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CD98 heavy chain protein is overexpressed in non-small cell lung cancer and is a potential target for CAR T-cell
Moto Yaga1,2, Kana Hasegawa3, Shunya Ikeda4
1Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Abstract:
Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for non-small cell lung cancer (NSCLC) by targeting CD98 heavy chain (hc). R8H283-derived CAR T-cells demonstrated significant anti-tumor effects in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is highly effective against hematological malignancies but faces challenges in treating solid tumors like non-small cell lung cancer (NSCLC).
- Limited identification of specific cell surface targets on NSCLC hinders CAR T-cell efficacy.
Purpose of the Study:
- To identify novel cell surface targets for CAR T-cell therapy in NSCLC.
- To evaluate the therapeutic potential of CAR T-cells targeting CD98 heavy chain (hc) in NSCLC.
Main Methods:
- Screening of over 10,000 monoclonal antibody (mAb) clones against NSCLC cell lines.
- Development and testing of CAR T-cells derived from anti-CD98hc mAbs (H2A011 and R8H283).
- In vivo efficacy assessment using a xenograft NSCLC model.
Main Results:
- CD98 heavy chain (hc) protein was identified as overexpressed on NSCLC cells.
- CAR T-cells derived from anti-CD98hc mAb R8H283 showed specific reactivity against NSCLC cells from patients and exerted significant anti-tumor effects in vivo.
- CAR T-cells derived from mAb H2A011 could not be established due to T-cell reactivity issues.
Conclusions:
- CD98hc is a potential target for CAR T-cell therapy in NSCLC.
- R8H283-derived CAR T-cells represent a promising new therapeutic strategy for NSCLC.
- Further investigation into off-tumor reactivity is warranted.
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