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Advances in adoptive cell therapies in small cell lung cancer
Eljie Isaak Bragasin1, Justin Cheng1, Lauren Ford1
1Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Abstract:
Small cell lung cancer (SCLC) is an aggressive tumor characterized by early metastasis and resistance to treatment, making it a prime target for therapeutic investigation. The current standard of care for frontline treatment involves a combination of chemotherapeutic agents and immune checkpoint inhibitors (ICIs), though durability of response remains limited. The genetic heterogeneity of SCLC also complicates the development of new therapeutic options. Adoptive cell therapies show promise by targeting specific mutations in order to increase efficacy and minimize toxicity. There has been significant investigation in three therapeutic classes for application towards SCLC: antibody drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR)-T cell therapies. This review summarizes the recent advances and challenges in the development of adoptive cell therapies. Genetic targets such as delta-like ligand 3 (DLL3), trophoblast cell surface antigen 2 (Trop2), B7-H3 (CD276), gangliosides disialoganglioside GD2 (GD2) and ganglioside GM2 (GM2) have been found to be expressed in SCLC, which makes them prime targets for therapy development. While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC.
Insights
Adoptive cell therapies offer new hope for aggressive small cell lung cancer (SCLC). Targeting specific mutations with agents like CAR-T cells and ADCs shows promise for improved efficacy and reduced toxicity in SCLC treatment.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Therapeutics
Background:
- Small cell lung cancer (SCLC) is highly aggressive, characterized by early metastasis and treatment resistance.
- Current standard treatments (chemotherapy + immune checkpoint inhibitors) offer limited response durability.
- Genetic heterogeneity in SCLC poses challenges for developing effective therapies.
Purpose of the Study:
- To review recent advances and challenges in adoptive cell therapies for SCLC.
- To highlight promising therapeutic strategies targeting specific SCLC mutations.
- To discuss the potential of antibody drug conjugates, bispecific T-cell engagers, and CAR-T cells in SCLC treatment.
Main Methods:
- Review of current literature on adoptive cell therapies for SCLC.
- Identification of key genetic targets expressed in SCLC, including DLL3, Trop2, B7-H3, GD2, and GM2.
- Analysis of clinical trial outcomes for novel SCLC therapeutic agents.
Main Results:
- Several genetic targets (DLL3, Trop2, B7-H3, GD2, GM2) are identified as promising for SCLC therapy.
- While some therapies like Rova-T have failed, insights have driven development of new agents.
- Promising agents include sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells.
Conclusions:
- Adoptive cell therapies, including ADCs, BiTEs, and CAR-T cells, show significant promise for SCLC treatment.
- Overcoming challenges requires improved molecular testing and refined targeted approaches.
- Continued investigation into novel agents and targets is crucial for advancing SCLC therapy.
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