Lou, Yanyan

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

e20595 Background: Circadian regulation of immune function has been proposed as a modifier of immune checkpoint inhibitor (ICI) efficacy, with retrospective studies suggesting improved outcomes with earlier infusion timing. Whether these findings translate to routine oncology practice, where ICIs are administered across multiple lines, frequently combined with chemotherapy, and subject to treatment interruptions, remains uncertain. We evaluated the association between ICI infusion timing and overall survival (OS) in a real-world cohort of patients with non-small cell lung cancer (NSCLC). Methods: A retrospective cohort study included adults with NSCLC who received at least one line of ICI therapy at a community oncology center between January 2018 and December 2024. Infusion timing was defined at the patient level as morning-only ( < 1300 hours), evening-only (≥1300 hours), or mixed timing, reflecting receipt of infusions exclusively in different time-of-day categories across treatment lines. OS was measured from diagnosis to death or last follow-up. Kaplan-Meier and Cox proportional hazards models were used. Multivariable analyses adjusted for stage, ECOG performance status, body mass index, and premature ICI discontinuation. Line of therapy was excluded due to collinearity with mixed-timing classification and risk of immortal time bias. Results: A total of 127 patients were included (morning-only n = 77; mixed timing n = 36; evening-only n = 14). Staging data were available for 99.2%, and 94 deaths occurred. Median OS was 495 days for morning-only, 850 days for mixed timing, and 388 days for evening-only patients. Kaplan-Meier analysis showed no statistically significant OS differences across groups. In sensitivity analysis excluding patients with mixed infusion timing, morning-only and evening-only groups demonstrated overlapping survival curves, with no evidence of a time-of-day–specific survival advantage. In univariate analysis, mixed timing was associated with a borderline reduction in mortality compared with morning-only infusions (HR 0.63, 95% CI 0.39-1.00), while evening-only timing was not (HR 1.63, 95% CI 0.85-3.16). In multivariate analysis restricted to stage III-IV disease, infusion timing was not independently associated with OS. ECOG performance status, premature ICI discontinuation and advanced staging were the strongest predictors of mortality. Conclusions: In this real-world NSCLC cohort, ICI infusion timing was not independently associated with overall survival after adjustment for patient fitness and treatment continuity. These findings suggest that in pragmatic settings, clinical factors may outweigh subtle chronotherapy effects reported in more selected populations.

e18149 Background: Laryngeal neuroendocrine carcinoma (LNEC) is rare and biologically heterogeneous. The independent prognostic roles of tumor differentiation and stage remain incompletely defined. Methods: Patients diagnosed with LNEC (2000–2022) were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were estimated using a Kaplan–Meier analysis. Tumor differentiation (Diff) was harmonized across SEER grade fields: legacy Grade Recode (through 2017) was used when available; otherwise, Grade Clinical/Pathological (2018+) codes (1=well, 2=moderate, 3=poor, 4=undifferentiated) defined Diff. Multivariable Cox regression adjusted for stage, Diff, age, and sex. Cases with missing survival time, stage, or Diff were excluded (n=97). Results: The cohort included 157 patients (median age 63 years; 63% male). Diff was well in 4%, moderate in 29%, poor in 34%, and undifferentiated in 12% of patients. At diagnosis, 22% of patients had localized, 27% had regional, and 28% had distant disease. Treatments included surgery in 31%, chemotherapy in 42%, and adjuvant radiation in 13% of patients. Median OS differed significantly by Diff, ranging from 52.5 months (mo) for well, 90 mo for moderate, 12 mo for poor, and 17 mo for undifferentiated (p<0.001). Five-year OS was 50%, 58%, 23%, and 37%, respectively, with a similar gradient for CSS (p=0.001). Survival remained differentiation-associated within surgical (p=0.004) and chemotherapeutic subgroups (p<0.001). Median OS by stage was 96 mo for localized disease, 30 mo for regional nodes only, 8.5–7.5 mo for regional direct extension ± nodes, and 11 mo for distant disease. On multivariable analysis, stage and differentiation—driven primarily by poorly differentiated tumors—were independently associated with OS. Conclusions: Both tumor differentiation and stage independently predicted survival in LNEC, indicating that tumor biology and anatomic extent each contribute to prognosis. Outcomes remain suboptimal in poorly differentiated and advanced-stage LNEC, underscoring the need for treatment optimization and clinical trial development. Variable HR (95% CI) p Differentiation (Diff) Moderate vs Well 1.76 (0.49–6.31) 0.39 Poor vs Well 6.11 (1.63–22.93) 0.007 Undifferentiated vs Well 2.28 (0.60–8.76) 0.23 Stage Nodes only vs Localized 2.21 (1.14–4.38) 0.023 Direct extension only vs Localized 14.04 (2.44–80.97) 0.003 Direct + nodes vs Localized 7.49 (3.19–17.63) <0.001 Distant vs Localized 3.34 (1.63–6.83) 0.001 Male vs Female 2.28 (1.34–3.89) 0.002