Trace Elements Zinc and Selenium: Their Significance in the Conditions of the Covid-19 Pandemic

Within the conditions of the ongoing COVID-19 pandemic, when many questions regarding prevention and treatment strategies remain unsolved and the search for the best antiviral agents is underway, attention should be paid to the role of trace elements zinc and selenium in increasing the body's resistance to viral infections and their direct antiviral activity against SARS-CoV-2. Experimental data show that trace elements zinc and selenium not only actthrough regulating the immune response at all levels of humoral and cellular immunity, but also can play a significant role in adjuvant therapy for viral diseases. This is especially relevant in the case of COVID-19. Studies of the direct antiviral effect of these micro-elements testify to its 3 main ways to SARS-Cov-2: I - counteraction to virus replication and its transcription through: (i) their covalent binding to the SH-group of the cysteine of the main protease M(Pro) of the virus;(ii) inhibition of its RNA polymerase activity by zinc;II - preventing the penetration of the virus into cells due to blocking SH-groups of protein disulfide isomerase (RDI) of the protein of its spikes (peplomers);III - decreasing the adsorption capacity of the virus due to the blocking of the electrostatic interaction of SARS-CoV-2 peplomers and angiotensin-converting enzyme (ACE-2) in ultra-low, uncharacteristic oxidation states (Zn+1and Se-2). The intensity of the antiviral action of these trace elements may depend on their chemical form. It was found that zinc citrate (a five-membered complex of zinc with citric acid) and monoselenium citric acid obtained with the help of nanotechnology have a greater intensity of action and higher chemical purity. Taking into account the immunostimulating and direct antiviral effect of zinc and selenium, their use in the form of pharmaceuticals and dietary supplements should be considered as adjunctive therapy for SARS-CoV-2 in patients, or as a preventive strategy for uninfected people from risk groups during the spread of COVID-19.Copyright © Publisher PH <<Akademperiodyka>> of the NAS of Ukraine, 2023.

The Effect of FOXP3+Regulatory T Cells on Infectious and Inflammatory Diseases

CD4+CD25+FOXP3+regulatory T cells (Tregs) contribute to the maintenance of immune homeostasis and tolerance in the body. The expression levels and functional stability of FOXP3 control the function and plasticity of Tregs. Tregs critically impact infectious diseases, especially by regulating the threshold of immune responses to pathogenic microorganisms. The functional regulatory mechanism and cell-specific surface markers of Tregs in different tissues and inflammatory microenvironments have been investigated in depth, which can provide novel ideas and strategies for immunotherapies targeting infectious diseases.Copyright © 2021. All rights reserved.

Development of a Lymphoid Organ-Chip to Evaluate Covid Vaccine Boosting Strategies

Background: Secondary lymphoid organs provide the adequate microenvironment for the development of antigen (Ag)-specific immune responses. The tight collaboration between CD4+ T cells and B cells in germinal centers is crucial to shape B cell fate and optimize antibody maturation. Dissecting these immune interactions remains challenging in humans, and animal models do not always recapitulate human physiology. To address this issue, we developed an in vitro 3D model of a human lymphoid organ. The model relies on a microfluidic device, enabling primary human cells to self-organize in an extracellular matrix (ECM) under continuous fluid perfusion. We applied this Lymphoid Organ-Chip (LO chip) system to the analysis of B cell recall responses to SARS-CoV-2 antigens. Method(s): We used a two-channel microfluidic Chip S1 from Emulate, where the top channel is perfused with antigen (spike protein or SARS-CoV-2 mRNA vaccine), while the bottom channel contains PBMC (n = 14 independent donors) seeded at high-density in a collagen-based ECM. Immune cell division and cluster formation were monitored by confocal imaging, plasmablast differentiation and spike-specific B cell amplification by flow cytometry, antibody secretion by a cell-based binding assay (S-flow). Result(s): Chip perfusion with the SARS-CoV-2 spike protein for 6 days resulted in the induction CD38hiCD27hi plasmablast maturation compared to an irrelevant BSA protein (P< 0.0001). Using fluorescent spike as a probe, we observed a strong amplification of spike-specific B cell (from 3.7 to 140-fold increase). In line with this rapid memory B cell response, spike-specific antibodies production could be detected as early as day 6 of culture. Spike perfusion also induced CD4+ T cell activation (CD38+ ICOS+), which correlated with the level of B cell maturation. The magnitude of specific B cell amplification in the LO chip was higher than in 2D and 3D static cultures at day 6, showing the added value of 3D perfused culture for the induction of recall responses. Interestingly, the perfusion of mRNA-based SARS-CoV-2 vaccines also led to strong B cell maturation and specific B cell amplification, indicating that mRNA-derived spike could be expressed and efficiently presented in the LO chip. Conclusion(s): We developed a versatile Lymphoid Organ-Chip model suitable for the rapid evaluation of B cell recall responses. The model is responsive to protein and mRNA-encoded antigens, highlighting its potential in the evaluation of SARS-CoV-2 vaccine boosting strategies.

