Abstract CT058: Final results of a first-in-human (FIH) study of intratumoral pan-ErbB-targeted CAR-T cell therapy for head and neck squamous cell carcinoma (HNSCC): T4 immunotherapy

Abstract Background: Advanced HNSCC has a dismal prognosis despite multiagent treatment. Epidermal growth factor receptor (EGFR, ErbB-1) is upregulated in most tumors, although EGFR-targeted therapy yields modest benefit. Other ErbB family members are commonly co-expressed, providing a rationale for targeting of the extended ErbB network in HNSCC. We present final toxicity and response data for this FIH dose escalation trial of intratumorally administered pan-ErbB-targeting CAR-T cells (T4 immunotherapy) in patients (pts) with advanced HNSCC. Methods: Eligible pts had locally advanced, recurrent or metastatic HNSCC (excluding brain), accessible tumor site(s) for T4 administration and radiologically measurable disease. Peripherally harvested T cells were transduced to co-express pan-ErbB-targeting CAR T1E28ζ and chimeric IL-4/IL-2 receptor 4αβ. Cells were expanded ex vivo in IL-4 to generate T4 immunotherapy, which was injected as a fresh product into single or multiple locoregional tumor sites. Doses ranged from 1×107 to 1×109 cells across 7 cohorts, using 3+3 dose escalation in cohorts 1-5. Cohorts 6 and 7 received 1×108 cells preceded by lymphodepleting (LD) cyclophosphamide and fludarabine chemotherapy. Cohort 7 received additional nivolumab 480mg q4w for 3 cycles. Primary endpoint was dose limiting toxicity (DLT) within 28d. Secondary endpoints included radiologic response at 6w, presence of tumoral and circulating T4+ T cells and serum and tumoral immunomodulatory markers. Results: 19 pts (median age, 62; M:F,15:4) received T4 immunotherapy: 3 in each cohort 1-6 and 1 in cohort 7. Site of origin was oral cavity in 11 (57.9%), oropharynx, 4 (21.1%); nasopharynx, 2 (10.5%); hypopharynx and occult primary 1 each (5.3%). Pts had received a median of 2 (1-5) prior treatment lines. No DLTs were observed. All pts experienced TRAEs, largely G1/2; most common were local swelling, pain or infection, fever, CRS, chills, fatigue and nausea, with cytopenias in LD cohorts. Of 4 instances of CRS, 3 were G1 and 1 was G2. At 6 weeks, 10 pts (52.6%) had stable disease and 9 (47.4%) had progressed, with no association with T4 dose, LD or nivolumab. There were no radiologic responses though softer tumor consistency was noted in several pts. Median overall survival (mOS) was >10m. Subsequent treatments included palliative radiotherapy, chemotherapy +/- cetuximab, electrochemotherapy or trial in 8 pts; no treatment, 4; unknown, 3. One pt had a durable complete response to subsequent local injection of talimogene laherparepvec with pembrolizumab. Conclusions: Intratumoral pan-ErbB-directed CAR-T cell injection was well tolerated and associated with disease stability in heavily pretreated HNSCC. mOS was longer than that expected for this cohort. The lack of radiologic responses highlights the need for improved advanced cell therapies for solid tumors. Citation Format: Cienne Morton, Fiona Wang, Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, Fiona Reid, Maria Elstad, Nicholas Beckley-Hoelscher, Abdel Douiri, Marc Delord, Mike Lyne, Dharshene Shivapatham, Aysar Al-Rawi, Christopher Fisher, Andrew Hope, Sakina Gooljar, Arindam Mitra, Linda Gomm, Ana C. Parente-Pareira, David M. Davies, Farzin Farzaneh, Teresa Guerrero-Urbano, Jean-Pierre Jeannon, James Spicer, John Maher. Final results of a first-in-human (FIH) study of intratumoral pan-ErbB-targeted CAR-T cell therapy for head and neck squamous cell carcinoma (HNSCC): T4 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT058.