T4 Immunotherapy Of Head And Neck Squamous Cell Carcinoma Using Pan-Erbb Targeted Car T-Cells

Striking progress has been achieved in CD19 + hematologic malignancies using chimeric antigen receptor (CAR) T-cells following lymphodepletion. Nonetheless, toxicity remains significant, due to cytokine release syndrome (CRS) and neurologic dysfunction. The frequent emergence of resistance due to antigen loss provides a strong rationale for engagement of multiple targets. Solid tumors impose additional challenges. Foremost, a paucity of targets that are tumor-specific, or restricted to dispensable tissues. Moreover, active CAR T-cells need to home to, penetrate and persist within profoundly immunosuppressive tumors. Cognizant of these obstacles, we designed T4 immunotherapy. T4 + T-cells are retroviral transduced to co-express (i) T1E28ζ, a CAR coupling a promiscuous ErbB ligand derived from EGF and TGFα to a fused CD28+CD3ζ endodomain; and (ii) 4αβ, a chimeric cytokine receptor containing the IL-4Rα ectodomain coupled to the IL-2Rβ endodomain. T1E28ζ engages 8/9 possible ErbB dimers, providing broad anti-tumor activity while minimizing risk of antigen escape. 4αβ enables IL-4-driven selective enrichment and expansion of CAR T-cells during manufacture. Pre-clinical data demonstrate potent anti-tumor activity in head and neck squamous cell carcinoma (HNSCC), mesothelioma, ovarian and breast cancer. However, risk of on-target off-tumor toxicity is significant, due to low-level ErbB expression in normal tissues. Indeed, CRS can be modeled when human T4 + T-cells are administered to the peritoneal cavity of SCID Beige mice. To de-risk T4 immunotherapy in man, a dose-escalation intra-tumoral Phase I trial was commenced, without lymphodepletion. HNSCC was selected due to the unmet need presented by locally advanced or recurrent disease. Ninety percent of patients were lymphopenic yet T4 immunotherapy was successfully generated from a 130mL blood draw, in a closed manufacturing process. Batches contained up to 7.5 x 10 9 cells, of which 63.8+ 12.1% were T4 + , comprising a variable mixture of central and effector memory CD4 + and CD8 + T-cells. Cohorts of 1, 3 and 10 x 10 7 T4 + T-cells were treated. Patient 5 died of advanced HNSCC, prior to treatment. Intra-tumoral 1-2mL injections of T4 immunotherapy were administered as a single dose. Treatment-related AEs were + T-cells were not seen. Disease control rate was 44% with all three patients in cohort 3 achieving stable disease (RECIST 1.1 at 6 weeks). These data demonstrate the safe intra-tumoral administration of T4-immunotherapy in patients with advanced HNSCC, with disease control observed at the highest dose tested. Further dose escalation and combination with immune-modulating agents is warranted. Citation Format: Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, May van Schalkwyk, Ana Parente Pereira, Leticia Bosshard-Carter, Lynsey Whilding, Sjoukje van der Stegen, David M. Davies, Teresa Guerrero-Urbano, Jean Pierre Jeannon, James Spicer, John Maher. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT118. doi:10.1158/1538-7445.AM2017-CT118