Multidisciplinary management of a quickly growing pediatric atypical Spitz nevus, mimicking melanoma, during the COVID-19 pandemic

Spitzoid melanoma is very rare tumour in the pediatric population, with clinical and non-uniform behaviour, different from adult melanoma [1]. It can be difficult to differentiate an atypical Spitz nevus from a Spitzoid melanoma, resulting in diagnostic problems. In addition, in our clinical case, the COVID-19pandemiccaused significant delays both in the diagnosis and in the surgical treatment of our patient. We present the clinical case of a 4-year-old child suffering from a localized polypoid cutaneous neoformation on the dorsum of the left hand, which started immediately before the lockdown and steadily increased during the COVID-19 pandemic. After a general clinical framing, the child underwent an excisional biopsy at our Department of Plastic and Reconstructive Surgery, at the Policlinico of Foggia. Subsequently, two independent anatomic pathology groups examined the specimen. Definitive diagnosis was made only after careful genetic analysis in combination with supporting histological and immunohistochemical examinations. This clinical case shows how during the pandemic we have been facing advanced forms of tumours, compared to the previous period and highlight show an interdisciplinary and multicenter collaboration allowed a quick diagnosis of certainty, demonstrating the utility of molecular pathology as a fundamental aid in clinical/surgical practice. © 2022 The Authors

Liposomal Co-Formulation of MPL and QS-21 Favors the Development of T-helper 1 Cells and Promotes the Induction of CD8+ T Cells Against SARS-CoV-2

Background. Benefit of COVID-19 vaccines is limited by need for freezing, high cost, requirement for multiple boosters, and waning immunity. An unmet need for safe and effective vaccines that can be quickly deployed worldwide during a pandemic exists. A barrier to developing scalable low-cost vaccines is the restricted access to vaccine- or adjuvant-formulations due to protection by intellectual property rights. This limits research to understand their mechanism of action and potential applicability towards vulnerable populations or emerging pathogens. Methods. We studied cellular and molecular mechanisms of action of adjuvant formulations developed for global open access in 4 distinct but complementary in vitro platforms that are human, age-specific, and enable the same individual to serve as control and test condition;generating data on adjuvant-induced responses in vitro that predict activity in vivo. Results. Whole blood assay that models magnitude of innate immune activation and identifies cell types activated showed that liposomal co-formulation of MPL +QS-21 activated monocytes and natural killer cells and induced cytokine production;tissue construct assay that models monocyte extravasation and autonomous differentiation into dendritic cells (DC) showed that only MPL+QS-21 co-formulation promoted CD14+ cells towards DC phenotype;monocyte-derived DC (MoDC) assay that interrogates immune activation type showed that MPL+QS-21 co-formulation in lipid nanoparticles promoted MoDC maturation by increasing CD40, CD86, CCR7 and HLA-DR expression and Th1-polarizing cytokine secretion;and dendritic cell-T cell interface assay that assesses potential of formulations to re-activate SARS-CoV-2 Spike antigen-specific T cells showed that only MPL+QS-21 coformulation enhanced activation of antigen-specific CD4+ and CD8+ T cells. Conclusion. Thus, human in vitro modeling provides new insight into the mechanism of action and synergistic effects of MPL+QS-21, and positions us to study them in vulnerable populations to assess potential age-specific application on vaccine development. Precision vaccinology coupled with global access may enable marked public health progress by accelerating, de-risking, and advancing affordable adjuvanted vaccines to the most vulnerable.

