A phase I trial of T4 CAR T-cell immunotherapy in head and neck squamous cancer (HNSCC).

Abstract

3046 Background: Recent FDA approvals make CAR T-cell therapy a clinical reality for hematologic malignancy. Toxicity and antigen loss-mediated resistance remain problematic. Solid tumors impose additional challenges, foremost the paucity of safe targets. Moreover, CAR T-cells need to home to, penetrate and persist in an active state within a profoundly immunosuppressive tumor microenvironment. To address these issues, we developed T4-immunotherapy: T-cells that co-express: (i) T1E28ζ, a CAR containing a promiscuous ErbB ligand coupled to a CD28+CD3ζ endodomain; and (ii) 4αβ, an IL-4-responsive chimeric cytokine receptor. T1E28ζ engages 8/9 ErbB homo/heterodimers, providing broad anti-tumor scope while minimizing risk of antigen escape. 4αβ enables IL-4-driven selective CAR T-cell enrichment/expansion during manufacture. Pre-clinical data demonstrate potent anti-tumor activity of T4-immunotherapy. However, risk of on-target off-tumor toxicity is significant, due to normal tissues low-level ErbB expression. Methods: We undertook a Phase I dose-escalation trial of T4-immunotherapy in HNSCC. T4-immunotherapy was manufactured using a blood draw (40-130mL) in a two-week closed process, employing IL-4 as the sole cytokine stimulus post transduction. CAR T-cell dose was escalated through 5 cohorts from 1x107 -1x109 T4+ T-cells administered as a single treatment, by multifocal intra-tumoral injection without lymphodepletion. Results: Despite a lymphopenia rate of 62%, T4 manufacture was successful in 13/13 cases, yielding 2.5-7.5Bn T-cells (69+/-13% transduced). Treatment-related AEs were ≤ grade 2, with no dose-limiting toxicities (CTCAE v4.0). Frequent AEs were steroid-responsive tumor swelling, pain, pyrexias, chills and fatigue. Circulating T4+ T-cells were undetectable in all patients at all times. At 6-weeks, stable disease (SD) was seen in patients treated with ≥10x107 T4+ T-cells. Overall disease control rate was 69% (RECIST 1.1), despite rapidly progressing tumors on trial entry. Subsequent PD1 + oncolytic virus therapy in one patient achieved a rapid complete clinical response. Conclusions: These data demonstrate the safe intra-tumoral administration of T4 in patients with advanced HNSCC. Clinical trial information: NCT01818323.