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PURPOSEThis phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).METHODSIn this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.RESULTSBetween March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.CONCLUSIONUsing a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.

This article examines how existing in a larger socio-political environment of contested national belonging shapes Muslims’ experiences in the Central African Republic (car). We draw on data gathered between 2017 and 2019 from various archival sources and in-depth interviews with Muslim religious leaders and non-Muslims in car’s capital, Bangui. We argue that through claims to autochthony a dual logic of exclusion co-occurs which shapes how Muslims experience their minority status. First, national level autochthony debates frame Muslim minority exclusion from the Central African national imagination. Second, at the Muslim intra-communal level, and particularly among religious leaders, autochthony encapsulates debates over “authentic” Muslimhood – fuelled not by contestation over Islamic practice and interpretation, but rather historical contestation based on ethnic exclusion. Specifically, we show that claims to “proper” Central African Muslimhood are premised on autochthony embedded in a dominant myth of primary settlement advanced by certain Muslim leaders.

We report what we believe is the first use of 19F NMR spectroscopy to directly measure in-vitro release (IVR) from polymeric nanoparticles (PNPs). Using 19F NMR we selectively measured IVR of AZD2811 from PNPs. Due to rapid nuclear relaxation in solid-like environments only AZD2811 in solution is detected, and physical separation from the PNPs isn't required. The NMR approach and ultra-centrifugation/UHPLC were shown to be equivalent. The selectivity of 19F NMR means it is readily applied to complex IVR media such as recombinant human serum albumin (rHSA).

Background With the recent approval of COVID‐19 vaccines, recovered COVID‐19 subjects who are vaccinated may be ideal candidates to donate COVID‐19 convalescent plasma (CCP). Case Series Eleven recovered COVID‐19 patients were screened to donate CCP. All had molecularly confirmed COVID‐19, and all but one were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11–21 days after they were vaccinated (Pfizer/Moderna). All showed dramatic increases (~50‐fold) in spike‐specific antibody levels and had at least a 20‐fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike‐specific antibody levels following vaccination were significantly higher than those seen in any non‐vaccinated COVID‐19 subjects tested to date at our facility. Conclusion Spike‐specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination after COVID‐19 infection, which significantly exceeded values seen with COVID‐19 infection alone. Recovered COVID‐19 subjects who are vaccinated may make ideal candidates for CCP donation.

We propose five research tasks targeting grammar teaching and learning, focusing on extending previous research and exploring under-studied features and contexts. The first two tasks outline replications and extensions of seminal studies on pedagogical grammar, Toth (2008) and Samuda (2001), designed to advance our understanding of the teacher role in providing rich practice opportunities. Another task examines how features of peer interaction during oral communication might encourage attention to grammar among young second language (L2) classroom learners in school-based foreign language programs, a common yet under-studied context. A fourth task investigates the unique properties of spoken grammar across languages and effective approaches for its teaching and learning, and the fifth explores the (re)design and use of corpus-based tools to enhance accessibility and learner autonomy in data-driven grammar learning. Each task is designed to be feasible across a variety of classroom contexts and target languages. We highlight concrete implications for language pedagogy and include suggestions for capturing both learning outcomes and participants’ perspectives on their learning and teaching, using a range of quantitative and qualitative methodologies. We end with some thoughts on repetitive practice for learning certain features of grammar, and recommendations for collaborative research that would encourage greater replication of future studies.

To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR).The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore.This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

