Citations

Abstract Background Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. Methods In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60. Results Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. Conclusions Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment. Clinical Trials Registration EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.

2598 Background: GI-102 (CD80-IL2v3) is a novel immunocytokine designed to direct IL-2v3 to immune cells and tumor cells. IL-2v3 of GI-102 abolished affinity to IL-2Rα minimizing the impact of IL-2 on Treg cells. Preferential targeting of immune cells and further inhibition of CTLA-4 and PD-L1 via CD80 synergize with potent activity of IL-2v3, resulting in robust proliferation and activation of CD8+ T and NK cells. Here we report preliminary safety and efficacy data of GI-102 from a phase 1/2a trial in patients with metastatic solid tumors. Methods: NCT05824975 is an ongoing, dose escalation (3+3 design) and expansion study to evaluate safety, tolerability, PK, PD and anti-tumor activity of GI-102. Each dose level allows to enroll additional 7 patients to fully inform the safety, PK and PD at that dose level. GI-102 was administered intravenously every 3 weeks until disease progression or unacceptable toxicities. Disease was assessed every 6 weeks using RECIST v1.1. Results: As of 12 Jan 2024, 32 patients were treated in dose escalation: 8 at dose level 0.06 mg/kg, 10 at 0.12 mg/kg, 9 at 0.24 mg/kg and 5 at 0.45 mg/kg. Patients had received median of 3 [1-7] prior lines of therapy, including 25.0% (8/32) who had received ≥ 5 lines and 68.8% (22/32) had experienced immune checkpoint blockade (ICB). No dose-limiting toxicities (DLTs) were observed until the highest dose of 0.45 mg/kg Q3W. The most common treatment-related adverse events (TRAEs, ≥ 10%) were pyrexia [43.8%] and chills [34.4%]. 5 patients [15.6%] had ≥ Grade 3 TRAEs and no patient reported TRAEs leading to discontinuation of GI-102. In 23 patients (7 cutaneous melanoma, 4 non-small cell lung cancer, 3 ovarian cancer and others) who had at least 1 post-treatment tumor assessment, objective responses were observed in 17.4% (4/23). In patients with metastatic melanoma who previously experienced ICB, overall response rate (ORR) and disease control rate (DCR) was 42.9% (3/7) and 85.7% (6/7), respectively, including 3 confirmed partial responses (cPR). The median time to response (TTR) was 6 weeks and duration of response (DoR) was 6.0+, 2.4+ and 1.7+ month, respectively. In patients with metastatic ovarian cancer, ORR and DCR were 33.3% (1/3) and 66.7% (2/3), respectively, including 1 cPR [TTR of 6 weeks; DoR 1.9+ month]. Preliminary PK profile showed target-mediated drug disposition with a half-life of ~48 hours. 0.24 mg/kg of GI-102 resulted in a significant expansion of peripheral lymphocytes, CD8+ T cells (effector & memory) and NK cells, by 4.4 [2.1-9.6], 3.9 [2.0–5.7] and 20.4 [9.5–32.6]-fold change from baseline, respectively. There was no meaningful increase in Treg cells. Conclusions: GI-102 was well tolerated up to dose of 0.45 mg/kg Q3W with meaningful monotherapy activity, regardless of previous ICB experience, in patients who failed on standard of care. The dose-escalation is currently ongoing to identify RP2D. Clinical trial information: NCT05824975 .

