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Introduction: Epcoritamab (Epcor) is a novel subcutaneous CD3xCD20 bispecific antibody (bsAb) that is currently approved as monotherapy for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 systemic therapies. The combination of Epcor with standard treatment regimens has been shown to be safe and efficacious; Epcor in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival outcomes in a transplant-ineligible R/R diffuse large B-cell lymphoma (DLBCL) patient (pt) population, of which 99% were from the US and Europe (EPCORE NHL-2; NCT04663347). Another CD3xCD20 bsAb, intravenous glofitamab, has been studied in combination with gemcitabine and oxaliplatin (Glofi+GemOx) in the randomized STARGLO trial (NCT04408638) and demonstrated benefit over rituximab plus GemOx (R-GemOx), despite not demonstrating superiority over R-GemOx in patients from the US and Europe. In the absence of head-to-head data, this study used matching-adjusted indirect comparisons (MAICs) to assess the comparative efficacy of Epcor+GemOx vs R-GemOx and vs Glofi+GemOx. Methods: Individual pt-level data from EPCORE NHL-2 arm 5 and aggregated data from pts in each of the STARGLO arms were used to conduct an MAIC. Logistic propensity score models were used to weight Epcor+GemOx-treated pts to create matched cohorts with the R-GemOx and Glofi+GemOx arms separately. Weighting was conducted based on the distribution of baseline characteristics and prognostic factors such as age, sex, Eastern Cooperative Oncology Group performance status, previous therapies, and primary refractory status. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx, and vs Glofi+GemOx. Results: A total of 103 pts treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 91 pts treated with R-GemOx and 183 pts treated with Glofi+GemOx (median follow-up: 20.7 months), although differences in median follow-up time limited comparisons of longer-term survival outcomes. Match-adjustment mitigated differences in baseline characteristics across the 3 cohorts. After adjustment, Epcor+GemOx demonstrated a significant 44.8% advantage in ORR over R-GemOx (85.4% vs 40.7%), with a 110% increase in the likelihood of achieving a response (odds ratio [OR] 2.1; 95% CI 1.6-2.8; P<0.0001). Epcor+GemOx also demonstrated a significant 43.2% advantage in CR rate over R-GemOx (68.5% vs 25.3%), with a 170% increase in the likelihood of achieving a CR (OR 2.7; 95% CI 1.8-4.1; P<0.0001). With the current follow-up, Epcor+GemOx demonstrated superior PFS vs R-GemOx (hazard ratio [HR] 0.37; 95% CI 0.22-0.63; P<0.001), corresponding to a 63% reduction in the risk of progression. Median OS was not reached [NR] for Epcor+GemOx vs 13.9 months for R-GemOx, corresponding to a 43% reduction in the risk of mortality (HR 0.57 [95% CI 0.33-0.98]; P=0.04). After adjustment, Epcor+GemOx demonstrated a significant 15% advantage in ORR over Glofi+GemOx (83.3% vs 68.3%), with a 20% increase in the likelihood of achieving a response (OR 1.2; 95% CI 1.0-1.4; P=0.021). Epcor+GemOx demonstrated a trend toward higher CR rate than Glofi+GemOx (66.8% vs 58.5%; OR 1.1; 95% CI 0.90-1.5; P=0.277). Adjusted median PFS and OS for Epcor+GemOx, with limited follow-up and substantial censoring, was 12.9 months and NR, respectively. For Glofi+GemOx with longer follow-up, PFS and OS were 13.8 months and 25.6 months, respectively. Conclusions: Results show significantly superior efficacy for all outcomes with Epcor+GemOx vs R-GemOx from STARGLO. Epcor+GemOx also provided superior ORR and a trend toward higher CR rates vs Glofi+GemOx, indicating potential for better long-term efficacy outcomes. The Epcor+GemOx survival data are still maturing given shorter follow-up time, preventing a robust comparison of survival vs Glofi+GemOx. Findings support the efficacy of Epcor+GemOx as an alternative therapeutic regimen in transplant-ineligible patients with R/R DLBCL.

