Immunotherapy Research Articles

Advances in antiviral strategies targeting mosquito-borne viruses: cellular, viral, and immune-related approaches.

Mosquito-borne viruses (MBVs) are a major global health threat, causing significant morbidity and mortality. MBVs belong to several distinct viral families, each with unique characteristics. The primary families include Flaviviridae (e.g., Dengue, Zika, West Nile, Yellow Fever, Japanese Encephalitis), transmitted predominantly by Aedes and Culex mosquitoes; Togaviridae, which consists of the genus Alphavirus (e.g., Chikungunya, Eastern and Western Equine Encephalitis viruses), also transmitted by Aedes and Culex; Bunyaviridae (recently reorganized), containing viruses like Rift Valley Fever and Oropouche virus, transmitted by mosquitoes and sometimes sandflies; and Reoviridae, which includes the genus Orbivirus (e.g., West Nile and Bluetongue viruses), primarily affecting animals and transmitted by mosquitoes and sandflies. Despite extensive research, effective antiviral treatments for MBVs remain scarce, and current therapies mainly provide symptomatic relief and supportive care. This review examines the viral components and cellular and immune factors involved in the life cycle of MBVs. It also highlights recent advances in antiviral strategies targeting host factors such as lipid metabolism, ion channels, and proteasomes, as well as viral targets like NS2B-NS3 proteases and nonstructural proteins. Additionally, it explores immunomodulatory therapies to enhance antiviral responses and emphasizes the potential of drug repurposing, bioinformatics, artificial intelligence, and deep learning in identifying novel antiviral candidates. Continued research is crucial in mitigating MBVs' impact and preventing future outbreaks.

Micro Immune Response On-chip (MIRO) models the tumour-stroma interface for immunotherapy testing

Immunotherapies are beneficial for a considerable proportion of cancer patients, but ineffective in others. In vitro modelling of the complex interactions between cancer cells and their microenvironment could provide a path to understanding immune therapy sensitivity and resistance. Here we develop MIRO, a fully humanised in vitro platform to model the spatial organisation of the tumour/stroma interface and its interaction with immune cells. We find that stromal barriers are associated with immune exclusion and protect cancer cells from antibody-dependent cellular cytotoxicity, elicited by targeted therapy. We demonstrate that IL2-driven immunomodulation increases immune cell velocity and spreading to overcome stromal immunosuppression and restores anti-cancer response in refractory tumours. Collectively, our study underscores the translational value of MIRO as a powerful tool for exploring how the spatial organisation of the tumour microenvironment shapes the immune landscape and influences the responses to immunomodulating therapies.

Patient Characteristics, Diagnoses, and Management in a Combined Uveitis-Rheumatology Clinic.

Combined uveitis-rheumatology clinics (combined clinics) are a relatively recent clinical care model. Here we report the demographics, ocular and systemic disease characteristics, and medications utilized in patients seen in a combined clinic at a tertiary care hospital in the USA. Medical records were reviewed of patients seen at the Combined Clinic at the University of Colorado Hospital between January 1, 2016 and November 1, 2023. Data including age, sex, referral indication, ocular and systemic inflammatory disease diagnosis, and therapies utilized were obtained. A total of 171 patients were included in the study, of which 122 were diagnosed with a systemic inflammatory disease, the most common of which were spondyloarthritis and rheumatoid arthritis. Nearly half of patients referred to the combined clinic with a known ocular inflammatory disease (OID) and suspicion for a systemic process were eventually diagnosed with a systemic disease. The most common associations in patients with both OID and systemic disease were anterior uveitis with spondyloarthritis, and scleritis with rheumatoid arthritis. The most common systemic immunomodulatory therapies (IMT) used were adalimumab, methotrexate, and rituximab. Over 40% of patients underwent a change in IMT during their first evaluation. Most patients seen in the combined clinic had both ocular and systemic inflammatory disease and were treated with IMT. Many patients were diagnosed with a systemic inflammatory disease upon evaluation in the combined clinic, and nearly half were recommended to initiate or change IMT at their first visit. This highlights the utility of a combined clinic in the management of these complex patients, in addition to providing logistical benefits to patients and educational opportunities for trainees.

Real-world biomarker testing patterns, first line treatment and drivers of treatment choice in patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma in the United States and Europe.

