's affected parts and local conditions. The medicines formulated using crude drugs derived from natural sources (Kampo formulas) are prescribed for patients according to their specific Sho, and thus the Kampo medication system is very complex. However, our previous study strongly suggested that Kampo medication theory could be explained by chemometrics and informatic approaches [Okada et al. in J Nat Med 70:107-114, 2016]. Here, we studied a group of seven formulas with Bupleurum Root and Scutellaria Root as the principal crude drugs. First, decoctions of the formulas were prepared and their supernatants were analyzed by non-targeted direct infusion mass spectrometry (MS) and principal component analysis, which is a type of unsupervised machine learning. Next, supervised machine learning was used to perform partial least squares modeling of the MS data matrix trained on the patients' constitution of Excess, Deficiency, or Medium between these two states (EDM) in Sho. The results showed that the correlation between the chemical fingerprints obtained by MS analysis and EDM could be modeled well using this approach. This cheminformatics modeling approach successfully interpreted part of the complex Kampo medication system studied using the fingerprints of formulas obtained by MS analysis and was consistent with the predicted Sho.

Development of physiologically-based pharmacokinetic models for standard of care and newer tuberculosis drugs.

Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically‐based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N‐desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty‐four percent (area under the curve [AUC]) and 91% (maximum concentration [C max]) of simulated mean values were within 1.5‐fold of the observed data and the simulated drug‐drug interaction ratios were within 1.5‐fold (AUC) and twofold (C max) of the observed data for nine (AUC) and eight (C max) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients’ with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th–95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fumass), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within‐subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open‐source to aid further research.

METABOLIC ALKALOSIS DRIVING RESPIRATORY FAILURE IN POST ACUTECOVID-19 SYNDROME

TOPIC: Pulmonary Physiology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Survival of the acute phase of COVID-19 infection can leave patients with multiple long-term sequelae described as Post-acute covid-19 syndrome (PACS). We present a case of a patient with PACS manifested as pulmonary fibrosis, carbon dioxide retention and difficulty weaning from BIPAP that experienced dramatic improvement following treatment with Acetazolamide. CASE PRESENTATION: 66-year-old female presented for 7 days of worsening cough and shortness of breath. She was found to be hypoxic on presentation with COVID-19 test resulting positive and was admitted. Her hospital course was complicated by rapid increase in oxygen requirements with the initiation of BIPAP on hospital day 19. At this time, arterial blood gas (ABG) revealed mixed respiratory acidosis and metabolic alkalosis with pH 7.41, CO2 77 and HCO3 of 43. She was continued on BIPAP for several days before being weaned to high flow nasal cannula. On hospital day 44 she was noted to be increasingly lethargic. ABG obtained at this time showed pH of 7.3, CO2 >110 and HCO3 of 68. She was placed back on BIPAP and serial ABGs were monitored. At about 12 hours after the initiation of BIPAP, she developed a post-hypercapnic alkalosis with ABG demonstrating pH 7.46, CO2 90 and HCO3 50. At this time, BIPAP was stopped and Acetazolamide was administered at 500mg IV daily for 2 days.The patient experienced significant improvement in her mental status and work of breathing. She was weaned to nasal cannula. An ABG obtained the day following the second acetazolamide dose showed improvement in both metabolic alkalosis and respiratory acidosis with pH 7.42, CO2 62 and HCO3 34. DISCUSSION: The role of correcting metabolic alkalosis in hypercapnic respiratory failure has been described over the years. Trials conducted have utilized the carbonic anhydrase inhibitor Acetazolamide to promote renal bicarbonate excretion with goal statistical endpoints of early liberation from mechanical ventilation, reduced hospital stay or mortality but have generally failed to demonstrate statistically significant benefit.In the DIABOLO trial, mechanically ventilated COPD patients with metabolic alkalosis were assigned to either Acetazolamide infusion or placebo. The study concluded without statistically significant benefit in the primary outcome (duration of mechanical ventilation) or important secondary outcomes such as ICU mortality or ICU length of stay. However, the average serum bicarbonate level was only 27 between the two groups. This leads to the question if acetazolamide may have benefits in specific patients with a more severe alkalosis in the right clinical context as shown in this case study. CONCLUSIONS: Alkalosis may surpass compensation and perpetuate hypercapnic respiratory failure. This may be especially common ARDS patients managed with a fluid restricted approach. Administration of acetazolamide may benefit appropriately selected patients. REFERENCE #1: Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. Published online March 22, 2021. doi:10.1038/s41591-021-01283-z REFERENCE #2: Faisy C, Meziani F, Planquette B, et al. Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial. JAMA. 2016;315(5):480-488. doi:10.1001/jama.2016.0019 REFERENCE #3: Adamson R, Swenson ER. Acetazolamide Use in Severe Chronic Obstructive Pulmonary Disease. Pros and Cons. Ann Am Thorac Soc. 2017;14(7):1086-1093. doi:10.1513/AnnalsATS.201701-016FR DISCLOSURES: No relevant relationships by Jackson Heilbronn, source=Web Response no disclosure on file for Christina Kwon;No relevant relationships by Michael Ulrich, source=Web Response

A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.