HIGH RESPONSES RATES WITH SINGLE AGENT BELANTAMAB MAFODOTIN IN RELAPSED SYSTEMIC AL AMYLOIDOSIS

Background: Systemic AL amyloidosis is an incurable relapsing plasma cell disorder. Despite therapeutic advances, there are no approved treatments for relapse disease. Treatment is often challenging due to underlying organ dysfunction. Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen with approval for relapsed refractory myeloma. In multiply pre-treated myeloma, the DREAMM-2 phase II trial showed an overall response rate of 32% for those with 2.5 mg/kg dose administered every three weeks with 2/3rd patients reporting keratopathy. A small case series of 6 patients with relapsed AL amyloidosis (Zhang et al , ASH 2021) was recently reported and a phase 2 trial is recruiting for patients with refractory amyloidosis (NCT04617925). Aims: We report our initial results using Belantamab monotherapy for the treatment of patients with AL amyloidosis with relapsed disease. Methods: Data for consecutive patients who were administered Belantamab at a specialist referral centre, National Amyloidosis Centre, University College London, was analysed. Results: Eleven patients were included 8 male, 3 female. Median age at Belantamab initiation was 65 (range 42-74) years. Eight patients had λ AL-type and three κ AL-type. At diagnosis, median involved free light-chain concentration was 534 (range 73-7181) mg/l. A median of two organs involved at baseline (range 1-3): 4 had cardiac involvement (half Mayo stage 2;half Mayo stage 3a) and 8 had renal involvement. The median prior lines of therapy was 3 (range 2-5) with all exposed to prior immunomodulatory drugs, proteasome inhibitors and 73% to anti-CD38 antibody treatments. Thirty-six percent had relapsed after melphalan-conditioned autologous stem cell transplantation. A median of 3 cycles of belantamab were delivered (range 1-8). The most frequent adverse event was ocular toxicity which was experienced in 8 patients (grade 1-3), necessitating dose modification of the three-weekly schedule. One patient developed transient grade 1 dyspnoea and liver dysfunction. No patients developed cytopenias, unlike previous reports (Zhang et al , 2021), nor infections beyond COVID (2 patients mild with no hospital admissions). The majority of the cohort required dose reduction either at initiation (patient 4, due to end stage renal failure;patient 11, post-renal transplant) or during therapy (n=5;three to 1.9mg/kg, two to 1.25mg/kg) due to ocular toxicity. Only one patient remained on the standard dose of 2.5mg/kg for >3 cycles. Ocular toxicity improved after treatment interruption (drug intervals 4-6 weeks) and no patients required complete treatment cessation. One patient is too early to assess response. Haematological responses (PR or better) were seen in 7 patients with 3 complete responses and two very good partial responses (VGPR) which are ongoing. Both renal patients (patients 4 and 11) commenced a dose of 1.25mg/kg and sustained a VGPR with no additional toxicity. Patient 3 had a 42% reduction in sFLC after two doses but then a prolonged gap due to keratopathy and has lost the response. There were no cardiac or renal toxicities observed. Summary/Conclusion: Belantamab mafodotin demonstrates significant activity in patients with heavily pre-treated AL amyloidosis with 70% achieving a ≥PR. Apart from keratopathy requiring dose modification, no other substantial toxicity was observed. Two patients with renal impairment (stage V CKD and ESRD) and one patient post-renal transplant tolerated treatment with no additional toxicity. Belantamab mafodotin shows promise in treatment of relapsed AL and needs further prospective trials.