353 Background: For first line (1L) treatment (tx) in HER2- gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (AC), clinical guidelines recommended platinum-fluoropyrimidine (PF) chemotherapy (CT) in patients (pts) with a PD-L1 combined positive score (CPS) <5 and PF CT in combination with immunotherapy (IO) for CPS ≥5. There is little contemporary evidence into IO tx uptake in the real world. This real world study examined biomarker testing, 1L tx characteristics, and reasons for 1L tx choice in pts with HER2- G/GEJ AC to identify unmet needs and opportunities for optimal clinical practice. Methods: Data were derived from the Adelphi G/GEJ Cancer Disease Specific Programme: a systematic approach involving multi-national, multi-faceted data sources including cross-sectional surveys capturing data from physicians and their consulting pts. Physicians reported pt demographics, clinical characteristics, tx received and reasons for tx decisions, via chart review. Data were collected across US and Europe (EU: France, Germany, Spain, the UK) between Oct 2022 to Apr 2023. All pts were alive at data collection and analyses were descriptive. Results: Overall, 243 treating physicians (US n=60/EU n=183) provided data on 642 HER2- pts (US n=83/EU n=559) receiving 1L tx at data collection. For pts from US/EU, median age was 66/67 years, 84%/79% had an ECOG of 0-1 and 52%/75% had metastatic disease at data collection. In the US/EU, 87%/80% of pts were tested for PD-L1 status respectively, of which 63%/69% had a known CPS. For US/EU, 67%/45% of pts (n=30/n=139) had a CPS ≥5. Differences in biomarker testing rates were observed in US v EU pts respectively for MSI/dMMR (66% v 58%), NTRK-gene fusion (31% v 4%) and FGFR2 (27% v 3%). Of US/EU physicians, 70%/85% (n=60/n=183), reported the main reason for conducting biomarker testing was ‘to inform tx decisions’. Cost related concern (50%/39%) and time constraints (23%/15%) were the main perceived barriers to testing. Among pts with PD-L1 CPS <5, 27% of US pts and 2% of EU pts received IO + CT; in pts with CPS ≥5, 63% of US pts and 76% of EU pts received IO + CT. Whilst progression free survival/overall survival benefit were the most common reasons selected by physicians for 1L tx choice across the US/EU (75%/74% and 60%/61%), differences across regions were reported for tx choice based on maintaining and improving pt’s QoL (4%/28%) and pt’s performance status (2%/24%). Conclusions: PD-L1 testing was not performed by 19% of physicians and approximately one third of pts with CPS ≥5 across the US/EU were not receiving IO + CT in 1L. As informing 1L tx choice was a key driver for biomarker testing, there may be scope for improvement in 1L tx by increasing testing rates. Further studies are needed to address barriers to biomarker testing and uptake of IO in pts who can benefit from 1L IO tx.

Impact of Renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with Metastatic Renal Cell Carcinoma

BackgroundThe renin-angiotensin-aldosterone system (RAAS), traditionally associated with blood pressure and fluid regulation, also plays a role in tumorigenesis. Renin-angiotensin-aldosterone system inhibitors (RAASI), including angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes in various malignant neoplasms. In metastatic urothelial cancer, the use of RAASI have been associated with higher rates of tumor regression in patients receiving immunotherapy (IO) with PD1/L1 inhibitors. This is thought to be due to RAASI-induced downregulation of TGF-beta, for which increased expression is a known mechanism of PD1/L1 inhibitor resistance. We hypothesized that concurrent RAASI in patients with mRCC receiving IO is associated with increased tumor regression. MethodsWe conducted a retrospective analysis of patients with mRCC receiving IO as a first- or second-line therapy from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RAASI on tumor regression. The primary endpoint was any regression of tumor on imaging. ResultsData were available for 128 patients with mRCC who received IO as a first- (n=91, 71.0%) or second- (n=37, 28.9%) line treatment. Patients who received RAASI during IO were more likely to have tumor regression compared to patients who were not on concurrent RAASI (OR 3.84 [95% CI 1.81-8.47, p=<0.001). This held true regardless if patients received IO as a first-line (OR 2.83 [95% CI 1.2-6.94], p=0.0173) or second-line (OR 9.5 [95% CI 1.89-73.1], p=0.005) treatment. ConclusionsOur hypothesis generating study suggests that in our mRCC population, concurrent use of RAASI in patients receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RAASI in combination with IO for mRCC patients. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population. MicroAbstractRenin-angiotensin-aldosterone system inhibitors (RAASI) have been shown to improve outcomes in various malignancies. In this retrospective, single-center study, we found that concurrent use of RAASI in patients with mRCC receiving IO is associated with a significantly increased likelihood of tumor regression. Our findings suggest the potential therapeutic advantage of RAASI in combination with IO for mRCC patients.

A cross-sectional analysis from a real-world cohort of patients with microsatellite instability colorectal cancer (MSI-CRC) with metastatic disease from the Spanish RETUD registry.