BackgroundPatients presenting to the Oral and Maxillofacial Surgery (OMFS) department with odontogenic or cervico‐facial infections are at risk of sepsis. The Sepsis Six bundle significantly reduces mortality if completed within 1 h. This study describes the use of a novel pro forma for OMFS which aims to improve compliance with Sepsis Six.MethodsA pilot retrospective audit was completed to determine compliance with the Sepsis Six bundle. Data were collected from consecutive patient case notes referred to a single UK OMFS department. A custom pro forma sheet was designed. Two further audit cycles were carried out over a 4‐year period and dental core trainees focus group gave feedback on the new pro forma.ResultsA pilot retrospective audit showed no compliance with the original Sepsis Six bundle. Completion of the new pro forma for patients presenting with cervico‐facial and odontogenic infection increased to 59% in the second cycle. There was a 66% increase in the delivery of intravenous antibiotics within the first hour and lactate measurement rose to 50% by the second cycle. Importantly, initial observation of vital signs improved throughout the audit, reaching 97%. The focus group generally supported improvements in compliance, effective communication, and good record‐keeping using the pro forma.ConclusionThe introduction of a custom pro forma for OMFS appears to improve completion of the Sepsis Six bundle which could reduce morbidity and mortality. Continual team education is required, and further audit would be useful to determine if this intervention alone is the reason for increased compliance.

IntroductionSince the publication of GDC guidance, there have been small, but rising numbers of Fitness to Practise (FtP) cases made against qualified dentists, relating to the use of social media. Prior to graduation, dental students currently receive training in the appropriate use of social media, but more work is needed to determine the most effective methods do this. The aim of this study is to explore the impact of the digital professionalism awareness training provided at one UK‐based institution.Materials and MethodsIn year 2, a "brown envelope" is compiled using an online publicly available Facebook profile search for every student. All year 2 to 5 dental undergraduate students at one UK dental school who had completed the "brown envelope" were invited to participate in focus groups to examine its impact on behaviour change. A qualitative framework analysis method was applied to the transcripts.ResultsEleven dental undergraduate students participated in two focus groups. All students had experienced the "brown envelope" intervention. Four main themes emerged, including: a clear expression of dental student autonomy and rejection of regulation; that online activity in dentistry is different to medicine; that the intervention is useful and changed online behaviour; and constructive suggestions for improving training.ConclusionThe interactive "brown envelope" intervention for digital professionalism awareness training was well received and appeared to result in actionable behavioural change on student profiles (eg alterations in privacy settings or restricting access to their own "friends lists").

We assessed the long-term effects of intensive instruction on different aspects of L2 oral production. Adopting the tridimensional model of oral production (Munro & Derwing, 1995a), we compared high school learners who had received intensive ESL instruction (N = 42) with non-intensive learners (N = 39) on perceptual measures of L2 fluency, comprehensibility, and accentedness 4 years after a 5-month intensive instruction period. After controlling for academic ability and L2 proficiency, listeners’ ratings of fluency and comprehensibility were significantly higher for the IG; however, there was no specific group advantage for accentedness, suggesting both groups exhibited similar L2 accents. This study provides new empirical evidence that the oral fluency and comprehensibility benefits of an intensive experience may be long lasting, even when learners’ subsequent classroom exposure to the language is much more limited.