Introduction: Epcoritamab, a novel subcutaneously administered CD3xCD20 bispecific antibody (bsAb) being developed as a core therapy across several lymphoma subtypes, is currently approved for the treatment of adults with different types of R/R LBCL after ≥2 systemic therapies. The combination of epcoritamab with standard treatments has been shown to be safe and efficacious; epcoritamab in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival benefits in a transplant-ineligible R/R DLBCL study population, of which 99% was from the United States and Europe (EPCORE NHL-2; NCT04663347). The rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen has been a widely used treatment for patients with R/R DLBCL ineligible for transplant, albeit with suboptimal efficacy outcomes. In the absence of direct comparisons of these regimens, this study assessed the comparative efficacy of Epcor+GemOx vs R-GemOx in patients with R/R DLBCL ineligible for transplant. Methods: Individual patient-level data (IPD) from EPCORE NHL-2 arm 5 were compared to 2 sources of clinical practice data for patients with R/R DLBCL treated with R-GemOx: published data from Cazalles et al (2021) and IPD from the US-based COTA electronic health record database. The Cazalles study reports the results of a large retrospective analysis of patients with R/R DLBCL treated in 2 academic centers in France. The COTA database includes de-identified IPD with demographic and clinical information from numerous academic and community clinical sites in the US. For the comparison to Cazalles, logistic propensity score models were used to weight the Epcor+GemOx cohort to create match-adjusted distributions of baseline characteristics with the R-GemOx cohort in Cazalles. For the comparison to COTA, inverse probability of treatment weighting was employed to balance covariates between the Epcor+GemOx and R-GemOx cohorts. Analyses were restricted to chimeric antigen receptor T-cell therapy (CAR T)-naive patients from EPCORE NHL-2, as the comparator cohorts did not include patients treated with CAR T. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx. Results: A total of 74 patients treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 196 R-GemOx-treated patients from Cazalles et al (median follow-up: 22 months). After match-adjustment, Epcor+GemOx (ORR 86.8%) demonstrated significantly higher ORR, corresponding to a 48.5% advantage over R-GemOx (ORR 38.3%) with an odds ratio (OR) of 2.3 (95% CI 1.8-2.9; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx vs R-GemOx (71.2% vs 32.7%; 38.6% difference; OR 2.2 [95% CI 1.6-3.0]; P<0.0001). Median PFS was significantly longer with Epcor+GemOx (26.7 months) vs R-GemOx (4.8 months; hazard ratio [HR] 0.38 [95% CI 0.22-0.67]; P<0.001). Median OS was not reached (NR) for Epcor+GemOx vs 10.0 months with R-GemOx (HR 0.54 [95% CI 0.29-1.0]; P=0.05), corresponding overall to a 62% reduction in the risk of a progression event and a 46% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. A total of 72 patients were treated with R-GemOx in COTA (median follow-up: 7.5 months) and compared to 74 Epcor+GemOx patients. After adjustment, ORR was significantly higher with Epcor+GemOx vs R-GemOx (88.5% vs 35.6%; OR 2.5 [95% CI 1.8-3.4]; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx (63.9% vs 10.2%; OR 6.3 [95% CI 3.1-12.7]; P<0.0001). Adjusted median PFS was significantly longer with Epcor+GemOx (11.2 months) vs R-GemOx (2.4 months; HR 0.23 [95% CI 0.15-0.36]; P<0.0001). Adjusted median OS was also significantly longer with Epcor+GemOx (21.6 vs 8.3 months; HR 0.47 [95% CI 0.30-0.74]; P=0.002), corresponding overall to a 77% reduction in the risk of a progression event and a 53% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. Conclusions: In this indirect treatment comparison analysis,Epcor+GemOx provided significantly superior efficacy benefits in terms of ORR, CR, PFS, and OS vs standard-of-care R-GemOx. While subject to the limitations of comparisons outside of controlled trials, findings indicate the compelling efficacy of Epcor+GemOx as a novel therapeutic option for transplant-ineligible patients with R/R DLBCL.

Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Rosai–Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic neoplasm. Although the disease classically presents as massive painless lymphadenopathy in young adults, RDD can also involve the central nervous system in some patients. CNS lesions, can cause headaches, neurologic deficits, and even neurologic deficits. The imaging appearance of CNS RDD typically mimics that of meningiomas: well-circumscribed dural-based lesions that often have dural tails. However, some imaging clues also exist that might help a radiologist recognize RDD, even before histopathologic confirmation. This radiology-pathology report of a patient with CNS RDD highlights the most pertinent clinical, imaging, and pathologic features of CNS RDD, and discusses what the neuroradiologist needs to know about the disease.