CILTACABTAGENE AUTOLEUCEL IN LENALIDOMIDE-REFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY: CARTITUDE-2 BIOLOGICAL CORRELATIVE ANALYSES AND UPDATED CLINICAL DATA

Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is assessing ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in patients with multiple myeloma (MM) who received 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide (len). This population is difficult to treat and has poor prognosis. Aims: To present updated results from CARTITUDE-2 Cohort A. Methods: All patients provided informed consent. Eligible patients had progressive MM after 1-3 prior LOT that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were len-refractory and had no prior exposure to BCMA-targeting agents. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) after lymphodepletion. Cilta-cel safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity at 10-5 by next generation sequencing. Patient management strategies were used to reduce the risk of movement and neurocognitive adverse events (MNTs). Other assessments included pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood), levels of cytokine release syndrome (CRS)-related cytokines (e.g., IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up: 17.1 months [range: 3.3-23.1]), cilta-cel was administered to 20 patients (male: 65%;median age: 60 years [range: 38-75]). Median number of prior LOT was 2 (range: 1-3);median time since MM diagnosis was 3.5 years (range: 0.7-8.0). 95% of patients were refractory to their last LOT;40% were triple-class refractory. Overall response rate was 95%, with 90% of patients achieving ≥complete response and 95% achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3);median time to best response was 2.6 months (range: 0.9-13.6). All MRD-evaluable patients (n=16) achieved MRD negativity at 10-5. Median duration of response was not reached. The 12-month progression-free survival rate was 75% and the 12-month event-free rate was 79%. CRS occurred in 95% of patients (grade 3/4: 10%), with a median time to onset of 7 days (range: 5-9) and median duration of 3 days (range: 2-12). 30% of patients had neurotoxicity (5 grade 1/2 and 1 grade 3/4). ICANS occurred in 3 patients (15%;all grade 1/2);1 patient had facial paralysis (grade 2). No MNTs were observed. 1 death due to COVID-19 occurred and was assessed as treatment-related by the investigator;2 deaths due to progressive disease and 1 due to sepsis (not related to treatment) also occurred. Based on preliminary PK analyses of CAR transgene by qPCR, peak expansion of CAR-T cells occurred at day 10.5 (range: 8.7-42.9);median persistence was 153.5 days (range: 57.1-336.8). Summary/Conclusion: A single cilta-cel infusion led to deepening and durable responses at this longer follow-up (median 17.1 months) in patients with MM who had 1-3 prior LOT and were len-refractory. Follow-up is ongoing. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide novel insights into biological correlates of efficacy and safety in this difficult-to-treat patient population, which is being further evaluated in the CARTITUDE-4 study (NCT04181827;enrollment concluded).

TALQUETAMAB, A G PROTEIN-COUPLED RECEPTOR FAMILY C GROUP 5 MEMBER D X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED PHASE 1 RESULTS FROM MONUMENTAL-1

G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799). Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range: 5.0-800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03;cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria. As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified. 30 patients received 405 μg/kg QW (median 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up [mF/U]: 7.5 mo [range 0.9-15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;mF/U: 3.7 mo [range 0.0-12.0]). No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%;1 grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/ kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D;6-month DOR rate was 67% (95% CI: 41-84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines. SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. (Figure Presented) .

