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Background: Relapsed/refractory (R/R) Classic Hodgkin lymphoma (cHL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is an intergroup Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (N), and ipilimumab (I) in patients with R/R cHL. Here we present the efficacy and safety data on the full adult cohort of patients treated in Phase 2 randomized between BV/N and BV/N/I. Methods: Patients with confirmed R/R cHL were randomized between the doublet of BV/N with BV 1.8mg/kg and N 3mg/kg and BV/N/I with I 1mg/kg. BV and N were administered every 3 weeks, and I every 12 weeks for up to 1 year for BV and up to 2 years for N and I. Results: One hundred twenty-six patients were enrolled and treated; 8 patients (4 from each arm) were excluded from efficacy analysis based on ineligibility. Patients were not heavily pretreated, 65% had one prior line of therapy and an additional 27% had two prior lines, and 8% had more than 2 prior lines. The median age was 34; 51% of patients were male. Sixteen patients had prior BV: 10 (BV/N arm) and 6 (BV/N/I). Response: One hundred eighteen patients are evaluable for response: 61 treated with BV/N and 57 with BV/N/I. With BV/N 37 of 61 (60.7%) of patients had a complete response (CR) compared to 38 of 57 (66.7%) with BV/N/I for a difference of 6.7% (p-value 0.31). Additionally, 17 (28%) with BV/N and 12 (21%) of patients treated with BN/N/I had a partial response (PR) for an overall response rate (ORR) of 88% in both arms. In a planned analysis of patients with prior treatment with BV the CR rate was 25% in BV/N arm (2 of 8) and 60% in BV/N/I arm (3 of 5). The median follow-up for progression free survival (PFS), duration of response (DOR), and overall survival (OS) is 24.8 months and 33.7 months. The median PFS, duration of response and OS have not been reached for either arm with 24 months of follow-up ( Figure 1). In B/N 30 of 61 patients came off study to receive alternative treatments (primarily autologous stem cell transplant (SCT)) and in BV/N/I 23 of 57 patients did. Safety: Table 1 shows treatment-related Grade 3+ toxicity occurring in > 1 patient and adverse events (AE) of special interest. All 126 patients (118 eligible and 8 ineligible) are evaluable for safety. The rate of Grade 3+ treatment related toxicity is 43% (28/65) and 52% (32/61) for BV/N and BV/N/I, respectively. However, when rash is excluded the rate of treatment related toxicities is similar between the two arms 38.5% vs 39.3%. There was no grade 4 rash, and the rash was treatable in all cases with topical or oral steroids. There were no Grade 5 toxicities in either arm. Conclusion: In this randomized Phase 2 study comparing BV/N vs. BV/ N/I the difference in CR rate of 6.7% between the doublet and the triplet was not statistically significant. Additionally, the triplet had more grade 3 rash than the doublet, there was otherwise no significant difference in grade 3 or greater toxicity between the two arms. With a median follow-up of 24 months the PFS and DOR have not been reached for either arm, suggesting excellent disease control from both regimens. Differences in response for BV pre-treated patients between the two arms is intriguing especially as more patients are treated with BV in the frontline, but the sample size is too small to draw firm conclusions. Correlative studies are underway to elucidate a response vs. resistance signature, and biological understanding of differential benefit.