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

Background: Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is approved for adult HLA-A*02:01+ patients with unresectable or metastatic uveal melanoma (mUM). In the Ph2 IMCgp100-102 study of pts with previously treated mUM (NCT02570308), tebentafusp demonstrated a median OS of 16.8 months and 1-year OS of 61% after a minimum 2 yrs of follow-up, nearly double the historical observed rates.12, Here we present the final analysis of OS of the Ph2 IMCgp100-102 study. Methods: 127 HLA-A*02:01+ 2L+ pts with mUM were dosed weekly with intravenous tebentafusp following intra-patient dose escalation of 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Primary objective was overall response rate and secondary objectives included safety and OS. OS was estimated by Kaplan-Meier method. Survival for ctDNA evaluable patients was assessed. Analyses are based on a 17 Oct 2022 database lock. Results: With a median follow-up of 46 months, median OS was 16.8 (95% CI: 12.3-21.3) months, consistent with previous reports. Estimated 1-yr, 2-yr, 3-yr and 4-yr OS rates were 61%, 36%, 21% and 11%, respectively. ctDNA clearance by week 9 (n=12) was associated with 100% 1-yr, 73% 2-yr, 45% 3-yr and 23% 4-yr survival. OS for patients with poor prognostic factors compared favorably relative to historical benchmarks (Table 1). Mean and median duration of treatment was 9.9 and 5.6 months. Majority of pts who received a subsequent line of therapy received immunotherapy (48/72; 67%) followed by liver-directed therapy (14/72; 19%). No new safety signals were identified. Conclusions: This study provides the longest follow-up of OS for a soluble TCR therapeutic to date. Tebentafusp continued to show unprecedented survival benefit for 2L+ mUM pts, including the poorest prognostic groups, with estimated OS rates that remain nearly double the historical rates observed in this population at a median follow-up of ~4 years. Early ctDNA clearance was associated with indication of survival benefit. 1. Carvajal et al. Nat Med 2022 2. Sacco et al. J Immunother Canc 2021 Table 1. OS in Ph2 IMCgp100-102 versus historical benchmarks Ph2 IMCgp100-102 Historical benchmarks*,† Population 1-yr 2-yr 3-yr 1-yr 2-yr 3-yr Overall 2L+ 61% 36% 21% 37% 15% 9% Subgroups Age ≥ 65 yrs 51% 31% 25% 38% 12% 6% LDH > ULN 44% 22% 11% 23% 8% 3% Baseline largest liver lesion ≥ 3cm 52% 26% 14% 32% 11% 4% *OS benchmark for 2L+ patients calculated from Rantala et al 2019 †OS benchmarks for pt subgroups (all lines of therapy) estimated from digitized OS curves presented in Khoja et al. 2019 Citation Format: Joseph J. Sacco, Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M. Piulats, Matthew Rioth, Douglas B. Johnson, Jason J. Luke, Erique Espinosa, Serge Leyvraz, Laura Collins, Chris Holland, Michelle L. McCully, Takami Sato. Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT223.

Background: ImmTAC molecules are TCR-CD3 bispecific fusion proteins that can redirect and activate polyclonal T cells to kill tumors. Tebentafusp, which targets gp100, is the first ImmTAC to demonstrate an overall survival benefit and is approved for the treatment of HLA-A*02:01 adult patients with unresectable or metastatic uveal melanoma1. Clinical benefit was observed in patients with both high and low gp100 expression2, suggesting direct and indirect mechanisms of tumor control, which we explored using in vitro models. Method: Uveal and cutaneous melanoma cell lines were pulsed with 0-1 µM peptide concentrations or were treated with supernatants from ImmTAC-activated PBMC, with or without blocking antibodies against IFNβ, IFNγ, TNFα, and IL6. Peptide-HLA (pHLA) molecules on tumor cell surface were quantified by microscopy. ImmTAC-redirected T cell activation and killing were measured by ELISPOT, MSD, and xCelligence assays. Antigen presentation machinery (APM) gene expression was measured by qPCR. Linear regression models were used to assess the influence of variables on ImmTAC-mediated T cell activation. Results: Peptide-pulsing of tumor cells showed a dose response relationship between surface pHLA number and ImmTAC-mediated T cell killing (R2= 0.85), which was confirmed by ImmTAC redirected killing assays using tumor lines with differential endogenous expression of pHLA targets. Higher effector: target (E: T) and higher pHLA number are the key factors, by regression analyses, influencing ImmTAC mediated T cell activation. These account for 53% and 29% variability in IFNγ production (p Conclusions: In vitro, ImmTAC bispecifics kill cancer cells by both direct and indirect mechanisms. Redirection of polyclonal T cells to kill melanoma cells is greatly influenced by surface pHLA number and E:T ratio. ImmTAC-induced cytokines inhibited tumor growth, increased tumor apoptosis and resulted in higher antigen presentation demonstrating the indirect effect of ImmTAC. These observations highlight how ImmTAC-treated melanoma patients could benefit through direct and indirect mechanisms of tumor control, and in part help to explain how patients with low gp100 expression can derive benefit from tebentafusp. References: 1. Nathan, P. et al. NEJM 385, 1196-1206 (2021) 2. Leach E. et al. JITC 10.1136, 868 (2021) Citation Format: Esra Güç, Anna Broomfield, Sang S. Seo, Aleksandra Raczka, Alex Greenshields-Watson, Laura Collins, Adel Benlahrech. Melanoma patients with high and low target expression can benefit from TCR-CD3 bispecifics through direct and indirect mechanisms of tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3289.