178 Background: Survival of microsatellite instability (MSI) metastatic colorectal cancer (mCRC) patients (pts) has remarkably increased with immune checkpoint inhibitors (ICI). Here, we present our real-world data regarding the management and clinical outcomes of a cohort of 214 MSI-mCRC patients included in the Spanish Group of Treatment of Digestive Tumors TTD Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-mCRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics, treatments and treatment response are descriptively presented. Tumoral response was evaluated according to RECIST 1.1 criteria. First line progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Among 679 MSI-CRC pts included in RETUD, a total of 214 mCRC pts were evaluable. Pts’ age at diagnosis was 69.6 (26-96) years, and they were predominantly Caucasian (97.7%) and female (53.7%). Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 for 168 (78.5%) pts. Seventeen (10.7%) pts presented Lynch syndrome. Main tumor biological characteristics are described at Table 1 and the molecular profile (when available) was: KRAS mutation (24.3%), NRAS mutation (3.5%) and BRAF v600E mutation (53.0%). Surgical resections: 158 (73.8%) pts for primary tumor and 42 (19.6%) pts for metastasis. First line systemic treatment was administered to 187 (97.1%) pts: 92 (49.2%) pembrolizumab, 83 (44.4%) chemotherapy (CT), 4 (2.1%) other ICIs, 8 (4.3%) not reported. With a median follow up period of 17.4 months, the median (95% CI) OS and first-line PFS of the total mCRC population were 32.6 (22-72.4) and 11.1 (8.2-17.9) months (m), respectively. In immunotherapy (IT) pts mOS was not achieved (22.0-NA) and PFS was 26.5 m (12.9-NA) while the mOS was 28.9 m (16.3-69.3) and PFS 7.5 (5.4-9.3) m in CT pts. The overall response rate (ORR) was 54.2% in IT pts vs. 37.3% in CT pts. Conclusions: The introduction of IT has changed the evolution of MSI-H mCRC management, offering a beneficial impact in the OS and PFS survival in contrast to other conventional therapies in a real-world context. Tumor characteristics at initial diagnosis of CRC. Stage at initial diagnosis of CRC I/II, n (%) 4 (1.9) / 26 (12.1) III/IV, n (%) 66 (30.8) / 118 (55.1) Location of primary tumor a , n (%) right colon /left colon /rectum 160 (74.8) /37 (17.3) /19 (8.9) Main metastatic location b , n (%) Liver 84 (39.3) Peritoneal 76 (35.5) Lymph 71 (33.2) Lungs 41 (19.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. Data missing for 4 (1.9%) pts. b Pts with more than 1 metastatic site; the percentage may be over 100%.

Assessment of clinical value and barriers to use of new investigational targeted agents in the community setting: A study of claudin 18.2 and zolbetuximab.

500 Background: Rapid integration of novel agents in clinical practice can be lifesaving. However, community-based practices may experience extended adoption times, due to practical barriers. REFLECT was developed to assess new drug implementation in the community setting. Methods: REFLECT consists of a 20-minute prerecorded presentation, followed by a data-collection event for community oncologists. It was developed to evaluate and assess challenges of implementing novel targeted agents in the community practice setting. In this pilot study, awareness of zolbetuximab (zolbe), a potential first-in-class claudin 18.2 (CLDN18.2) monoclonal antibody and companion diagnostic, was assessed. Between April and August 2024, 53 data-collection events were held representing 26 states across the US. Data from 492 oncologists were recorded and analyzed. Results: Nearly half the community oncologists (47%) were not familiar with CLDN18.2 as a therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancer. Awareness of zolbe data was low among community oncologists; 79% indicated they had not seen the results from the phase 3 studies. However, 96% of oncologists reported the data will at least moderately impact their treatment of CLDN18.2+ patients with metastatic (m)G/GEJ cancer. Only 40% of oncologists reported having access to CLDN18.2 testing. Uncertainty regarding availability of CLDN18.2 testing was high among oncologists in the Central US (52%), representing a significant awareness gap for CLDN18.2 testing. Opinions were divided regarding the treatment approach for CLDN18.2+, immunosensitive patients (Table). In a HER2–, CLDN18.2+ patient with mG/GEJ cancer and a combined positive score (CPS) of 10; 58.1% would recommend first-line chemotherapy (chemo) plus immunotherapy (IO) and 40.4% would recommend chemo plus zolbe. Conclusions: First-in-class targeted agents often encounter additional challenges and knowledge gaps regarding adoption in the community practice setting, particularly associated with molecular testing. Timely education on patient identification and correct utilization may accelerate adoption of new regimens, and potentially save lives. Data-sharing and -collection platforms including REFLECT can be instrumental in the identification of challenges associated with widespread and rapid implementation of novel agents in the community oncology setting. What treatment approach would you recommend in a patient with the following characteristics, if all treatments were available? mGEJ adenocarcinoma, HER2– disease, CLDN18.2+ staining in &gt;75% of tumor cells, CPS 10. Treatment Total: N = 492% (n) Chemo mFOLFOX6 1.0 (5) CAPOX 0 (0) Chemo + IO mFOLFOX6 + IO 52.8 (260) CAPOX + IO 5.3 (26) Chemo + zolbe mFOLFOX6 + zolbe 33.9 (167) CAPOX + zolbe 6.5 (32) Other 0.4 (2)

Patient (pt) characteristics, treatment patterns, and outcomes in unresectable hepatocellular carcinoma (uHCC) treated with first-line (1L) systemic therapy in the United States (US).

