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Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer
Loïc Reppel1, Ourania Tsahouridis1, Jason Akulian2
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
Background:
We explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells.
Methods:
GD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated.
Results:
GD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity.
Conclusions:
GD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.
Insights
Disialoganglioside GD2 (GD2) is expressed in lung cancers and can be targeted by chimeric antigen receptor (CAR) T cells. Epigenetic drug treatment can increase GD2 expression, improving CAR T-cell therapy efficacy.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Disialoganglioside GD2 (GD2) is a cell surface antigen implicated in various cancers.
- The expression of GD2 in small cell lung cancer (SCLC) and non-SCLC (NSCLC) requires further investigation for targeted therapy.
- Chimeric antigen receptor (CAR) T-cell therapy offers a promising avenue for cancer treatment by engineering T cells to target specific antigens.
Purpose of the Study:
- To determine the expression of GD2 in SCLC and NSCLC.
- To evaluate the potential of GD2-specific CAR T cells as a therapeutic strategy for lung cancer.
- To investigate methods for enhancing GD2 expression on lung cancer cells to improve CAR T-cell targeting.
Main Methods:
- GD2 expression was assessed in lung cancer cell lines and tumor biopsies using flow cytometry and immunohistochemistry.
- GD2-specific CAR T cells, engineered with IL-15 for persistence and an inducible caspase 9 safety switch, were developed.
- Antitumor activity was evaluated through in vitro co-cultures and in vivo xenograft models. The effect of epigenetic drugs on GD2 expression was also studied.
Main Results:
- GD2 was detected on a subset of SCLC and NSCLC cell lines and in a significant percentage of tumor biopsies.
- GD2.CAR-T cells demonstrated antigen-dependent cytotoxicity against GD2-expressing lung tumors in vitro and in vivo.
- Pretreatment with the EZH2 inhibitor tazemetostat upregulated GD2 expression on GD2-low/negative lung cancer cells, enabling CAR T-cell-mediated killing.
Conclusions:
- GD2 represents a viable therapeutic target for CAR T-cell therapy in lung cancer.
- Enhancing GD2 expression through epigenetic modulation, such as with tazemetostat, can sensitize lung tumors to GD2-targeted CAR T-cell therapy.
- This approach holds potential for treating lung cancers that initially exhibit low GD2 expression.