DISCUSSION AND CONCLUSION Chimeric antigen receptor (CAR)-T cells directed against B-cell maturation antigen (BCMA), have yielded impressive results in clinical trials for multiply relapsed/refractory multiple myeloma (MM). However, progression-free survival is short, demonstrating a need for improvements. While numerous advances have been made to improve this treatment modality, these have not always translated to superior clinical outcomes. A major limitation is that novel therapeutics are often not tested in a relevant in vivo model. These novel strategies have been largely tested only in immunodeficient models of MM. To better recapitulate the host-tumour-effector cell interactions, particularly in the TME, we sought to develop a system to study CAR-T cell activity in the Vk*MYC model of MM. Here, we report on the first known successful model of CAR-T cell activity in an immunocompetent model of MM. We sought to identify a BCMA CAR construct that is capable of binding to both human and mouse BCMA. A novel nanobody recognizing BCMA was developed by immunizing llamas with human BCMA and the resulting single-domain antibodies (sdAbs) were subsequently isolated and cloned. These sdAbs were then screened for binding to mouse BCMA. A binder capable of recognizing both human and mouse BCMA was identified and cloned into our murine CAR construct, with CD28 and CD3z signaling domains, herein referred to as sdBCMA2.CD28.CD3z. Murine CAR-T cells were then generated by transducing activated healthy murine splenocytes with a retroviral vector carrying the sdBCMA2.CD28.CD3z construct. These CAR-T cells were then characterized in vitro using standard cytotoxicity, proliferation, and cytokine release assays. To assess activity in an immunocompetent model, female C57BL/6J mice were injected intravenously with Vk12598 Vk*MYC cells. CAR-T cells were later administered intravenously. Mice were bled weekly to quantify M-protein disease burden by serum protein electrophoresis and for phenotypic characterization of circulating cells. When co-cultured with BCMA+ human MM cell lines and with Vk*MYC cell lines, murine sdBCMA2.CD28.CD3z CAR-T cells effectively lysed target cells, proliferated, and released inflammatory cytokines. To assess the in vivo activity of these CAR-T cells, we injected intravenously female C57BL/6J mice with Vk12598 cells, and then administered sdBCMA2.CD28.CD3z CAR-T cells intravenously. While there was some evidence of survival improvement, the median overall survival (mOS) of 35 days compared to 28 days, for CAR-T vs. Mock T-cells, respectively, the difference was non-significant, and the survival benefit was not durable. To address this, we incorporated lymphodepletion by total body irradiation (TBI) followed by CAR-T cell administration the next day. By incorporating lymphodepletion prior to CAR-T cell administration we were able to significantly reduce M-protein surrogates of disease burden, as well as achieve durable remissions in the TBI + CAR-T arm with an mOS not yet reached after experimental day 91, compared to an mOS of 42 days in the TBI + Mock T-cell arm. The addition of TBI also significantly improved the engraftment of CAR-T cells, as assessed by flow cytometry. The TBI + CAR-T arm also had significantly increased IL-6, IL-1b, IL-2, and TNF-a in the serum, compared to the TBI + Mock arm, at 7 days post administration of CAR-T cells. The durable remission achieved using the combination of our novel sdBCMA2.CD28.CD3z CAR-T cells with lymphodepletion is a pivotal advancement in modelling MM CAR-T cell activity in this clinically relevant model system. Our approach represents the first time that CAR-T cells were successfully used to treat the Vk12598 model of MM that faithfully recapitulates relapsed MM. The incorporation of lymphodepletion significantly improves CAR-T cell engraftment, in line with clinical CAR-T cell therapy paradigms. The cytokine profile observed is consistent with the cytokine elevations typically observed after CAR-T cell administration in patients. As our construct is capable of binding to both human and mouse BCMA, we are therefore able to fully characterize our lead assets in a relevant model system. Our strategy will enable further research to dissect host-tumour-effector cell interactions, to better inform the design and characterization of novel CAR-T cell therapies in MM.

Aims Both anatomical and reverse total shoulder arthroplasty (aTSA and rTSA) provide functional improvements. A reported benefit of aTSA is better range of motion (ROM). However, it is not clear which procedure provides better outcomes in patients with limited foward elevation (FE). The aim of this study was to compare the outcome of aTSA and rTSA in patients with glenohumeral osteoarthritis (OA), an intact rotator cuff, and limited FE. Methods This was a retrospective review of a single institution’s prospectively collected shoulder arthroplasty database for TSAs undertaken between 2007 and 2020. A total of 344 aTSAs and 163 rTSAs, which were performed in patients with OA and an intact rotator cuff with a minimum follow-up of two years, were included. Using the definition of preoperative stiffness as passive FE ≤ 105°, three cohorts were matched 1:1 by age, sex, and follow-up: stiff aTSAs (85) to non-stiff aTSAs (85); stiff rTSAs (74) to non-stiff rTSAs (74); and stiff rTSAs (64) to stiff aTSAs (64). We the compared ROMs, outcome scores, and complication and revision rates. Results Compared with non-stiff aTSAs, stiff aTSAs had poorer passive FE and active external rotation (ER), whereas there were no significant postoperative differences between stiff rTSAs and non-stiff rTSAs. There were no significant differences in preoperative function when comparing stiff aTSAs with stiff rTSAs. However, stiff rTSAs had significantly greater postoperative active and passive FE (p = 0.001 and 0.004, respectively), and active abduction (p = 0.001) compared with stiff aTSAs. The outcome scores were significantly more favourable in stiff rTSAs for the Shoulder Pain and Disability Index, Simple Shoulder Test, American Shoulder and Elbow Surgeons score, University of California, Los Angeles score, and the Constant score, compared with stiff aTSAs. When comparing the proportion of stiff aTSAs versus stiff rTSAs that exceeded the minimal clinically important difference and substantial clinical benefit, stiff rTSAs achieved both at greater rates for all measurements except active ER. The complication rate did not significantly differ between stiff aTSAs and stiff rTSAs, but there was a significantly higher rate of revision surgery in stiff aTSAs (p = 0.007). Conclusion Postoperative overhead ROM, outcome scores, and rates of revision surgery favour the use of a rTSA rather than aTSA in patients with glenohumeral OA, an intact rotator cuff and limited FE, with similar rotational ROM in these two groups. Cite this article: Bone Joint J 2023;105-B(12):1303–1313.

