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Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at the locally advanced stage and show heterogeneous tumor response, including therapy resistance. Previously, we showed that low SLC3A2 mRNA and low expression levels of its protein product CD98hc are associated with better locoregional control in patients with HNSCC treated with primary radiochemotherapy or postoperative radiochemotherapy (1,2). This suggests that CD98hc could be a target for HNSCC radiosensitization. One of the strategies for tumor radiosensitization is targeted immunotherapy. However, Chimeric Antigen Receptor (CAR)-equipped T-cell therapy cannot be fully controlled. Therefore, the switchable Universal CAR (UniCAR) system was developed (3, 4) that is currently in phase I clinical trial (NCT04230265) (5). UniCAR T cell activity and specificity are controlled by the presence of target modules (TM). Our previous proof-of-concept study showed that eradicating CD98hc positive cells by retargeted UniCAR T cells significantly inhibited tumor growth in mice xenograft models (6). We aim to define the clinical value of new treatment approaches by combining radio(chemo)therapy with CD98hc-targeted immunotherapy.

We have used previously described radioresistant Cal33 HNSCC cells for spheroid formation (2). These spheroids were co-cultured with UniCAR T cells in the presence or absence of a novel CD98 TM as a monotherapy or combined with radio(chemo)therapy. Specific cell lysis and viable cell percentage after UniCAR treatment as well as CD3⁺ T cell infiltration and T cell activation were assessed as described previously (6,7).  

Our data show that CD98hc-redirected UniCAR T cells can induce significant cell lysis of radioresistant Cal33 spheroid in vitro. Combination therapies of immunotherapy and radio(chemo)therapy increased the efficacy of the treatment resulted in the disintegration of the spheroids. We demonstrated enhanced infiltration of CD3⁺UniCAR T cells in the presence of CD98TM. The validation of these results for other HNSCC cell lines is ongoing.

Overall, we showed that radioresistant Cal33 spheroids can be significantly eliminated via the UniCAR system and combination therapies including radiotherapy and radiochemotherapy. This system can be used to approach the combination of the UniCAR system with radio(chemo)therapy for synergistic improvement of treatment efficacy of patients with metastatic radioresistant tumors. The most promising combination of the therapeutic approach will be further tested in xenograft tumor models to evaluate the best performing combination of immunotherapy and radio(chemo)therapy.

References:

1. Linge A, et al., Clin Cancer Res. 2016.

2. Digomann D, et al., Clin Cancer Res. 2019.

3. Koristka S, et al., Blood. 2014.

4. Bachmann M, et al., Immunol Lett. 2019.

5. Wermke M. et al., Blood. 2021.

6. Arndt C, et al., Oncoimmunology. 2020.

7. Zboralski D, et al., Cancer Immunol Res. 2017.