572 Background: Guidelines recommend systemic therapy for uHCC ineligible for locoregional therapy. Until the approval of tremelimumab + durvalumab for uHCC, in Oct 2022, 1L systemic therapies in the US included multikinase inhibitors and atezolizumab (A) + bevacizumab (B). It is crucial to understand factors driving real-world treatment decisions and outcomes in uHCC. Characteristics, treatment patterns, and outcomes were assessed in US pts with uHCC treated with 1L systemic therapy. Methods: Data were collected from electronic medical records from US Mayo Clinic sites. Pts with uHCC who initiated an NCCN-recommended 1L systemic therapy between Jun 2020–Oct 2022 (A + B was the only approved 1L immunotherapy (IO)-based regimen) with ≥2 follow-up visits, were included. Index was the date of first 1L systemic therapy. Pts were assessed by risk of post-index gastrointestinal (GI) bleeding (pts with Child-Pugh class B or C, pre-index GI bleeding, uncontrolled hypertension [HTN] [≥2 anti-HTN drugs or ≥2 vital entries of SBP &gt;140 mmHg or DBP &gt;90 mmHg]), or significant varices and band ligation). Treatment patterns, overall survival (OS), and post-index GI bleeding were assessed. Results: A total of 186 pts met the inclusion criteria. Most common etiologies of liver disease were metabolic dysfunction-associated steatohepatitis (42.7%) and hepatitis C virus (40.2%). Pre-index GI bleeding was reported in 29.0% of pts, of which 46.3% occurred within 6 months (mo) pre-index; 62.4% of pts had EGD, of which 72.4% had varices. There were 128 (68.8%) pts with GI bleeding risk and 58 (31.2%) pts without GI bleeding risk. The most common 1L systemic therapies for pts with GI bleeding risk were A + B (72.7%) and A only (9.4%), while for pts without GI bleeding risk, A + B (29.3%), nivolumab + ipilimumab (13.8%), and B + chemotherapy (13.8%) were the most common. Median OS and OS rates at 12, 18, and 24 mo were lower, and post-index GI bleeding rate was higher in pts with vs without GI bleeding risk (Table). For pts treated with A + B, median OS and OS rates at 12, 18, and 24 mo were lower in pts with vs without GI bleeding risk (Table). Conclusions: In this network, prior to the approval of other 1L IO-based regimens for uHCC, many pts received A + B, despite risk of post-index GI bleeding. Median OS with A + B was shorter in pts with vs without GI bleeding risk. Data highlight the complexity of uHCC and the unmet need for guidance on characteristics-driven treatment decisions. Full cohort A + B cohort All ptsN=186 GI bleeding risk N=128 No GI bleeding risk N=58 All pts N=110 GI bleeding risk N=93 No GI bleeding risk N=17 Median follow-up, mo 20.6 20.9 20.4 21.3 21.6 20.3 Median OS, mo 14.4 11.4 40.3 13.9 12.8 Not reached OS rates, % 12 mo 55.2 48.9 68.9 55.2 52.3 70.6 18 mo 45.3 38.1 61.1 44.1 41.6 57.8 24 mo 39.4 31.8 56.8 37.1 34.6 51.3 Post-index GI bleed, % 17.2 23.4 3.4 17.3 19.4 5.9

Anti-cancer and immunomodulatory photodynamic therapy application of novel porphyrin derivatives

Anti-cancer and immunomodulatory photodynamic therapy application of novel porphyrin derivatives

A prospective multi-site translational study investigating the association of gut microbiome (GM) diversity with pathological complete response (pCR) after neoadjuvant treatment in early stage rectal and esophageal cancer.

TPS849 Background: The diversity of the GM is defined as the number and relative abundance distribution of distinct types of microorganisms colonizing within the gut. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and impacts response to immunomodulating therapies. The influence of the GM diversity on the pathological response after neoadjuvant chemotherapy and radiotherapy is unclear. Some studies have suggested that the GM may offer predictive biomarkers for response to chemoradiation in rectal cancer. Other studies in early-stage rectal cancer patients indicated an association between GM diversity and pathological outcomes following neo-adjuvant therapy (NAT). We hypothesize that a more diverse GM constitution at baseline leads to an improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional translational study investigating the impact of the GM diversity on the efficacy of NAT in GI cancers by assessing its association with pathological response. The study population includes patients with early-stage rectal or esophageal cancer due to commence NAT (including chemotherapy and chemoradiation) who are planned for definitive surgery. Exclusion criteria includes prior allogenic tissue/solid organ transplantation and prior receipt of anti-cancer therapy. The study assessments include fecal sampling of the GM prior to NAT, upon completion and again six months post completion of therapy. Fecal samples are analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. Exploratory analysis will include the assessment of the association between cf-DNA and the GM diversity as well as an assessment of the association between cf-DNA at baseline and pCR. Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index will be used to calculate beta diversity. Following planned study recruitment, classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Logistic regression analysis adjusting for potential confounding factors will be employed to assess the primary endpoint of the association between GM and complete pCR in the final statistical analysis. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. This trial accrued 11 patients between May 2023 and Sept 2024. Out of the 11 patients enrolled, 9 patients have undergone their planned surgery. We are expecting to have 30 patients accrued prior to Jan 2025.

