2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.14: Combination surface targeting strategies in relapsed small cell lung cancer (SCLC) to overcome intratumoral heterogeneity associated with treatment resistance

PP01.14: Combination surface targeting strategies in relapsed small cell lung cancer (SCLC) to overcome intratumoral heterogeneity associated with treatment resistance

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The document reports on a study investigating novel therapeutic strategies for relapsed small cell lung cancer (SCLC), focusing on overcoming intratumoral heterogeneity that contributes to treatment resistance. The study thanks numerous funding sources, including the NIH/NCI, DOD, CPRIT, and various foundations. The research was primarily conducted at the University of Texas MD Anderson Cancer Center.<br /><br />SCLC typically shows early spread and transient responses to initial chemotherapy and immune checkpoint inhibitors, but is marked by rapid relapses. New therapeutic paradigms target specific cell surface proteins with methods such as bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cells. A promising example is Tarlatamab—an approved DLL3-targeting BiTE that yields sustained responses in some patients.<br /><br />The study hypothesizes that targeting multiple surface proteins simultaneously using diverse strategies—such as BiTEs combined with ADCs—can address intratumoral heterogeneity and enhance antitumor responses. To test this, the team analyzed biopsies and patient-derived xenografts (PDXs) from relapsed SCLC cases, employing techniques like bulk and single-cell RNA sequencing and surfaceome mass spectrometry to identify target protein expression.<br /><br />Key findings demonstrate that combined targeting of surface proteins like DLL3, TROP2, and HER2 with both immune and payload strategies is more effective than single-agent approaches in overcoming resistance in SCLC models. These strategies offer potential in targeting distinct cell populations, including drug-tolerant persister cells (DTPCs), revealed through mass spectrometry analyses.<br /><br />The study emphasizes the effectiveness of integrated therapeutic approaches, specifically combining CAR T-cells and ADCs for targeting mutually exclusive surface proteins, and underscores the utility of PDX-derived organoids for testing these strategies in vitro. Overall, this research suggests promising avenues for improving outcomes in patients with relapsed SCLC.

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C. Allison Stewart

Keywords

small cell lung cancer

intratumoral heterogeneity

treatment resistance

therapeutic strategies

bispecific T-cell engagers

antibody-drug conjugates

chimeric antigen receptor T-cells

DLL3-targeting

drug-tolerant persister cells

patient-derived xenografts