OPTIMIZATION OF TSHR-CART CELL THERAPY TO TRANSLATE INTO A FIRST IN HUMAN PHASE I CLINICAL TRIAL IN METASTATIC THYROID CANCERS

• Published in: Cytotherapy (Oxford, England) England), 2024-06, Vol.26 (6), p.S182-S183
• Main Authors: Roman, C. Manriquez, Siegler, E., Demirer, A. Alasonyalilar, Pawlush, M., Huynh, T.N., Mai, L.K., Tapper, E., Sakemura, R., Stewart, C.M., Can, I., Sirpilla, O.L., Yun, K., Ogbodo, E.J., Olivier, G.R., Allickson, J., Copland, J.A., Kenderian, S.
• Format: Article
• Language: English
• Subjects: CART cells; MAPK inhibitors; Thyroid cancer
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2024.03.361

Thyroid cancer is the most common endocrine cancer in the US, and its incidence is rising. Most thyroid cancer deaths are due to treatment-refractory, metastatic tumors. Thyroid stimulating hormone receptor (TSHR) expression is largely limited to the thyroid gland and is abundantly expressed on thyroid tumor cells, making TSHR a compelling target for advanced thyroid cancer diagnostics and therapeutics. Here, we generated novel TSHR-targeted chimeric antigen receptors (CAR), tested TSHR-CART cell activity in preclinical models, selected a lead candidate, and initiated product development work. We also identified TSHR downregulation in anaplastic thyroid cancers (ATC) as a potential escape mechanism to TSHR-CART cells. To overcome this downregulation, we developed a strategy to combine TSHR-CART cells with mitogen-activated protein kinase inhibitors (MAPKi), which upregulate TSHR expression and enhances TSHR-CART cell activity. Healthy donor T cells were lentivirally transduced to express TSHR-CARs. TSHR-CART cells cocultured with TSHR+ thyroid cancer cells showed potent antigen-specific killing and proliferation (Fig. 1A-B). Treatment of NOD-SCID-γ-/- (NSG) mice bearing subcutaneous TSHR+ thyroid tumors with TSHR-CART cells led to dose-dependent antitumor activity and prolonged survival compared to unstransduced (UTD) cells (Fig. 1C-D). We then selected a lead CAR to advance to a phase I clinical trial. Next, we developed a strategy to target ATC with downregulated TSHR (confirmed by immunohistochemistry of patient biopsies, Fig. 1E). We sought to restore TSHR expression with MAPKi to sensitize ATC to TSHR-CART cells. TSHR expression was upregulated in patient-derived xenograft (PDX) ATC models after one week of daily MAPKi administration (Fig. 1F). Finally, we tested combination therapy of TSHR-CART and MAPKi in vivo. NSG mice engrafted with ATC PDX tumors received daily oral treatment with placebo or MAPKi. One week later, mice received either UTD or TSHR-CART and either stopped MAPKi treatment or continued until study endpoints. Antitumor activity was improved with MAPKi and TSHR-CART combination treatment vs monotherapy but was superior with continuous MAPKi treatment and TSHR-CART (Fig. 1G). Our data show that MAPKi upregulated TSHR expression in de-differentiated thyroid cancers and enhanced TSHR-CART antitumor activity. This work represents a viable strategy to improve outcomes of patients with metastatic thyroid cancers of different histologies.