Citations

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT243.

The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Background: Shoulder function after spinal nerve grafting in pan–brachial plexus injuries (pan-BPI) is not well described. The authors evaluated shoulder abduction (ABD) and external rotation (ER) after spinal nerve grafting to the suprascapular nerve, axillary nerve, or posterior division of the upper trunk and determined patient characteristics, injury severity and characteristics, and nerve graft factors that influenced outcomes. Methods: A total of 362 patients undergoing pan-BPI reconstruction and spinal nerve grafting for shoulder reanimation in a single institution between 2001 and 2018 were reviewed. Patient demographics, Injury Severity Score (ISS), graft characteristics, strength, range of motion for shoulder ABD and ER, and patient-reported outcomes were recorded. Patients were divided into 3 groups based on recovery of shoulder function: no return, ABD only, and ABD and ER. Results: A total of 110 patients underwent spinal nerve grafting, with 41 meeting inclusion criteria. Seventeen (41.5%) had no return of shoulder function, 14 (34.1%) had ABD alone, and 10 (24.4%) had ABD and ER. Patients with recovery of both ABD and ER were significantly younger (18.6 ± 5.56 years), had lower body mass index (22.4 ± 4.0), and had a lower ISS (10.5 ± 6.24; P = 0.003). Multivariable analysis found that with increasing age (OR, 0.786; 95% CI, 0.576, 0.941) and ISS (OR, 0.820; 95% CI, 0.606, 0.979), odds for return of ABD and ER decreased significantly. Conclusions: In pan-BPI, 24.4% of patients demonstrated return of both ABD and ER after spinal nerve grafting to suprascapular nerve and either axillary nerve or posterior division of the upper trunk. Age, body mass index, and ISS were associated with poorer recovery of shoulder function. Careful patient selection and consideration of age, body mass index, and ISS may improve outcomes of spinal nerve grafting for shoulder reanimation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of 286 possible measures, 33 measures made the final set. International normalized ratio testing was not required for diagnostic or therapeutic paracentesis as well as diagnostic endoscopy. Plasma transfusion should be avoided for all paracenteses and diagnostic endoscopy. No consensus was achieved for these items in therapeutic intent or emergent endoscopy. The risks of prophylactic platelet transfusions exceed their benefits for outpatient diagnostic paracentesis and diagnostic endosopies. For the other procedures examined, the risks outweigh benefits when platelet count is >20,000/mm 3 . It is uncertain whether risks outweigh benefits below 20,000/mm 3 in other contexts. No consensus was achieved on whether it was permissible to continue or stop systemic anticoagulation. Continuous aspirin was permissible for each procedure. Clopidogrel was permissible for diagnostic and therapeutic paracentesis and diagnostic endoscopy. We found many areas of consensus that may serve as a foundation for a common set of practice metrics for the periprocedural management of coagulopathy in cirrhosis.

AbstractINTRODUCTIONGlial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid‐β (Aβ)‐positive individuals, making GFAP a potential blood‐based biomarker for Alzheimer's disease (AD).METHODSWe assessed plasma GFAP in 72 Aβ‐positive participants diagnosed with the visual or language variant of AD who underwent Aβ‐ and tau‐PET. Fifty‐nine participants had follow‐up imaging. Linear regression was applied on GFAP and imaging quantities.RESULTSGFAP did not correlate with Aβ‐ or tau‐PET cross‐sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level.DISCUSSIONAmong Aβ‐positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

Abstract On June 1, 2020, NYC Health + Hospitals, in partnership with the NYC Department of Health and Mental Hygiene, other city agencies, and a large network of community partners, launched the New York City Test & Trace (T2) COVID-19 response program to identify and isolate cases, reduce transmission through contact tracing, and provide support to residents during isolation or quarantine periods. In this paper, we describe lessons learned with respect to planning and implemention of case notification and contact tracing. Our findings are based on extensive document review and analysis of 74 key informant interviews with T2 leadership and frontline staff, cases, and contacts conducted between January and September 2022. Interviews elicited respondent background, history of program development, program leadership and structure, goals of the program, program evolution, staffing, data systems, elements of community engagement, trust with community, program reach, timeliness, equity, general barriers and challenges, general facilitators and best practices, and recommendations/improvement for the program. Facilitators and barriers revealed in the interviews primarily revolved around hiring and managing staff, data and technology, and quality of interactions with the public. Based on these facilitators and barriers, we identify suggestions to support effective planning and response for future case notification and contact tracing programs, including recommendations for planning during latent periods, case management and data systems, and processes for outreach to cases and contacts.