Myopericarditis and Pericardial Effusion as the Initial Presentation of Systemic Lupus Erythematosus in a Patient with Sickle Cell Trait: A Case Report

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with rare but severe cardiac manifestations, including myocarditis and pericarditis. The coexistence of SLE with sickle cell trait (SCT), an inherited hemoglobinopathy prevalent among individuals of African descent, is exceptionally rare and presents significant diagnostic challenges due to overlapping clinical features. Objective: To describe the case of an Afro-Ecuadorian male with SLE and sickle cell trait who developed an uncommon presentation of myopericarditis and pericardial effusion. Case report: A 48-year-old African American male with no prior medical history presented with persistent fever, polyarticular arthralgias, and pleuritic chest pain. Investigations revealed sickle cell trait (SCT) and myopericarditis with pericardial effusion, marking the initial manifestation of SLE. Diagnostic delays occurred due to overlapping symptoms and a family history of sickle cell disease. Laboratory findings showed elevated hemoglobin S (&lt;50%), positive ANA (1:1280, coarse speckled pattern), and anti-Smith/RNP antibodies, meeting EULAR/ACR 2019 criteria for SLE. Cardiac MRI confirmed myopericarditis. Treatment with pulse methylprednisolone, oral prednisone, and mycophenolate mofetil resulted in clinical improvement, with stable disease control on immunomodulatory therapy during follow-up. Conclusions: This case highlights the diagnostic complexity of SLE in patients with SCT, particularly when presenting with myopericarditis as the initial manifestation. It emphasizes the importance of a comprehensive diagnostic approach and timely initiation of immunosuppressive therapy to optimize clinical outcomes. This report broadens the understanding of overlapping syndromes involving SLE and SCT.

Prognostic scores for predicting overall survival in patients with metastatic renal and urothelial cancer undergoing immunotherapy - which one to use?

PurposeEvaluation of the prognostic significance of four different scoring systems in a real-world cohort of patients with metastatic urothelial carcinoma (mUC) or renal cell carcinoma (mRCC) undergoing immunotherapy (IO).MethodsFor 120 patients with mUC (n = 67) and mRCC (n = 53) who received IO between July 2016 and December 2020 at the tertiary Urological University Medical Centre Mannheim, the following scores were recorded at pre-treatment baseline: modified Glasgow prognostic score (mGPS), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER). Overall survival (time between the beginning of IO until the patients’ death or last contact) was determined for every patient.ResultsKaplan-Meier analyses revealed that high baseline mGPS, SII (> 979) and NLR (> 3) were associated with poor overall survival (OS) (p < 0.05). Cox proportional hazards regression analyses showed that baseline mGPS and NLR had a significant independent prognostic influence on OS (p < 0.05), of which mGPS had a greater significance (p < 0.001, mGPS Score 2 vs. Score 0: HR 4.1, 95% CI 1.9–8.8). Although a high baseline NER (63.9) was associated with poor OS, it did not reach statistical significance. Baseline NER was also not identified as a significant score in the regression analyses.ConclusionmGPS, SII and NLR are scoring systems that are easy to record in routine clinical practice. As they provide good prediction of OS in patients with mUC and mRCC under IO, they may allow identification of patients at high-risk and monitor them more cautiously in addition to imaging.

P-2006. Individuals on Immunosuppressive or Immunomodulatory Therapies Remain at Increased Risk of COVID-19 Hospitalization, Despite Vaccination: Findings from INFORM, a Retrospective Health Database Study in England

