Abstract CT153: TiTAN: a phase 1 study of GEN-011, a neoantigen-targeted peripheral blood-derived T cell therapy with broad neoantigen targeting
Authors: Gillison Maura , Niu Jiaxin , Olson Daniel , Stein Mark , Aggen David , Acharya Utkarsh , Creelan Benjamin , Hernandez Richard , Price Jessica , Mancini Kevin J. , Dowal Louisa , Foti James , Vemulapalli Vijetha , Shainheit Mara , Golshadi Masoud , Stapleton Raymond D. , Flechtner Jessica B. , Davis Thomas A. 
Published: June 2022

TiTAN™ is an open-label, multi-center Phase1/2a trial evaluating safety, tolerability, T-cell persistence and proliferation, and clinical activity in patients with some solid tumors. Adoptive T-cell therapies (ACT) have resulted in durable clinical responses in some patients, but many are resistant. Resistance may be due to multiple factors including antigen heterogeneity or loss, immune editing, exhausted immune responses or naturally occurring immune suppressive T-cell responses. Tumors can also express Inhibigens™, antigenic targets of suppressive T cells, which may be inadvertently expanded in the non-specific ACT manufacturing process. In animal models, Inhibigen-specific responses drive tumor hyperprogression. GEN-011, a neoantigen-targeted, autologous peripheral T cell (NPT) therapy, contains tumor-specific T cells with broad neoantigen specificity. Patients undergo sequencing of tumor from fixed tissue and selection of neoantigens by ATLAS™, an ex vivo assay that directly identifies immunogenic neoantigens for use in manufacturing NPTs, and also Inhibigens for exclusion. The patient’s peripheral T cells and monocyte-derived dendritic cells are incorporated into the proprietary PLANET™ manufacturing process where they are specifically stimulated with up to 30 ATLAS-confirmed neoantigens in a scalable, closed system. The TiTAN clinical trial is testing a low dose regimen of GEN-011 without lymphodepletion and a single dose of GEN-011 with lymphodepletion and IL-2. To date, 19 patients with assorted solid tumors have been screened with ATLAS, prioritizing an average of 12 neoantigens (range 0-43) and excluding 14 Inhibigens (range 1-55) per patient. Of the 10 patients entering PLANET, 100% have successfully yielded a released drug product. To date, 5 patients with NSCLC or SCCHN have been dosed with escalating cell numbers and lymphodepletion/IL-2 regimens without DLT. Early data show effector and central memory T-cell proliferation by day 5 post infusion, which peak between days 8 and 15. Neoantigen-specific T cells remain detectable in the peripheral blood for at least 36 days. Early best response from 4 evaluable patients are one PD and one mixed response in the low dose cohort, and in the more intense regimen a SD with reduction in tumor with resolution of pain and neuropathy extending for 2 months, and the fourth had stable disease. Maximum grade 2 CRS and one grade 2 ICANS peaked around day 8 in parallel to cell expansion and no patients required tocilizumab or corticosteroids. Upcoming patients will receive more intensive lymphodepletion and then higher dose IL-2. Taken together, these early data support the biological activity of GEN-011. Using a personalized immune assay to identify neoantigens, and to exclude Inhibigens, to generate tumor specific T cells may offer a more accessible and promising ACT for treating solid tumors.

Citation Format: Maura Gillison, Jiaxin Niu, Daniel Olson, Mark Stein, David Aggen, Utkarsh Acharya, Benjamin Creelan, Richard Hernandez, Jessica Price, Kevin J. Mancini, Louisa Dowal, James Foti, Vijetha Vemulapalli, Mara Shainheit, Masoud Golshadi, Raymond D. Stapleton, Jessica B. Flechtner, Thomas A. Davis. TiTAN: a phase 1 study of GEN-011, a neoantigen-targeted peripheral blood-derived T cell therapy with broad neoantigen targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT153.