Abstract Cytotoxic CD8+ T cells play a key role in response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) therapy. However, the exact effector molecules that are regulated by PD-1 signals in cytotoxic CD8+ T cells have not been completely defined. Lack of this knowledge is a crucial problem in addressing how to overcome the low clinical response rate to ICI therapy. When exploring why certain patients not responding to ICI therapy, we found non-responders did not have an elevated NKG7 expression in CD8+ T cells as responders to ICI therapy. The difference in NKG7 expression in CD8+ T cells between non-responders and responders to anti-PD-1 therapy prompted us to investigate the potential role of PD-1 signaling in regulating NKG7 expression. To that end, we generated a CD8+ T cell-specific Pdcd1 conditional knockout mice (CD8 E8ICre-Pdcd1fl/fl, also known as CD8-PD-1 cKO) where Pdcd1 is deleted after thymic selection of single positive CD8+ T cells. We observed a delayed tumor growth and prolonged survival in CD8-PD-1 cKO mice compared to control mice after B16-OVA melanoma tumor challenge. On Day 12, when the CD8-PD-1 cKO mice demonstrated their ability to control tumor growth, we conducted single cell RNA sequencing on isolated tumor infiltrating CD8+ T cells, revealing a significant increase of Nkg7 expression in effector CD8+ T cells in the Pdcd1 deficient CD8+ T cells compared to the control wild type T cells. Pdcd1-deficient effector CD8+ T cells also had increased expression of genes linked to NFAT/Calcineurin signaling pathway including Nfatc1, S100a4, Tbet and Tox, suggesting Nkg7 could be regulated by Pdcd1 via the NFAT pathway. To determine the impact of increased NKG7 expression in CD8+ T cells, we used OVA protein as a surrogate tumor antigen in vaccination. We found a complete B16-OVA tumor rejection in CD8-PD-1 cKO mice compared to control mice when tumor cells were injected on day 7 after vaccination with OVA protein and poly (I:C) (as an adjuvant), but only a partial rejection on day 21. The CD8-PD-1 cKO mice that were tumor-free for 30-40 days rejected 2nd tumor challenge with B16-OVA tumors. This long-term protection is tumor antigen (OVA) specific because these mice did not reject B16F10 tumor cells that do not express OVA antigen. We also found effector memory CD8+ T cells with high cytotoxicity increased in the spleen of CD8-PD-1 cKO mice after OVA antigen immunization compared to control. In conclusion, we found NKG7 is one of the effector molecules in cytotoxic CD8+ T cells, which can be regulated by PD-1 signals through NFAT signaling. Targeting the PD-1-NFAT pathway may be a new option to overcome low responses of T cells to ICI therapy in treatment of refractory cancer. Citation Format: Zhiming Mao, Joanina Gicobi, Jacob Hirdler, Xin Liu, Michelle Hsu, Emilia Dellacecca, Wenjing Zhang, Fabrice Lucien-Matteoni, Hai dong. PD-1 signals regulate NKG7 that is required for CD8+ T cells to sustain cytotoxicity and durable antitumor memory responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3979.

Abstract Background: Although targeting myeloid cells has become one of the next generation targets for cancer immunotherapy, there is a lack of therapeutic tools to specifically target these cells. Our group has developed a novel humanized PD-L1-targeting antibody, H1A, that induces PD-L1 degradation via blockade of PD-L1 and CMTM6, therefore limiting PD-L1 intrinsic signaling while also preventing interactions with PD-1. In the immune cell compartment, CMTM6 expression is restricted to myeloid cells, making these cells the primary target of H1A. Recently, we unexpectedly found that targeting intrinsic PD-L1 in myeloid cells via H1A resulted in increased release of CCL2 from myeloid cells. In this study, we examined the role of CCL2/CCR2 signaling in CD8 T cell function using human peripheral blood-derived immune cells and evaluated the therapeutic potential of H1A antibody using our humanized PD-L1/PD-1 mouse model. Methods: Human PBMCs derived from healthy donors were treated with H1A or Atezolizumab, a blocking PD-L1 antibody, followed by mass cytometry and flow cytometry to evaluate immune cell phenotype and functional states. PD-L1 expressing myeloid cells isolated from human PBMCs were treated with H1A or Atezolizumab and assessed for CCL2 secretion using multiplex immunoassays. CCL2 production and transcription were confirmed by flow cytometry and single-cell RNA-sequencing. CCR2 blockade was used on human PBMCs to evaluate the effects of CCL2/CCR2 signaling on T cell function alongside H1A treatment. Finally, in vivo antitumor activity of H1A and Atezolizumab were compared in two humanized PD-L1 tumor models. Results: H1A reduced the frequency of regulatory T cells and increased effector T cells, in whole PBMCs upon global T cell activation with anti-CD3/CD28. H1A enhanced the secretion and production of CCL2 from myeloid cells, which was confirmed at a transcript level. CCR2 blockade diminished CD8 T cells’ ability to differentiate into effector cells in H1A treated PBMCs. H1A demonstrated comparable therapeutic effects with Atezolizumab in treatment of immunogenic and ICI-responsive mouse tumor MC38, which is CD8 T cell-dependent, but showed superior therapeutic effects in treatment of ICI-insensitive mouse tumor E0771 compared to Atezolizumab. Both treatments elicited durable memory specific immune responses upon E0771 tumor rechallenge. Conclusion: H1A demonstrated a superior antitumor activity compared to Atezolizumab in our preclinical models via a new mechanism by which H1A caused degradation of intrinsic PD-L1 in myeloid cells. This causes more release of CCL2 to improve T cell function via CCR2 upon T cell activation. Thus, H1A is emerging as a new immunotherapy tool to target PD-L1/CMTM6 in myeloid cells for treatment of cancers that are refractory to current immune checkpoint inhibitor therapy. Citation Format: Michelle Alexandria Hsu, Xin Liu, Ying Li, Whitney Barham, Kevin Pavelko, Jake Hirdler, Fabrice Lucien, Haidong Dong. Targeting PD-L1/CMTM6 in myeloid cells results in elevated release of CCL2 to improve CD8 T cell-mediated antitumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2664.