ILC3–T cell interactions regulate the gut microbiota (from Fig. 1C of Hakozaki et al., Cancer Immunol Res 2020)Group 3 innate lymphoid cells (ILC3) regulate host–microbe interactions in the intestines, but whether they have a role in colorectal cancer (CRC) is not known. Goc et al. show that ILC3s in human and mouse CRC are dysregulated. In mice, this reduces ILC3 interactions with CD4+ T cells, which decreases gut colonization by microbiota that induce type-1 immunity and thereby promotes CRC progression and resistance to PD-1 blockade. Patients with inflammatory bowel disease have dysregulated ILC3s and microbiota that do not induce type-1 immunity when transferred to mice, but rather promote CRC resistance to PD-1 blockade. The data identify new avenues for immunotherapeutic intervention.Goc J, …, Sonnenberg GF. Cell 2021 Aug 17. DOI: 10.1016/j.cell.2021.07.029.Autologous TIL ACT is effective and safe (by Shyamal via Wikimedia Commons)Adoptive cell therapy (ACT) for metastatic non–small cell lung cancer (NSCLC) has not yet been evaluated. Creelan et al. report on a phase I clinical trial testing ACT using autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic NSCLC that progressed despite nivolumab treatment. Autologous TIL ACT is effective and safe, and assessment after TIL treatment shows tumor-specific T cells are elevated in responding patients. The data highlight a potential new therapy option for patients with metastatic NSCLC.Creelan BC, …, Antonia SJ. Nat Med 2021 Aug 12;27:1410–8.HBV-specific CD8+ T cells infiltrate HCC (from GrahamColm at English Wikipedia via Wikimedia Commons)Hepatocellular carcinoma (HCC) is often associated with chronic hepatitis B virus (HBV) infection, but whether HBV-specific T cells can control HCC growth is not known. Through comprehensive analysis of CD8+ T cells in samples from 46 patients with HCC, Cheng et al. show that HCC infiltration with HBV-specific CD8+ T cells associates with improved relapse-free survival. Intratumoral HBV-specific CD8+ T cells are enriched in two of five detectable subsets of tissue-resident memory T cells (Trm): CD103+CD57+ Trm and CD103+CD57− Trm. These cells are clonally expanded and lack gene signatures of terminally exhausted T cells, suggesting they could be harnessed therapeutically.Cheng Y, …, Newell EW. Immunity 2021 Aug 10;54:1825–40.e7.Overcoming treatment resistance in NSCLC can be achieved (from Librepath via Wikimedia Commons)Strategies to overcome resistance to anti–PD-1 immune checkpoint blockade in patients with cancer are much needed. By using genetically engineered models of non–small cell lung cancer (NSCLC), Martinez-Usatorre et al. identify mechanisms behind resistance to PD-1 blockade, antiangiogenic therapy, and the combination thereof. Tumor-associated macrophages of monocyte origin and alveolar origin contribute to resistance, and targeting these cells using a CSF1R inhibitor and cisplatin, respectively, improves responses to combination antiangiogenic therapy and PD-1 blockade. The data provide insight into the potential for targeting macrophages to overcome resistance to PD-1 blockade in patients with NSCLC.Martinez-Usatorre A, …, De Palma M. Sci Transl Med 2021 Aug 11;13:eabd1616.Improved CAR design improves performance (by Chris Phutully via Wikimedia Commons)Improving the antigen sensitivity of chimeric antigen receptor (CAR) T cells has the potential to improve responses in patients with tumors having low target antigen expression. Salter et al. compare T-cell receptor and CAR signaling in primary human T cells and show that multiple CD3 chains are not or are only weakly phosphorylated after CAR stimulation, indicating lower antigen sensitivity. Modifying the CAR construct to improve CD3 engagement increases CAR T-cell activation and efficacy in low antigen settings. The data highlight how understanding receptor signaling events can guide therapy design and provide potential construct alterations to improve CAR T-cell efficacy.Salter AI, …, Riddell SR. Sci Signal 2021 Aug 24;14:eabe2606.Immune profiling reveals inter- and intratumoral immune heterogeneity in PDAC (from Fig. 4C of Liudahl et al., Cancer Discov 2021)A deeper understanding of the pancreatic ductal adenocarcinoma (PDAC) tumor immune microenvironment is needed if effective immunotherapies are to be developed for this cancer. By analyzing 135 human PDAC samples using a single-cell multiplexed immunohistochemistry platform, Liudahl et al. provide insight into the inter- and intrapatient heterogeneity in density, complexity, phenotype, and spatial relationships of myeloid and lymphoid cells in PDAC. The data provide a comprehensive immune atlas of PDAC that can serve as a resource to stimulate further investigations.Liudahl SM, …, Coussens LM. Cancer Discov 2021 Aug 1;11:2014–31.

Immunological response after mild COVID-19: How long will it last?

Immunological response after mild COVID-19: How long will it last?

Vaccination after prior COVID-19 infection: Implications for dose sparing and booster shots.

Vaccination after prior COVID-19 infection: Implications for dose sparing and booster shots.

Anti–SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY?

Anti–SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY?

Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

Antibody response after third BNT162b2 dose in recipients of allogeneic HSCT

Antibody response after third BNT162b2 dose in recipients of allogeneic HSCT

SARS-CoV-2 spike and its adaptable furin cleavage site

SARS-CoV-2 spike and its adaptable furin cleavage site