BackgroundTebentafusp, a bispecific fusion protein consisting of affinity-enhanced T cell receptor targeting a gp100 derived peptide fused to anti-CD3 effector, has shown overall survival (OS) benefit in untreated metastatic uveal melanoma (mUM). The OS benefit derives from all RECIST response categories, even progressive disease (PD). In Ph2 trial of previously treated mUM (NCT02570308), one-third (35%) of 48 evaluable patients with best response of PD had ctDNA reduction (³0.5 log reduction) and longer OS (median 16.9 months) compared to the group without ctDNA reduction (median OS 8.5 months).Methods34 of 127 mUM patients from Ph2 trial1 were selected based on best response of PD and no ctDNA reduction (Group A, n=17) or 0.5 log ctDNA reduction (Group B, n=17). One patient per group were excluded due to poor image quality or limited CT/MRI sequences. Tumor lesions were manually segmented on CT and MRI. Radiomics features were extracted at baseline and Week-8 (first assessment). The objective was to use unsupervised machine-learning to develop two signatures using 16 features to classify the two groups. The per-patient analysis signature (n=32) combined 8 volumetric features on CT-scan at baseline and change by Week-8. The per-lesion analysis signature (n=148) combined 4 features (volume and 3 radiomics features previously associated with outcome to checkpoint immunotherapy in cutaneous melanoma) at two timepoints using CT and MRI. Performance was evaluated using area under the receiver operating characteristic curve (AUC).ResultsThe median OS for Groups A and B were 8.5 and 16.9 months, respectively. In the per-patient analysis, a volumetric signature classified patients into the groups with AUC 0.71 (95%CI: 0.53–0.90) with 63% specificity and 81% sensitivity at the optimal threshold (0.57). In the per-lesion analysis, a radiomic signature reached an AUC of 0.70 (95%CI: 0.58–0.81) with 66% specificity and 74% sensitivity at the optimal threshold (0.53). Group B had lower baseline tumor lesion volume (AUC=0.65), distinct baseline tumor heterogeneity (AUC=0.66), and distinct change in tumor heterogeneity by week 8 (AUC = 0.66/0.69 on CT/MRIConclusionsA radiomic analyses of a subset of PD patients was able to predict Group B, patients with ctDNA reduction and longer OS, at a patient and lesion level. The strongest radiomic predictor by CT/MRI was decrease on treatment in tumor heterogeneity. Confirmation in a larger dataset of these signatures is needed to identify which patients may be benefiting from tebentafusp despite radiographic progression.Trial RegistrationNCT02570308Reference1. Sacco JJ, Carvajal R, Butler MO, et al. A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). Ann Oncol 2020;31:S1442–S1143.Abstract 819 Figure 1Percent change in tumor measurement from baseline at week 8 per independent review committee by Group A and BAbstract 819 Figure 2Kaplan-Meier plot comparing overall survival rates in group A and group B patientsAbstract 819 Figure 3Blue color represents a high probability of the patient being in Group A while red color indicates high probability of being in Group B

Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention, post-exposure prophylaxis, or therapy. However, the titer of neutralizing antibodies required for protection against SARS-CoV-2 infection remains poorly characterized. We previously described two potently neutralizing mAbs COV2-2130 and COV2-2381 targeting non-overlapping epitopes on the receptor-binding domain of SARS-CoV-2 spike protein. Here, we engineered the Fc-region of these mAbs with mutations to extend their persistence in humans and reduce interactions with Fc gamma receptors. Passive transfer of individual or combinations of the two antibodies (designated ADM03820) given prophylactically by intravenous or intramuscular route conferred virological protection in a non-human primate (NHP) model of SARS-CoV-2 infection, and ADM03820 potently neutralized SARS-CoV-2 variants of concernin vitro. We defined 6,000 as a protective serum neutralizing antibody titer in NHPs against infection for passively transferred human mAbs that acted by direct viral neutralization, which corresponded to a concentration of 20 μg/mL of circulating mAb.