Abstract T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection. Thus, by expressing a broad range of SELF epitopes against which minimal functional T cell reactivities exist because of thymic deletion, AIRE acts as a master controller of SELFNESS, effectively cloaking the tumor from T cell attack. Moreover, we describe a completely novel immunotherapy in which engineered changes in AIRE expression in tumor cells alters their profile of SELFNESS, exposing both AIRE-modified, and parental unmodified, tumor cells to T cell attack. Consistent with our studies, patient RNAseq shows expression of AIRE predicts response to immune therapies with a strong correlation between AIRE expression and markers of TCR signaling. Therefore, by re-setting the immunological SELFNESS of cancer cells, this novel AIRE-mediated immunotherapy 1). converts a highly tolerized T cell compartment into a heteroclitic tumor-reactive T cell population; 2) confers de novo sensitivity to immune checkpoint blockade upon non-immunogenic tumors; 3). completely removes the need to identify potentially immunogenic tumor-associated antigens as targets for generation of de novo CD8+ and helper CD4+ T cell responses; and 4) leads to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors.

Abstract The field of infectious diseases (ID) offers a rewarding career path and is widely viewed as an essential subspecialty in medicine. However, in recent years, these positive aspects have been overshadowed by concerns surrounding low fellowship match rates, undercompensation, and burnout. The Infectious Diseases Society of America Fellowship Training Program Directors Committee met in 2023, discussed the future of ID as a specialty, and sought to develop strategies to highlight the value and opportunities of ID for future generations, as well as underscore the importance of and provide tools for positive messaging to trainees about the subspecialty. This paper presents ideas generated at this meeting and is meant to serve as a reference for ID training program directors, as well as the wider ID community, in uplifting and shaping the future of the field.

Abstract The prognosis for pediatric high-grade gliomas associated with mutations in the H3-A3 histone gene is very poor. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant (DHG), we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens (TAs). We used the RCAS/tv-A system to target the expression of H3/G34R and PDGFb, and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. To identify TAs, we implemented a new computational workflow to identify nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two DHG patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele. Splenocytes isolated from successfully treated mice were analyzed through bulk TCR sequencing, and in comparison with control mice and publicly-accessible TCR libraries, 6 highly-represented TCR clonotypes were identified only in treated mice. In summary, we demonstrate that effective TAs can be extracted from RNAseq data, and can be targeted with DC vaccination to generate a systemic anti-tumor cytotoxic T cell response to eliminate DHG in a novel immunocompetent mouse model.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

ABSTRACT Introduction Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only preferred treatment regimens for patients with transplant‐ineligible (TIE) newly diagnosed multiple myeloma (NDMM). As there are no randomized head‐to‐head studies of DRd versus VRd, this analysis aimed to compare real‐world time‐to‐next‐treatment (TTNT) or death in this population. Methods Patients with NDMM who received front‐line (FL) DRd or VRd were identified from the Acentrus database (January 1, 2018 to May 31, 2023). Those with a record of a stem cell transplant or aged < 65 years were excluded to limit analysis to the TIE population. Inverse probability of treatment weighting was used to balance baseline patient characteristics. A doubly robust Cox proportional hazards model was used to compare TTNT or death between cohorts. Results A total of 149 and 494 patients who initiated DRd and VRd, respectively, were identified. After weighting (weighted N DRd = 302, weighted N VRd = 341), cohorts had similar baseline characteristics. Of these, 98 (32.4%) DRd and 175 (51.2%) VRd patients either received a subsequent line of therapy or died, with a median TTNT or death of 37.8 months in the DRd cohort and 18.7 months in the VRd cohort (hazard ratio: 0.58, 95% confidence interval: 0.35, 0.81; p < 0.001). Conclusion Treatment of TIE NDMM patients with DRd led to a significantly longer TTNT or death compared to VRd, evidenced by a 42% risk reduction, supporting the effectiveness of DRd over VRd as FL treatment in this patient population.