AbstractIn addition to the primary aim of seizure freedom, a key secondary aim of pediatric epilepsy surgery is to stabilize and, potentially, optimize cognitive development. Although the efficacy of surgical treatment for seizure control has been established, the long‐term intellectual and developmental trajectories are yet to be delineated. We conducted a systematic review and meta‐analysis of studies reporting pre‐ and postsurgical intelligence or developmental quotients (IQ/DQ) of children with focal lesional epilepsy aged ≤18 years at epilepsy surgery and assessed at >2 years after surgery. We determined the IQ/DQ change and conducted a random‐effects meta‐analysis and meta‐regression to assess its determinants. We included 15 studies reporting on 341 patients. The weighted mean age at surgery was 7.1 years (range = .3–13.8). The weighted mean postsurgical follow‐up duration was 5.6 years (range = 2.7–12.8). The overall estimate of the mean presurgical IQ/DQ was 60 (95% confidence interval [CI] = 47–73), the postsurgical IQ/DQ was 61 (95% CI = 48–73), and the change was +.94 IQ/DQ (95% CI = −1.70 to 3.58, p = .486). Children with presurgical IQ/DQ ≥ 70 showed a tendency for higher gains than those with presurgical IQ/DQ < 70 (p = .059). Higher gains were determined by cessation of antiseizure medication (ASM; p = .041), not just seizure freedom. Our findings indicate, on average, stabilization of intellectual and developmental functioning at long‐term follow‐up after epilepsy surgery. Once seizure freedom has been achieved, ASM cessation enables the optimization of intellectual and developmental trajectories in affected children.

Background: High-quality lateral radiographs with the wrist in neutral (0°) or near neutral (less than 15° flexion or extension) are felt to be important for diagnosing carpal instability using intracarpal angular measurements, but may be unavailable. In addition, radiolunate (RLA) and capitolunate (CLA) measurement angles for defining carpal instability have poor validation. We sought to establish 95% confidence intervals (CIs) for predicted RLA and CLA throughout the arc of wrist motion in normal cadaveric wrists. Methods: Fresh frozen cadaveric upper extremities were secured in a limb positioner. Scaphopisocapitate lateral radiographs were obtained throughout the arc of motion and RLA and CLA, and wrist flexion or extension angles (WA) were measured by a board-certified hand surgeon. Scatter plots of variables were constructed, and correlation coefficients calculated for areas under the curves. Regression equations for predicted RLA and CLA based on WA were developed. Results: Both RLA and CLA correlated strongly with WA for each measurement in both flexion and extension ( r = 0.7-0.8). Linear regression modeling demonstrated a good relationship between RLA ( R 2 = 84%) and CLA ( R 2 = 80%) with WA. Regression equations were constructed to give predicted values for RLA and CLA based on WA and 95% prediction CI. Conclusions: If RLA and CLA exceed 20° with neutral (0°) wrist alignment, it likely represents pathologic carpal alignment. Presented tables demonstrate 95% CI of RLA and CLA throughout the arc of wrist flexion/extension. Values outside of the 95% CI are also likely to indicate pathologic carpal alignment.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 ( P = 0.014) and IL-16 ( P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group ( P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Abstract Background Treatment for first recurrent Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk (FMS; formerly SER-109), an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores. Methods Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models. Results At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (P&gt;0.05). At Week 1, Shannon diversity (Fig 1) was greater vs baseline (P&lt; 0.001); gains were not significantly different between subgroups (P&gt;0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P&lt; 0.001); similar gains were seen between subgroups (P&gt;0.05) (Fig 2). Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups (frCDI, 6.5% [5/77] vs mrCDI, 10.3% [28/271]). Conclusion After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment. Disclosures Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds