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Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer
Yi Zhang1, Silvia K Tacheva-Grigorova1, Janette Sutton1
1Allogene Therapeutics, South San Francisco, California.
Purpose:
Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications.
Experimental Design:
A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells.
Results:
A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated.
Conclusions:
In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.
Insights
CAR T-cells targeting Delta-like ligand 3 (DLL3) show promising preclinical efficacy against small cell lung cancer (SCLC). These DLL3 CAR T-cells demonstrated potent anti-tumor activity without significant brain or pituitary toxicity in mouse models.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic strategies.
- Delta-like ligand 3 (DLL3) is a tumor-associated antigen highly expressed in SCLC and other neuroendocrine tumors.
- DLL3's restricted expression in normal tissues presents an opportunity for targeted cancer therapies.
Purpose of the Study:
- To evaluate the preclinical efficacy and safety of chimeric antigen receptor (CAR) T-cells targeting DLL3 (DLL3 CAR T-cells) for SCLC treatment.
- To assess the potential for on-target, off-tumor toxicities, particularly in the brain and pituitary gland.
Main Methods:
- Characterization of a panel of anti-DLL3 scFv-based CAR T-cells for in vitro and in vivo activity.
- Establishment of DLL3-expressing tumors in mice (subcutaneous and intracranial models).
- Treatment of tumor-bearing mice with DLL3 CAR T-cells to evaluate anti-tumor efficacy and assess potential toxicities.
Main Results:
- Selected DLL3 CAR T-cells exhibited high sensitivity and long-term killing capacity against low-DLL3 expressing targets in vitro.
- In vivo administration of DLL3 CAR T-cells resulted in significant anti-tumor responses, including complete regressions in SCLC models.
- CAR T-cell infiltration into the pituitary was observed, but no discernible tissue damage or ablation of pituitary function occurred.
Conclusions:
- Preclinical data support the potential of DLL3 CAR T-cells as a viable therapeutic candidate for SCLC.
- The observed safety profile, with no significant neurotoxicity or pituitary dysfunction, warrants further clinical investigation.
