Design of a Phase I Clinical Trial to Evaluate Intratumoral Delivery of ErbB-Targeted Chimeric Antigen Receptor T-Cells in Locally Advanced or Recurrent Head and Neck Cancer

Abstract

Despite several advances, 5-year survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unchanged at only 50%. The commonest cause of death is locally advanced/recurrent disease. Consequently, there is an unmet need for new approaches to improve local control in HNSCC. T4 immunotherapy is an autologous cell therapy in which peripheral blood T-cells are genetically engineered using a retroviral vector to coexpress two chimeric receptors: (i) T1E28z is a chimeric antigen receptor that engages multiple ErbB dimers that are commonly upregulated in HNSCC; (ii) 4αβ is a chimeric cytokine receptor that converts the weak mitogenic stimulus provided by interleukin (IL)-4 into a strong and selective growth signal, allowing preferential expansion and enrichment of T4⁺ T-cells ex vivo. T4 immunotherapy exerts antitumor activity against HNSCC cell lines and tumors in vivo, without significant toxicity. Human T4⁺ T-cells also engage mouse ErbB receptors, permitting safety testing in SCID Beige mice. Severe toxicity caused by cytokine release syndrome ensues when human T4⁺ T-cells are administered at high doses to mice, particularly with advanced tumor burdens. However, such toxicity is not required for efficacy and is never seen if T-cells are administered by the intratumoral route. To exploit this, we have designed a first-in-man clinical trial in which T4⁺ T-cells are administered to patients with locally advanced/recurrent HNSCC. Cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 10⁷ cells (cohort 1), escalating to 10⁹ cells (cohort 5). If maximum tolerated dose remains undefined, cohorts 6/7 will receive either low- or high-dose cyclophosphamide before 10⁹ T4⁺ T-cells. A panel of routine/in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous antitumor immunity, immunogenicity, and T-cell trafficking.

Van Schalkwyk and colleagues outline a protocol for phase I clinical testing of intratumoral immunotherapy in locally advanced or recurrent head and neck squamous cell carcinoma (HNSCC). In this protocol, chimeric antigen receptor–transduced T cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 107 cells (cohort 1) and escalating to 109 cells (cohort 5).