Abstract Background Use of immunosuppressive or immunomodulatory therapies (IITs) may be a risk factor for severe COVID-19 outcomes. The INFORM (INvestigation oF cOvid-19 Risk among iMmunocompromised populations) study (ISRCTN53375662) uses routinely collected, national primary/secondary care data in England to provide a comprehensive, population-based assessment of COVID-19 impact, risk, and cost among immunocompromised (IC) and other high-risk populations. Here we assess risk of COVID-19 hospitalization in IC individuals receiving IITs during the Omicron period in 2023. Methods Retrospective cohort study using pseudonymized electronic health records of a random sample of 25% of the population of England aged ≥ 12 years, registered and active in the NHS from January 1 to June 30, 2023. Crude incidence rates (IRs) per 1000 person-years (PY) and incidence rate ratios adjusted for age, sex, and comorbidities (aIRRs) for COVID-19 hospitalization were estimated for the overall population and those who received ≥ 4 COVID-19 vaccines by January 1, 2023 (fully vaccinated individuals). Results Of the 12,024,035 individuals in this analysis, 477,025 (4.0%) were IC (Table 1). Of the 5835 hospitalizations, 1335/5835 (22.9%) were among IC individuals (Table 2). In fully vaccinated individuals, there were 4135 hospitalizations, with 1010/4135 (24.4%) among IC individuals (Table 3). Recent or active treatment with IITs was associated with higher risk of hospitalization. Among fully vaccinated individuals, secondary immunodeficiency was associated with an aIRR for hospitalization of 2.5 (95% CI: 2.2, 2.9); aIRR for hospitalization for those with secondary immunodeficiency with active IIT was 3.6 (95% CI: 2.6, 4.9). Fully vaccinated individuals with solid tumors and hematological malignancies were associated with aIRRs for hospitalization of 1.4 (95% CI: 1.3, 1.5) and 3.0 (95% CI: 2.6, 3.4), respectively; aIRRs for fully vaccinated individuals with active cancer treatment were 4.0 (95% CI: 3.3, 4.9) and 9.2 (95% CI: 7.4, 11.3), respectively. Conclusion Despite vaccination, IC individuals treated with IIT are at increased risk of COVID-19 hospitalization. Additional COVID-19 preventative measures should be considered for IC individuals, especially for those receiving IIT. Disclosures Sabada Dube, PhD, AstraZeneca: Employee of, and may hold stock and/or stock options Lucy Carty, PhD, AstraZeneca: Employee of, and may hold stock and/or stock options Carla Talarico, PhD, MPH, AstraZeneca: Employee of AstraZeneca and may hold stock and/or stock options Renata Yokota, PhD, P95 Epidemiology &amp; Pharmacovigilance/AstraZeneca: Employee of P95 Epidemiology &amp; Pharmacovigilance, which received a consultancy fee for the conduct of the current study from AstraZeneca Richard McNulty, MD, AstraZeneca: Employee of, and may hold stock and/or stock options Michelle Harley, MBBS, MRCP, MRCGP, AstraZeneca: Employee, holds or may hold stock Jurgens Peters, MD, MPH, MSc, MBA, AstraZeneca: Employee, holds or may hold stock Nahila Justo, PhD, MBA, Evidera/AstraZeneca: Employee of Evidera, which received funding for the conduct of the current study from AstraZeneca Ana Goios, PhD, P95 Epidemiology &amp; Pharmacovigilance: Employee of P95 Epidemiology &amp; Pharmacovigilance, which received a consultancy fee for the conduct of the current study from AstraZeneca Kathryn Evans, MPH, Evidera/AstraZeneca: Employee of Evidera, which received funding for the conduct of the current study from AstraZeneca Yi Lu, PhD, Evidera/AstraZeneca: Employee of Evidera, which received funding for the conduct of the current study from AstraZeneca Sylvia Taylor, PhD, MPH, MBA, AstraZeneca: Employee of, and may hold stock and/or stock options in, AstraZeneca Jennifer Quint, PhD, Asthma + Lung UK: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|Evidera: Advisor/Consultant|Evidera: Funding|GSK: Advisor/Consultant|GSK: Grant/Research Support|Health Data Research UK (HDR UK): Grant/Research Support|Insmed: Advisor/Consultant|Medical Research Council (MRC): Grant/Research Support Rachael A. Evans, PhD FRCP, Boehringer Ingelheim: Speaker fees|Chiesi: Support for attending the British Thoracic Society (BTS)|Chiesi: Serving non-paid as the European Respiratory Society (ERS) Group 01.02 Pulmonary Rehabilitation and Chronic Care secretary|Chiesi: Serving non-paid as the American Thoracic Society (ATS) Pulmonary Rehabilitation Assembly chairperson|Evidera: Funding for providing advice throughout the current study|Genetec/Roche: Grant/Research Support|Moderna: Speaker fees|NIHR: Grant/Research Support|UKRI: Grant/Research Support|Wolfson Foundation: Grant/Research Support

P-1864. Early Combination Therapy with Isavuconazole and Immune Checkpoint Inhibitors Improves Infection Outcomes and Alleviates Paralyzed Antifungal Host Immunity in Neutropenic Mice with Invasive Pulmonary Mucormycosis