Scholars advocate for more classroom attention to be paid to spoken grammar which deviates from commonly taught rules of writing. However, these recommendations have not considered potential barriers that learners may encounter when using spoken grammar with L1 speakers. We investigate one such challenge: the effect of learners’ accents and degree of accentedness on how their use of these forms is subjectively perceived by L1 speakers. Ten non-expert raters rated the grammatical acceptability of four frequent spoken grammar forms, read out by 15 speakers (10 L1 Tagalog, 5 L1 English) rated as having heavy, moderate, or no accents. A one-way ANOVA revealed a significant effect of accent on grammaticality scores. Post-hoc tests showed a strong correlation between accent and perceived grammaticality, with more accented speakers scoring significantly lower on grammaticality. The discussion considers implications for spoken grammar teaching, and future research on the relationship between accent and perceived grammaticality.

Background Central venous catheters (CVCs) for apheresis procedures require regular locking/flushes to maintain adequate flow rates. Literature comparing locking solutions for apheresis, where the time interval between procedures can be longer than for hemodialysis (many days to weeks), is lacking. In this study, catheter malfunction rates using recombinant tissue plasminogen activator (rt-PA) vs heparin for locking CVC between apheresis procedures were compared. Study design and methods A retrospective review of 93 extracorporeal photopheresis procedures in 10 patients was performed at our institution. About 1000 U/mL heparin or 2 mg rt-PA was used as the locking solution. Heparin locks were changed at least once per week and rt-PA locks could be left in place for up to 4 weeks. Following these locks, inadequate blood flow noted on accessing CVC and/or during the procedure was scored on as: no issues, some issues, or significant issues. Binary logistic regression was used to evaluate for potential statistical difference in outcomes. Cost analysis was also performed. Results No statistically significant difference was noted in outcomes between heparin and rt-PA lock (P value = 0.15). Total cost of heparin lock administration ($91-$362.50) was found to be more than rt-PA lock ($76) when more than one flush was needed between procedures. Conclusions For apheresis use, rt-PA and heparin CVC locks seem to have similar outcomes in preventing CVC malfunction. The convenience of not needing any flushes between procedures and overall cost of administering fewer locks favors rt-PA use when the interval between procedures is >7 days.

We report what we believe is the first use of

Introduction: Tebentafusp, an investigational TCR bispecific (gp100xCD3) fusion protein (ImmTAC) that targets gp100 and activates T cells, had superior overall survival (OS) versus investigator’s choice (HR 0.51) in a randomized Phase 3 trial in previously untreated metastatic uveal melanoma [1]. We previously reported that CD163+ M2 macrophages can inhibit ImmTAC-mediated T cell killing of tumor cells in vitro and demonstrated that a low CD163:CD3 ratio in tumor biopsies was associated with better OS in a Phase 2 trial of tebentafusp in previously treated metastatic uveal melanoma (NCT02570308) [2]. Here we sought to confirm this finding using biopsies collected from the randomized Phase 3 trial (NCT03070392). Methods: Previously untreated HLA-A*02:01+ mUM patients were randomly assigned 2:1 to either the tebentafusp or investigator’s choice arm. Tumor samples were obtained prior to dosing from both primary (eye) and metastatic (predominantly liver) tumors. Expression of CD3, CD8 and CD163 was determined by immunohistochemistry (IHC), and digital image analysis enumerated immune cells per mm2 (up to N=178 in the tebentafusp arm, N=81 in the control arm). A low quartile cut-off (low) vs ≥ lower quartile (higher) was used for biomarker correlations with OS. Results: Individually, the numbers of tumor infiltrating CD3+ or CD8+ T cells and CD163+ macrophages at baseline were not associated with better OS in either the tebentafusp or investigator’s choice arm. Consistent with data reported from the previously treated tebentafusp trial, patients randomized to tebentafusp with low baseline CD163:CD3 ratio had improved OS compared to patients with higher ratio (HR=0.6, p=0.03; 1-year OS low=80% vs higher=65%). This association with OS was not as strong in the investigator’s choice arm (HR=0.7, p=0.3; 1-year OS low=52% vs higher=48%) in which the majority of patients were treated with pembrolizumab. Furthermore, tebentafusp showed superior OS compared to investigator’s choice in patients with low (HR=0.4, p=0.01) or higher (HR=0.5, p=0.001) CD163:CD3 ratio at baseline. Discussion: In patients with previously untreated metastatic uveal melanoma, tebentafusp was superior to investigator’s choice regardless of the macrophage to T cell ratio in tumor biopsies. Low baseline macrophage to T cell ratio was more strongly associated with OS on the tebentafusp arm than investigator’s choice arm. These results demonstrate the importance of the tumor micro-environment in the anti-tumor response on tebentafusp in metastatic uveal melanoma. Reference: 1.Nathan P., et al. NEJM 2021; 2.Hassel J., et al. AACR #1673 2021 Citation Format: Sophie Piperno-Neumann, Sarah Stanhope, Camille Britton-Rivet, Simone Bischetti, Shaad Abdullah, Laura Collins, Koustubh Ranade, Emma Leach, Piotr Rutkowski. Low baseline macrophage to T cell ratio is predictive of overall survival with tebentafusp in a phase 3 trial in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB510.