CARTITUDE-2 UPDATE: CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY, IN LENALIDOMIDEREFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is assessing cilta-cel in patients (pts) with multiple myeloma (MM) under various clinical settings and evaluating the suitability of outpatient administration. Updated results of CARTITUDE-2 cohort A are presented here. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to BCMA-targeting agents. A single cilta-cel infusion at a target dose of 0.75×106 CAR+ viable T cells/kg was given 5-7 d after start of lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10-5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs). Response was assessed per International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). Results: As of April 15, 2021 (median follow-up of 9.7 mo), 20 pts (65% men;median age 60 y [range 38-75]) received cilta-cel, with 1 pt treated in an outpatient setting. Pts had a median of 2 prior LOT (range 1-3);60% had 1-2 prior LOT and 40% had 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response (Figure). Median time to first response was 1.0 mo (range 0.7-3.3) and median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;progression-free survival (PFS) at 6 mo was 90% (95% CI 65.6-97.4). Of 13 MRD-evaluable pts, 92.3% (95% CI 64.0-99.8) were MRD-negative at 10-5. Hematologic AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). 95% of pts had CRS (gr 3/4: 10%);median time to onset was 7 d (range 5-9) and median duration was 4 d (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 d and duration of 51 d. No movement and neurocognitive treatment-emergent adverse events (TEAEs) were reported. One death due to COVID-19 was assessed as treatment-related. Safety was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. No movement and neurocognitive TEAEs occurred, suggesting successful implementation of monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.

TGF-β SIGNALING PATHWAY SHAPES ADAPTIVE IMMUNITY in EARLY SARS-CoV-2 INFECTION

Background: SARS-CoV-2 induces cytokine response dysregulation and immune dysfunction. What remains unclear is how cytokine signaling shapes immune responses during early SARS-CoV-2 infection when adaptive immunity is developing. Our goal is to identify immune pathways that shape the early development of adaptive immune responses in COVID-19 patients. We performed paired single-cell transcriptomic and epigenomic profiling at two time-points of early SARS-CoV-2 infection to determine immune signatures of acute infection and epigenetic drivers that underpin immune response dynamics. Methods: PBMC samples were collected from four moderate to severe COVID-19 patients at two early time-points (n = 3 for Week 1 and n = 3 for Week 2 after symptom onset, including 2 participants having paired blood sampling at both time points) and from two healthy controls (n = 2). Using paired scRNA-Seq and scATAC-Seq, we captured transcriptomic and epigenomic profiles in the same single cells to identify chromatin accessibility changes as a potential mechanism for the surge and decline of immune responses elicited during acute SARS-CoV-2 infection. Using bioinformatic approaches, we identified heterogeneous immune cell populations, modeled cell differentiation trajectories, determined dysregulated immune pathways through gene set enrichment analysis, and connected chromatin co-accessible landscapes. Results: We captured transcriptomic and epigenomic profiles of 43,726 single cells and identified paired transcriptional and epigenetic landscapes in six major immune cell types: CD4+ T cells, CD8+ T cells, B cells, dendritic cells, monocytes, and NK cells. We found that early SARS-CoV-2 infection induced a surge in IL-2, IL-6, IFN-α, IFN-γ, TNF-α, and NF-κB responses at Week 1 that declined at Week 2 in adaptive immune cells (CD4+ T, CD8+ T, and B cells). In contrast, TGF-β responses surged early at Week 1 and continued to increase at Week 2 in these cells. In B cells and plasmablasts, we found early surges of IGHA1 (encoding IgA heavy chain) and SOX4 (an essential transcription factor for B cell development) expressions that correlated with expression of SMAD-dependent TGF-β signaling pathway. Further, we found a notable increase in chromatin accessibility at the SMAD binding regulatory element 150 kb upstream of SOX4 in B cells of infected patients. Conclusion: Our data suggest a significant increase in TGF-β activity that instructs dynamic B cell-associated protective immunity during early SARS-CoV-2 infection.

Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination.

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.

