A phase I trial of T4 CAR T-cell immunotherapy in head and neck squamous cancer (HNSCC).
2018; Lippincott Williams & Wilkins; Volume: 36; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2018.36.15_suppl.3046
ISSN1527-7755
AutoresSophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, May C I van Schalkwyk, Ana Parente Pereira, Leticia Bosshard‐Carter, Lynsey M. Whilding, Sjoukie van der Stegen, David M. Davies, Farzin Farzaneh, Teresa Guerrero Urbano, Jean‐Pierre Jeannon, James Spicer, John Maher,
Tópico(s)Cancer Research and Treatments
Resumo3046 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.
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