BackgroundWith the recent approval of COVID-19 vaccines, recovered COVID-19 subjects who are vaccinated may be ideal candidates to donate COVID-19 convalescent plasma (CCP).Case SeriesThree recovered COVID-19 patients were screened to donate CCP. All had molecularly confirmed COVID-19, and all were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11 to 21 days after they received the first dose of the vaccine (Pfizer). All showed dramatic increases (∼50 fold) in spike-specific antibody levels and had at least a 20-fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike-specific antibody levels following vaccination were significantly higher than those seen in any non-vaccinated COVID-19 subjects tested to date at our facility.ConclusionSpike-specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination post COVID-19 infection which significantly exceeded values seen with COVID-19 infection alone. Recovered COVID-19 subjects who are vaccinated may make ideal candidates for CCP donation.

Context Undergraduate student interest in becoming a physician continues to rise, but so too does the difficulty of earning acceptance to medical school. In this competitive environment, little is known about premedical students’ knowledge of their medical school options. Moreover, as undergraduate students’ emotional health continues to decline, little is known about whether premedical students experience or are at increased risk for the burnout symptoms reported by medical students and other physicians in training. Objective To examine premedical undergraduate students’ knowledge of osteopathic medicine, assess how they learned of osteopathic medicine, and collect information about any reported feelings of burnout. Methods In this institutional review board-approved study, we electronically distributed an anonymous survey to 342 premedical undergraduate students at a midsize, public research undergraduate institution. The survey included 56 questions. Students were surveyed on their preference of medical schools, knowledge of osteopathic medicine, and experience with burnout via the Maslach Burnout Inventory which measures exhaustion, cynicism, and professional efficacy. Of those who completed the survey, only those who confirmed that they currently considered themselves to be premedical students were included in our analysis. A 2×2 factorial analysis of variance (ANOVA) test was applied to assess main and interaction effects amongst respondents who preferred osteopathic or allopathic programs, whether they learned of osteopathic medicine programs by their own research, and their scores on the 3 measures of the Maslach Burnout Inventory: exhaustion, cynicism, and professional efficacy. Bivariate and factorial analyses were completed using SPSS v26 software (IBM). All tests were 2-tailed and used a .05 standard P value. Results Of 342 students to whom the survey was sent, 160 (46.8%) responded, and only 92 (26.9%) considered themselves premedical students. Of the 160 students analyzed in our study, 80 (50%) reported first learning of osteopathic medicine through their own research. A 2×2 factorial ANOVA revealed a significant interaction effect for cynicism in respondents who reported learning of osteopathic medicine programs on their own. Conversely, when respondents reported learning of osteopathic medicine programs from another source, they also reported significantly lower cynicism (F[1,1]5.23, P=.03) and exhaustion (F[1,13] 5.79, P=.02) scores. Of the 92 respondents, only 2 students (2.2%) answered all questions regarding general osteopathic medical knowledge correctly. Conclusion The results of this study suggest that among premedical students, knowledge of osteopathic medicine may be incomplete and may be impeding medical school applications. Furthermore, respondents who reported interest in osteopathic medical schools and learned of this option through their own research seemed to experience greater burnout. Based on these findings, increased outreach and education have the potential to not only better inform students of the osteopathic profession, but also to reduce burnout.