e19008 Background: Bispecific antibodies (BsAb) have emerged as a new treatment modality for relapsed/refractory non-Hodgkin lymphomas (R/R NHL). They exert their effect by binding to CD3 on T-cells and CD19 or CD20 on lymphoma cells, activating the T-cell to exert cytotoxic effects against the tumor and normal B-cells. Treatment related adverse events (TRAE) include infections, cytokine release syndrome (CRS), neurotoxicity (ICANS). This meta-analysis was conducted to assess prevalence of TRAEs from prospective clinical trials that evaluated BsAb in R/R NHL. Methods: A systematic review was conducted through PubMed, Embase, Scopus, Web of Science, and Cochrane to identify BsAb clinical trials in NHL through October 2023. Eligible studies included phase I-III trials evaluating BsAb in any type of NHL, either as monotherapy or combination therapy irrespective of prior lines of treatment. Primary outcomes of interest include infection, neutropenia, CRS, and ICANS. All studies were weighted equally. Pooled prevalence estimates of TRAE were calculated using common and random effects models. Heterogeneity tests were performed using Cochran’s Q test. Subgroup analysis examined infection rates in monotherapy versus combination therapy cohorts. Results: After screening 1039 studies, 36 clinical trials with 2162 patients were included. The lymphoma subtypes were diffuse-large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. The BsAbs included mosunetuzumab (13 studies), epcoritamab (10 studies), blinatumomab (5 studies), glofitamab (5 studies), odronextamab (2 studies), and AFM11 (1 study). The median age of patients was 66 years, and patients had received a median of two prior lines of therapy. Median follow-up duration was 9.1 months. The prevalence of all-grade infections was 35% (95% CI: 0.33-0.38; I2 = 79%). For grade ≥3 infections, the prevalence was 16% (95% CI: 0.14-0.18, (I2 = 77%). There were higher rates of all-grade infections in the combination therapy cohort (41%, 95% CI: 0.36-0.47) compared with the monotherapy cohort (33%, 95% CI: 0.30-0.36). All-grade and grade ≥3 neutropenia occurred in 31% (95% CI: 0.29-0.34; I2 = 80%) and 22% (95% CI: 0.20-0.24, I2 = 61%) of patients. CRS was observed in 45% of patients (95% CI: 0.43-0.48, I2 = 85%). Grade ≥3 CRS occurred in only 2% of patients (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). ICANS occurred in 12% (95% CI: 0.10-0.14, I2 = 90%) while grade ≥3 ICANS was rare, at 3% (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). Conclusions: BsAb is associated with nontrivial rates of infections and neutropenia. The rates of high grade CRS and ICANS are low. The heterogeneity of the findings could be attributed by an underreporting of TRAE and small sample sizes from various studies. These results highlight the need for vigilant practices to diagnose and treat infections early and consideration for antibacterial prophylaxis in this immunocompromised population.

5010 Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Abstract Chimeric antigen receptor T‐cell (CAR‐T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B‐cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR‐T therapy in older patients with RR LBCL in the real‐world setting. Patients aged ≥65 years with RR LBCL, treated with anti‐CD19 CAR‐T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65–89). Best objective and complete response rates were 86% and 62%, respectively. Median follow‐up after infusion was 18.3 months. The median progression‐free survival (PFS) was 6.9 months, with 6‐ and 12‐month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR‐T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR‐T in older patients, including those aged ≥80 years. The age at CAR‐T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR‐T therapy solely based on their chronological age.

Background: Cystic fibrosis (CF) is a genetic disorder in which patients have dysfunctional cystic fibrosis transmembrane regulatory (CFTR) proteins in the lungs that disrupt ion regulation resulting in a thick, viscous mucus layer on the airway epithelium. Consequential poor mucociliary clearance leads to repeated infections and chronic inflammation contributing to bronchiectasis which is associated with increased airway luminal area. CFTR modulator therapy can improve and even restore the function and expression of a mutated CFTR gene which has been shown to improve sweat chloride levels and pulmonary symptoms rapidly. However, the effect of CFTR modulator therapy on large conducting airway luminal area is unclear. We compared large conducting airway luminal area in patients with CF before and after initiating CFTR modulator therapy. We hypothesized that airway luminal area would normalize (decrease) after initiating CFTR modulator therapy. Methods: Twenty-three patients with CF (32±15 years, 11 female) with computed tomography (CT) imaging of their lungs before and after initiating CFTR modulator therapy were included in analyses. In each patient we measured seven large conducting airways (trachea, left and right main bronchus, bronchus intermediate, left and right upper lobe, and left lower lobe) before and after CFTR modulator therapy initiation. To control the potential effect of height, airway luminal area (mm2) was divided by patient height (cm). Paired t-tests compared differences between luminal area before after initiating CFTR modulator therapy. Results: Patients were taking CFTR modulator therapy for a median of 1.1 years (range: 22–2111 days) at the time of their CT imaging after initiating CFTR modulator therapy. Large conducting airway luminal area was not different before and after initiating CFTR modulator therapy in all seven airways: trachea (1.50±0.35 vs. 1.56±0.34 mm2/cm, p=0.14), right main bronchus (1.05±0.21 vs. 1.09±0.19 mm2/cm, p=0.11), bronchus intermediate (0.68±0.16 vs. 0.68±0.16 mm2/cm, p=0.54), right upper lobe (0.42±0.10 vs. 0.45±0.09 mm2/cm, p=0.27), left main bronchus (0.81±0.19 vs. 0.83±0.18 mm2/cm, p=0.21), left upper lobe (0.51±0.13 vs. 0.52±0.13 mm2/cm, p=0.45), and left lower lobe (0.44±0.11 vs. 0.46±0.10 mm2/cm, p=0.42). Conclusion: There was no change in large conducting airway luminal area after initiating CFTR modulator therapy suggesting CFTR modulator therapy may not reverse CF-associated airway luminal area changes. However, longitudinal analysis and investigation into the small airways are necessary for a comprehensive understanding of the effect of CFTR modulator therapy on airway luminal area changes. Funding: NIH (HL139854 to MJJ, HL131151 to SEB) and NSERC (PDF-577750-2023 to AHR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.