Journey of Natural Killer Cells and their Role in Liver Diseases

Natural Killer (NK) cells are the key lymphocyte subset of the natural immune system that arbitrates antiviral and anticancer responses. In the human body NK cells inhabit in the bone marrow, lymph nodes, tonsils, skin, liver, gut, and lungs. This bibliographic study covers the origins and evolution of these cells. This review of NK cells includes synopsis of their well-known and evolving themes including their development, functions of cytokine production, anticancer cytotoxicity, clearing of viral infections and exhaustion. Within the liver, NK cells are enhanced in lymphocytes and possess distinctive phenotypic characters and useful properties, which contain tumour cytotoxicity and explicit cytokine profiles. NK cells, while providing innate immunity in the liver, play important roles in providing protection versus pathogens and tumours utilising their cytotoxicity and cytokine production. Accruing substantiation from the last few decades proposes that NK cells perform a vital role in regulating viral hepatitis and liver tumours. In addition, they contribute to the pathogenesis of liver damage including its inflammation. Understanding the description of hepatic NK cell functions has aided us in better understanding the pathogenesis of diseases of the liver and consequently divulging novel therapeutic goals for treating these illnesses.

Ad26.COV2.S-Elicted Neutralizing Activities Against SARS-CoV-2 Variants of Concern in Phase 1/2a and Phase 3 Clinical Trials

Background. In a Phase 3 trial, the Janssen COVID-19 vaccine, Ad26.COV2.S, showed robust efficacy against severe-critical COVID-19 in countries where different SARS-CoV-2 variants were circulating. We evaluated Ad26.COV2.S-elicited antibody neutralizing activity against variants of concern (VOC) B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) in sera from participants in clinical trials following a single dose of Ad26.COV2.S. Methods. Neutralizing activities of Ad26.COV2.S (given at a dose level of 5 x 1010 viral particles [vp]) against VOC were assessed by wild-type virus neutralizing (wtVNA) and pseudovirion neutralization (psVNA) assays in sera from participants in Phase 1/2a and Phase 3 clinical trials, respectively. Geometric mean titers (GMTs) were determined at Days 29 and 71 after vaccination. Results. In serum samples from Phase 1/2a participants (n = 6), at Day 29 after 1 dose of Ad26.COV2.S, wtVNA titers against VOC were lower than for the original strain (GMT = 573), with GMT = 65, 14, and 15 for Alpha, Beta, and Delta, respectively, representing 8.8-, 40.9-, and 37.7-fold decreases. By Day 71 after vaccination (n = 14), fold differences between the original strain (GMT = 375) and VOC (GMT = 113, 27, and 28) were smaller (3.3-, 13.9-, and 13.4-fold) than at Day 29, suggestive of B-cell maturation (Figure 1). Day 71 titers against the Delta variant were maintained for at least 8 months following a single dose of Ad26.COV2.S (5 x 1010 vp). In serum samples from Phase 3 participants (n = 8), psVNA titers against VOC were lower than the original strain at Day 71 after vaccination, with the lowest titers observed for the Beta variant (3.6-fold decrease vs original strain). Smaller reductions in Nab titers for VOC were observed in the psVNA assay compared to wtVNA. Conclusion. Ad26.COV2.S-elicited serum neutralizing activity against VOC showed an overall decrease in titers relative to the original strain that was largest for the Beta variant, even though vaccine efficacy against severe-critical COVID-19 was maintained in countries where these variants were circulating versus in countries where they were not circulating. Over time, titers against variants increased, suggesting B-cell affinity maturation leading to increasing coverage of VOC.

Efficacy and Safety of Ciltacabtagene Autoleucel (Cilta-cel), a B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Lenalidomide-Refractory Patients with Progressive Multiple Myeloma after 1-3 Prior Lines of Therapy: Updated Results from CARTITUDE-2