Background Tebentafusp (IMCgp100) is a bispecific T cell redirector comprised of an affinity-enhanced TCR recognising melanocyte lineage antigen gp100 and a T cell engaging anti-CD3 scFv domain. Tebentafusp has shown activity as monotherapy in advanced cutaneous and uveal melanoma (Middleton et al., ASCO 2019), and we have previously reported that over half of uveal melanoma patients treated with tebentafusp display melanocyte-related adverse events (MRAE). These include vitiligo/skin hypopigmentation, leukotrichia, and hyperpigmentation and, collectively, are associated with better overall survival in uveal patients receiving tebentafusp (Orloff et al, AACR 2020). In this study, we dissected the mechanisms by which tebentafusp may induce MRAE and highlight the potential clinical significance. Methods In vitro studies were conducted to assess the direct and indirect effects of tebentafusp on epidermal melanocytes from healthy donors. Expression of gp100 and the gp100:HLA*02:01 target complex by melanocytes were quantified at the mRNA level and on the cell surface by confocal microscopy, respectively. Melanocytes co-cultured with PBMC and increasing concentrations of tebentafusp were assessed for their susceptibility to lysis and/or ability to stimulate cytokine production. These readouts were compared to gp100-positive and negative melanoma cancer cell lines. Melanin production by melanocytes was quantified and the melanin synthesis pathway interrogated at the mRNA and protein level following exposure to secretomes from tebentafusp-redirected PBMC against melanoma cancer cells. Results Healthy melanocytes expressed 2 to 3-fold lower levels of gp100 peptide-HLA complexes on their surface compared to gp100-positive melanoma cell lines. In the presence of tebentafusp, this lower target expression translated into 3–6 fold lower levels of IFNγ and more than 100 fold lower granzyme B production by redirected T cells and these melanocytes were resistant to direct tebentafusp-induced killing (EC50 for melanocytes greater than 1nM vs EC50 melanoma cell lines of 23–50 pM). Supernatants from T cells activated in response to melanoma cancer cells by tebentafusp downregulated the melanin content of healthy melanocytes (20–30% reduction). Western blotting revealed 30–40% inhibition of two key components of the melanin synthesis pathway; the tyrosinase-related protein (TRP)-1 and TRP-2. This inhibition was reversed by blocking IFNγ in supernatants from activated T cells. Conclusions MRAEs, especially vitiligo, associated with response to tebentafusp, may be explained, at least in part, by the downregulation of melanin biosynthesis pathway genes by IFNγ secreted by tebentafusp-activated T cells. Ethics Approval The study was approved by the South Central - Oxford A Research Ethics Committee (UK), REC reference 13/SC/0226 References Middleton, et al., Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma. Journal of Clinical Oncology. 2019. Orloff, et al., Vitiligo and other clinical melanocyte-related adverse events following tebentafusp (IMCgp100) exposure in patients with uveal melanoma. AACR (American Association for Cancer Research), 2020.

The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT).We identified patients with stage I-III ER+/HER2- BC treated with NCT from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling.76 women received NCT for ER+/HER2- BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24-40). Scores ranged between 5 and 77 with 50%25 and 5%11. Median Recurrence Score result was significantly higher among tumors achieving pCR vs. non-pCR response (61.5 vs. 23, pIn young women with ER+/HER2- BC who received NCT, higher pretreatment Recurrence Score result was associated with an increased likelihood of pCR. Gene expression profile assays may have a role in decision making in young women in need of neoadjuvant therapy.