Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth.

Abstract

BACKGROUND:

Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell.

METHODS:

As a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated.

RESULTS:

In vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells.

CONCLUSIONS:

Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.

• Authors: Xin Chen, Norhan Amar, Yuankui Zhu, Chunguang Wang, Chunjiao Xia, Xiaoqing Yang, Dongde Wu, Mingqian Feng
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (06 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32554616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Bispecific
• Antineoplastic Agents, Immunological
• DLL3 protein, human
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Chimeric Antigen

Topics

• Animals
• Antibodies, Bispecific (pharmacology, therapeutic use)
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Synergism
• Humans
• Immunotherapy, Adoptive (methods)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, immunology)
• Lung Neoplasms (immunology, pathology, therapy)
• Membrane Proteins (antagonists & inhibitors, immunology)
• Mice
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Proof of Concept Study
• Receptors, Chimeric Antigen (immunology)
• Small Cell Lung Carcinoma (immunology, pathology, therapy)
• T-Lymphocytes (drug effects, immunology, transplantation)
• Xenograft Model Antitumor Assays