DLL3 expression

Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.

Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.

Integrating CellSearch, DEPArray, and low-pass sequencing provides a minimally-invasive approach to compare genomic characteristics in DLL3-positive and negative CTCs from SCLC patients. Extension of this approach to a larger patient cohort and employing machine learning algorithms will facilitate identification of patterns within diverse CNA profiles, improving patient stratification and predicting treatment responses for personalized therapeutic strategies in SCLC.

This study highlights the discordance of subtype-specific proteins and therapeutic markers between SCLC primary tumors and LN metastases. Additionally, our findings have therapeutic and prognostic implications and warrant further clinical investigation.

P1/2, N=30, Recruiting, Boehringer Ingelheim | Trial completion date: Oct 2024 --> Feb 2025 | Trial primary completion date: Oct 2024 --> Feb 2025

In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.

P1, N=35, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented.

P1, N=250, Recruiting, Boehringer Ingelheim | Trial completion date: Sep 2024 --> Jul 2025

P1, N=35, Not yet recruiting, Boehringer Ingelheim | Trial completion date: Nov 2025 --> Aug 2026 | Trial primary completion date: Oct 2025 --> Aug 2026

No abstract available

There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.

P=N/A, N=41, Recruiting, Memorial Sloan Kettering Cancer Center | N=31 --> 41

Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.

Our results provide clinical insights into the diagnostic, prognostic and predictive significance of SCLC molecular subtype classifications.

While treatment with platinum and etoposide chemotherapy and a programmed death-ligand 1 (PD-L1) inhibitor has modest benefit for a subset of patients, most patients develop resistance and relapse. The increased cytotoxic activity observed with the combination of tarlatamab and chemotherapy and/or anti-PD-L1 treatment suggests that tarlatamab may be used together with standard of care therapy to increase response rate or durability. These data support the continued clinical evaluation of tarlatamab in patients with SCLC, including in combination with chemo-immune therapy in the first-line setting.

Furthermore, the tumor lysing capacity of CD70 armored CAR-T cells was not compromised to TGF-β (transforming growth factor β) inhibition compared to the conventional CAR-T cells. Conclusions Collectively, our study indicates a combine of a proximal targeting CAR and an armored CD70 construct improve CAR-T persistence and antitumor activity in vitro and in vivo, and result in a potential DLL3 CAR candidate for further preclinical and clinical studies.

Although SCLC with DLL3 had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

Delta-like ligand 3 (DLL3)-targeted drug Rova-T was terminated due to insufficient efficacy, considering other factors that may affect efficacy...In addition, patients were divided into low-risk and high-risk for survival analysis based on the best cut-off value of 49.11 for nomogram, indicating that the model had great discrimination ability (mOS 13.33 vs. 7.80m, p<0.001). Table: 2018P Conclusions The OS prediction model for SCLC patients in this study has excellent predictive performance in predicting the 12-m survival probability and may assist clinicians in making more accurate judgments and guiding therapy of SCLC patients.

In the dose escalation part, the primary endpoint is dose-limiting toxicity (DLT) occurrence in the MTD evaluation period; secondary endpoints include DLT occurrence in the on-treatment period, objective response and pharmacokinetics. Enrolment is ongoing.

Conclusions High DLL3 expression is associated with poor overall survival, advanced pathologic grade, and distinct immune landscape. Further development of DLL3-targeted therapies for high-grade NENs is warranted.

Future planned cohorts include every other week dosing and HPN328 + atezolizumab. Updated safety and efficacy results including pts recently enrolled in backfill cohorts will be presented.

Gastric NET G3 is a distinct entity with unique genetic characteristics, which are different from those of gNEC than gNET G2. Our results provide insight into some molecular alterations that may contribute to the development and progression of gNET G3 and serve as potential therapeutic targets.

P1, N=193, Recruiting, Boehringer Ingelheim | Trial completion date: Apr 2024 --> Sep 2024 | Trial primary completion date: Apr 2024 --> Sep 2024

P1, N=35, Not yet recruiting, Boehringer Ingelheim

P=N/A, N=31, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2026 | Trial primary completion date: Jun 2023 --> Jun 2026

P1, N=58, Recruiting, Phanes Therapeutics | Not yet recruiting --> Recruiting | Initiation date: Jan 2023 --> Jun 2023

P1/2, N=30, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.

P1b, N=41, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=100 --> 41 | Trial completion date: Apr 2027 --> May 2025 | Trial primary completion date: Apr 2026 --> Mar 2023

P1/2, N=30, Not yet recruiting, Boehringer Ingelheim

P1, N=190, Recruiting, Boehringer Ingelheim | N=110 --> 190

P1b, N=100, Recruiting, Amgen | N=60 --> 100 | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Oct 2023 --> Apr 2026

Lastly, human IL-18-secreting anti-DLL3 CAR T cells showed an increased memory phenotype, less exhaustion and induced durable responses in multiple SCLC models, an effect that could be further enhanced with anti-PD-1 blockade. Together, these results define DLL3-targeting CAR T cells that produce IL-18 as a promising novel strategy against DLL3-expressing solid tumors.

The SLR findings indicate that most studies assessing DLL3 in SCLC have relied on IHC methodology. Despite the range of thresholds used for evaluating positivity, DLL3 is notably expressed in SCLC. The frequency and impact of aberrant DLL3 localization was not addressed in these studies and minimal data on comparison of IHC with other methodologies exists.

We retrospectively reviewed post-surgical limited-stage (LS)-SCLC, and extensive-stage (ES)-SCLC patients treated with platinum and etoposide (PE) plus anti-PD-L1 antibody... SCLC with high DLL3 expression was characterized by resistance to immunochemotherapy due to suppressed tumor immunity, although those tumors had higher neoantigen loads.

P1/2, N=162, Recruiting, Harpoon Therapeutics | N=57 --> 162 | Trial completion date: Mar 2023 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Jan 2024

Atezolizumab and durvalumab, anti-PD-L1 antibodies, are approved in combination with platinum-doublet chemotherapy as part of front-line therapy for extensive-stage SCLC. These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combinatorial approach in patients. Clinical studies of HPN328 in combination with atezolizumab are planned.

Concomitant with anti-tumor immune response, we detected increases in memory T cells in the spleens of mice previously treated with HPN328. Together these results indicate that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, suggest a novel mechanism for its activity and efficacy in vivo.

Targeting SCLC cell surfaceome with cellular therapies have shown promising efficacy and tolerability in DLL3-targeting CAR T (AMG119) and Bispecific T-cell engager (tarlatamab)...Moreover, given that novel therapeutics are often tested in the relapsed setting, we tested target expressions in SCLC cell lines after treatment with cisplatin and etoposide (standard frontline chemotherapy for SCLC) to see if target levels change. This study demonstrated efficacy of CAR Ts targeting several cell surfaceome targets enriched in certain subtypes of SCLC. The data supports further investigation of a subtype-specific personalized treatment of SCLC using CAR T therapies against surfaceome targets.