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

Research output: Contribution to journalArticlepeer-review

113 Citations (Scopus)

Abstract

Despite several advances, five-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 co-express 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 anti-tumor 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 due to 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 intra-tumoral 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 prior to 109 T4+ T-cells. A panel of routine/ in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous anti-tumor immunity, immunogenicity and T-cell trafficking.
Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalHuman Gene Therapy Clinical Development
Volume24
Issue number3
DOIs
Publication statusPublished - 7 Oct 2013

Keywords

  • COOPERATIVE-ONCOLOGY-GROUP
  • ADOPTIVE TRANSFER
  • PLUS CETUXIMAB
  • BREAST-CANCER
  • CARCINOMA
  • EGFR
  • LYMPHOCYTES
  • RESISTANCE
  • EXPRESSION
  • DOMAINS

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this