Introduction: There are several treatment options for patients (pts) with progressive multiple myeloma (MM) who are refractory to lenalidomide but most pts relapse shortly after receiving salvage treatment. Cilta-cel is a CAR-T therapy expressing 2 BCMA-targeting, single-domain antibodies that demonstrated early, deep, and durable responses in pts with MM who had received ≥3 prior lines of therapy (LOT) in the phase 1b/2 CARTITUDE-1 study (Berdeja, Lancet, 2021). The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for pts with MM and exploring suitability of outpatient administration. Initial analysis (median follow-up 5.8 mo) of pts in CARTITUDE-2 cohort A (lenalidomide-refractory with 1-3 prior LOT) demonstrated an overall response rate (ORR) of 95%, with 75% of pts achieving complete response or better (≥CR) and 85% achieving very good partial response or better (≥VGPR). Here, we present updated results for this population. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and immunomodulatory drug (IMiD), were lenalidomide-refractory, and had no prior exposure to BCMA-targeting agents. Bridging therapy was allowed after apheresis. A single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) was given 5-7 d after start of lymphodepletion (daily cyclophosphamide [300 mg/m 2] and fludarabine [30 mg/m 2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10 -5. Secondary endpoints were ORR, duration of response (DOR), time and duration of MRD negativity, and incidence and severity of AEs. MRD was assessed by next-generation sequencing, response was assessed per IMWG criteria, and adverse events (AEs) were graded using CTCAEv5.0 (CRS and ICANS by ASTCT). Results: Initial results from this cohort were published at ASCO 2021. Here we report data as of the April 15, 2021, data cutoff (median follow-up 9.7 mo: range 3.3-13.4). 20 pts (65% male;median age 60 years [range 38-75]) received cilta-cel;1 pt was treated in an outpatient setting. Pts received a median of 2 prior LOT (range 1-3);60% received 1 or 2 prior LOT and 40% received 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. In all, 95% of pts were refractory to the last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) of pts had ≥CR, and 95% (95% CI 75.1-99.9) had ≥VGPR (Figure). Median time to first response was 1.0 mo (range 0.7-3.3);median time to best response was 3.3 mo (range 0.9-7.9);median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;6-mo PFS rate was 90% (95% CI 65.6-97.4). Of MRD-evaluable pts (n=13), 92.3% (95% CI 64.0-99.8) were MRD-negative at 10 -5. Hematologic AEs in ≥20% of pts were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). CRS occurred in 95% of pts (gr 3/4: 10%). Median time to CRS onset was 7 d (range 5-9), with a median duration of 4 d (range 2-11). CRS resolved within 7 d in 90% of pts. CAR T-cell neurotoxicity occurred in 4 pts (20%;all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had other neurotoxicities (gr 2 facial paralysis);time to onset was 29 d with a duration of 51 d. No movement and neurocognitive TEAEs were observed. One death occurred due to COVID-19 (assessed as treatment-related by the investigator). Safety profile was manageable in the pt treated in an outpatient setting. Conclusions: At a longer median follow-up of 9.7 mo, a single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. ORR in this cohort was consistent with the CARTITUDE-1 study in heavily pretreated pts;responses deepened over time, with 92% of MRD-evaluable pts achievi g MRD 10 -5 negativity. The safety profile was manageable;CRS was mostly gr 1/2, and no movement and neurocognitive TEAEs occurred, suggesting the efficacy of monitoring and pt management strategies that were implemented across phase 2/3 studies in the CARTITUDE program. Follow-up is ongoing, including additional enrollment in this cohort;this pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827). [Formula presented] Disclosures: Cohen: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Karyopharm: Research Funding;neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cohen: Janssen: Consultancy;Takeda: Consultancy;AstraZeneca: Consultancy;GlaxoSmithKline: Consultancy, Research Funding;BMS/Celgene: Consultancy;Novartis: Research Funding;Oncopeptides: Consultancy;Genentech/Roche: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Hillengass: Adaptive: Membership on an entity's Board of Directors or advisory committees;Beijing Medical Award Foundation: Speakers Bureau;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Beijing Life Oasis Public Service Center: Speakers Bureau;Curio Science: Speakers Bureau;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Oncotracker: Membership on an entity's Board of Directors or advisory committees;Axxess Network: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Skyline: Membership on an entity's Board of Directors or advisory committees. Goldschmidt: GSK: Honoraria;Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Adaptive Biotechnology: Consultancy;BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Incyte: Research Funding;Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Johns Hopkins University: Other: Grant;Molecular Partners: Research Funding;MSD: Research Funding;Mundipharma: Research Funding;Novartis: Honoraria, Research