Abstract Background Invasive pulmonary mucormycosis (IPM) is a severe opportunistic mold infection whose outcome is predominantly host-driven. Preclinical studies and several clinical case reports suggested a benefit of adjunct immunotherapy with immune checkpoint inhibitors (ICIs). However, the mechanisms of IPM-associated pulmonary immune paralysis and its mitigation by ICIs require further study. Timeline of experimental interventions. Abbreviations: CPM = cyclophosphamide, i.p. = intra-peritoneally, ISAV = isavuconazonium sulfate, IT = immunotherapy, PD-L1 = Programmed Death Ligand 1, p.o. = per os (oral gavage). Methods Eight-week-old cyclophosphamide-immunosuppressed BALB/c mice were infected intranasally with 50,000 Rhizopus arrhizus spores. The Mucorales-active triazole isavuconazonium sulfate (ISAV) was initiated on day (d) 3 post-infection (2×64 mg/kg/d by oral gavage). Additionally, mice received 2×0.25 mg/kg anti (α)-PD-L1 or a non-targeting isotype antibody either on d3+5 (early) or d6+8 (late) (Fig. 1). Infection severity was scored using the murine sepsis score (MSS; 0 = healthy – 3 = moribund, 4 = dead). nCounter-based transcriptomics and Ingenuity pathway enrichment analysis were performed on lung tissue homogenates. Murine sepsis scores (MSS, 0 = healthy – 3 = moribund, 4 = dead) of immunosuppressed mice with invasive pulmonary mucormycosis according to the treatment arm. Kruskal-Wallis test with Dunn’s post-test. * p&amp;lt;0.05, *** p&amp;lt;0.001. Abbreviations: ISAV = isavuconazonium sulfate, IT = immunotherapy, ns = not significant, PD-L1 = Programmed Death Ligand 1. Results Untreated neutropenic mice developed severe IPM (median day-10 MSS: 2.9, Fig. 2). Pulmonary transcriptomics at d4 revealed strong innate immune activation and induction of type-1 (Th1) and type-17 (Th17) T-helper-cell responses. However, by d7, proinflammatory signals had markedly decreased and nCounter analysis revealed impaired intercellular crosstalk and T-cell signaling (Fig. 3). Compared to ISAV + isotype (median d10 MSS, 2.0), early and late adjunct α-PD-L1 therapy improved median d10 MSS to 1.0 (p &amp;lt; 0.001) and 1.4 (p = 0.01), respectively (Fig. 2). While ISAV delayed the tipping point from immune activation to full-blown immune paralysis, early adjunct α-PD-L1 therapy elicited significantly stronger dendritic cell and classical (M1) macrophage signaling, activation of key cytokine pathways (e.g., IL-1, IL-2, IL-12), reinvigoration of Th1 and Th17 signaling, and suppression of IPM-induced co-inhibitory checkpoint pathways than both ISAV + isotype and ISAV + late α-PD-L1 (Fig. 3). Enrichment of selected immune-related pathways on day 10 after IPM infection (7 days after initiation of therapy) depending on the treatment arm and comparison with surrogates of immune paralysis in untreated infected mice. All differentially induced pathways were statistically significant (Benjamini-Hochberg adjusted p-values &amp;lt;0.05). Abbreviations: IPM = invasive pulmonary mucormycosis, ISAV = isavuconazonium sulfate, PD-L1 = Programmed Death Ligand 1. Conclusion IPM is associated with rapidly emerging immune paralysis. Combined antifungal and early immunomodulatory (α-PD-L1) therapy was the most effective strategy for early interception of immune paralysis and improvement of morbidity/mortality in our IPM model. Disclosures Sebastian Wurster, MD, MSc, Astellas Pharma: Grant/Research Support|Gilead Sciences: Grant/Research Support Dimitrios P. Kontoyiannis, MD, AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Knight: Advisor/Consultant|Merck: Advisor/Consultant|Scynexis: Advisor/Consultant

A Serum- and Feeder-Free System to Generate CD4 and Regulatory T Cells from Human iPSCs.

iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGFβ and ATRA. Using genetic engineering, we demonstrated high, non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs +/- HLA-A2-targeted CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T cell proliferation in vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale.

Emerging Immunotherapies for Disease Modification of Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is characterized by the progressive, autoimmune-mediated destruction of β cells. As such, restoring immunoregulation early in the disease course is sought to retain endogenous insulin production. Nevertheless, in the more than 100 years since the discovery of insulin, treatment of T1DM has focused primarily on hormone replacement and glucose monitoring. That said, immunotherapies are widely used to interdict autoimmune and autoinflammatory diseases and are emerging as potential therapeutics seeking the preservation of β-cell function among those with T1DM. In the past 4 decades of diabetes research, several immunomodulatory therapies have been explored, culminating with the US Food and Drug Administration approval of teplizumab to delay stage 3 (clinical) onset of T1DM. Clinical trials seeking to prevent or reverse T1DM by repurposing immunotherapies approved for other autoimmune conditions and by exploring new therapeutics are ongoing. Collectively, these efforts have the potential to transform the future of diabetes care. We encapsulate the past 40 years of immunotherapy trials, take stock of our successes and failures, and chart paths forward in this new age of clinically available immune therapies for T1DM.