Funding;Dietmar-Hopp-Foundation: Other: Grant;Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Takeda: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm: Consultancy Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Consultancy;Novartis: Honoraria;Pfizer: Honoraria. Raab: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria;Celgene: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy;Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Honoraria;Roche: Consultancy;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca: Janssen: Current Employment. Varsos: Janssen: Current Employment. Yeh: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock optionsin a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Corsale: Janssen: Current Employment. Akram: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Updated Phase 1 Results from MonumenTAL-1: First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Despite recent advances in treatment, patients with multiple myeloma (MM) continue to relapse. G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising target for immunotherapy in patients with MM due to its high expression in malignant plasma cells and limited expression in normal human tissue;unlike other antigens targeted by MM therapies, there is no indication that GPRC5D sheds into the periphery. Talquetamab (JNJ-64407564) is a first-in-class bispecific IgG4 antibody that redirects T cells to kill MM cells by binding to both GPRC5D and CD3 receptors. Here we report updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) from a phase 1 trial in relapsed/refractory MM (RRMM;NCT03399799). Methods: Eligible patients with MM had relapsed or refractory disease or were intolerant to standard therapies;patients previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range 5.0-800 µg/kg) weekly or biweekly. Step-up dosing was used as a patient management strategy to minimize the severity of cytokine release syndrome (CRS). The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Responses were investigator-assessed per International Myeloma Working Group criteria. Results: As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses. 30 patients received the 405 µg/kg weekly dosing schedule (median age: 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up: 7.5 mo [range 0.9-15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age: 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;median follow-up 3.7 mo [range 0.0-12.0]). There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%;1 patient had grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%);skin-related AEs occurred in 77% (all grade 1/2;nail disorders: 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%);skin-related AEs occurred in 65% of patients (grade 3: 13%;nail disorders: 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate: 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate: 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D;the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI: 41-84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines. Conclusions: These findings indicate that SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data from the 800 µg/kg biweekly cohorts indicate that less frequent, higher doses of SC talquetamab do not have a negative impact on the previously described safety profile. Further investigation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. [Formula presented] Disclosures: Krishnan: MAGENTA: Consultancy;BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau;JANSSEN: Consultancy, Research Funding;City of Hope Cancer Center: Current Employment;REGENERON: Consultancy;SANOFI: Consultancy;GSK: Consultancy;Amgen: Speakers Bureau. Minnema: Celgene: Other: Travel expenses;Alnylam: Consultancy;Cilag: Consultancy;BMS: Consultancy;Janssen: Consultancy;Kite/Gilead: Consultancy. Berdeja: Lilly, Novartis: Research Funding;Abbvie, Acetylon, Amgen: Research Funding;Celularity, CRISPR Therapeutics: Research Funding;EMD Sorono, Genentech: Research Funding;Poseida, Sanofi, Teva: Research Funding;Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy;GSK, Ichnos Sciences, Incyte: Research Funding. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk: Roche: Consultancy;Takeda: Consultancy;Cellectis: Research Funding;Amgen: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;BMS/Celgene: Consultancy, Honoraria;Novartis /bayer/servier: Consultancy. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Consultancy;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria;Regeneron: Honoraria. Askari: Janssen: Research Funding. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Honoraria;Bluebird bio: Honoraria;AbbVie: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa: BMS: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Speakers Burea . Verona: Janssen: Current Employment. Ma: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Yang: Janssen: Current Employment. Hilder: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Russell: Janssen: Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Chari: Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees;Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Research Funding;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Research Funding;Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.