Chronic Severe Neutropenia Associated With Intravenous Immunoglobulin for Multifocal Motor Neuropathy.

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy derived from pooled donor immunoglobulins and used for treatment of various autoimmune conditions. Here we report the diagnosis and management of IVIG-induced chronic severe neutropenia with absolute neutrophil count <0.5×103/µL in a patient with multifocal motor neuropathy. Serial blood count showed a cyclical pattern of neutropenia: worsening 24-48 h post-IVIG, then gradually improving before the next infusion. IVIG-induced neutropenia is rare, with previous reports of predominantly mild transient neutropenia. Our case describes chronic severe neutropenia that developed years after starting IVIG. We summarize available evidence and management strategies for IVIG-associated neutropenia.

A Comprehensive Review of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome

Background: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare autoimmune disorder, characterized by acute tubulointerstitial nephritis and uveitis. It poses diagnostic challenges due to the mostly asynchronous onset of renal and ocular manifestations, as well as the variety of differential diagnoses. This review provides an overview of the epidemiology, pathogenesis, clinical features, diagnostic criteria, and management strategies. Methods: A comprehensive review of the peer-reviewed literature, including studies and case reports, was conducted. Results: The etiology of TINU syndrome involves an autoimmune reaction to renal and ocular antigens, leading to interstitial inflammation and tubular damage in the kidneys, and anterior uveitis with acute onset of flares. Diagnostic criteria based on ocular examination, laboratory parameters, and renal biopsy emphasize the need to exclude other systemic diseases. TINU syndrome accounts for approximately 2% of all uveitis cases. Primary treatment consists of corticosteroids, while immunomodulatory therapies (methotrexate, azathioprine, mycophenolate mofetil, or biologic agents) are reserved for refractory cases. Recurrence of uveitis appears to be more common than that of nephritis. Conclusions: TINU syndrome is rare and requires clinical suspicion for accurate diagnosis. Early diagnosis and initiation of treatment are crucial for achieving favorable outcomes. Advances in the understanding of its pathogenesis and treatment have improved patient outcomes. Further research is needed to investigate the underlying triggers and mechanisms in order to develop targeted therapies.

Immunotherapy in Type 1 Diabetes: Emerging Therapies and Future Directions

Type 1 Diabetes Mellitus (T1D) is an autoimmune disordermarked by the destruction of insulin-producingpancreatic beta-cells. While insulin therapy remains thestandard of care, advancements in immunotherapypresent promising alternatives aimed at halting diseaseprogression and reducing insulin dependence. This briefreview highlights key immunomodulatory therapies,including teplizumab, which has demonstrated the abilityto delay the onset of T1D, and rituximab, known forpreserving beta-cell function, though its effects tend to betransient. Emerging treatments, such as stem-celltherapies, also show potential. However, significantchallenges remain, including high costs, long-term safetyconcerns, and the need for personalized care. As thistherapeutic landscape evolves, further research is criticalto optimizing these strategies and moving closer to apotential cure for T1D.Keywords: Type 1 diabetes mellitus, autoimmunity,immunotherapy, anti-CD3 monoclonal antibody,teplizumab,

P0658 Comparison of the Efficacy and Safety of Immunomodulator Use in Geriatric and Non-Geriatric Patients with Inflammatory Bowel Disease

Abstract Background The patterns of medication use among elderly inflammatory bowel disease patients vary due to several factors. This study aims to present the outcomes of immunomodulator therapy in both geriatric and non-geriatric patient groups, highlighting differences in treatment effectiveness, reasons for discontinuation, and the incidence of side effects between the two groups. Methods A retrospective database was established by reviewing the records of inflammatory bowel disease patients aged 18 and older who received immunomodulator therapy at our clinic over a seven-year period. Patients aged 65 years and above were designated as the geriatric cohort. In addition to demographic and clinical variables, disease activity in ulcerative colitis patients was assessed using the Mayo Disease Activity Index and the Rachmilewitz Endoscopic Activity Index, while the Harvey-Bradshaw Index was employed for Crohn’s disease patients. Results The study included 102 patients, comprising 44 with ulcerative colitis and 58 with Crohn’s disease. The median age was 66.5 years (range: 23–87), with 54 patients (52.94%) classified as geriatric (≥65 years). Immunomodulator therapy was discontinued due to side effects in 31 patients (30.39%) and due to remission in 11 patients (10.78%). Additionally, 23 patients (24.21%) showed no response to the treatment. No significant differences were observed between the geriatric and non-geriatric groups regarding the type of inflammatory bowel disease, duration of therapy, concomitant treatments, reasons for discontinuation, side effects, malignancy occurrence, malignancy type, or mortality. Conclusion With careful patient selection and close monitoring, immunomodulator therapy in elderly inflammatory bowel diseasepatients can achieve similar effectiveness and risk of side effects as observed in younger patient groups.