Abstract 2745: The PLANET manufacturing process reproducibly generates high-quality neoantigen-targeted peripheral T cells (NPTs) for adoptive T cell therapy in the TiTAN clinical trial
Authors: Zope Harshal , Nande Rounak , Jain Manish , Hubbard Charley , Dowal Louisa , Foti James , Loizeaux James , Cabral Crystal , DeOliveira Daniel B. , Yang Guohan , Reuter Mercay , Flechtner Jessica Baker , Stapleton Raymond 
Published: June 2022

Abstract
Background: Neoantigen (neoAg)-specific T cells can be found in the peripheral blood of patients with solid tumors, and the infiltration of fresh, peripherally derived T cells into tumors has been associated with successful outcomes after checkpoint blockade therapy. We previously described the development of our PLANET™ manufacturing process to create NPTs, based on the empirical identification of neoAgs using the ex vivo ATLAS™ bioassay, for adoptive transfer into patients with cancer. We have initiated the TiTAN™ clinical trial (NCT04596033) to evaluate this candidate immunotherapy, GEN-011, in subjects with checkpoint refractory solid tumors. Here we report the successful manufacturing of NPTs to support the ongoing trial.
Methods: Apheresis, FFPE tumor and saliva samples were procured from subjects who consented to participate in the trial. Monocytes and T cells were isolated and cryopreserved. Patient-specific neoAgs against which their T cells were responsive were identified with ATLAS, and up to 30 neoAgs were prioritized for manufacture; pro-tumor Inhibigens™ were excluded. Cryopreserved peripheral blood monocytes and T cells were thawed, monocytes derived into dendritic cells, and then neoAg-specific T cells expanded in the fully closed PLANET manufacturing process. The NPTs were formulated and cryopreserved for administration to patients after release testing.
Results: Subjects with five different solid tumor types contributed to these data: CSC, NSCLC, SCLC, SCCHN, and melanoma. A median of 2.1bn monocytes and 6bn T cells were cryopreserved from apheresis products (N=17). The median TMB was 1.8mut/Mb (range 0.01-36.6) with 473 somatic mutations (range 32-8893); the number of non-synonymous mutations ranged from 9 to 767. ATLAS screens identified a mean of 13±4 neoAgs and 11±3 Inhibigens, resulting in an average of 13 (range 2-30) unique neoAgs in each PLANET manufacturing process. Upon conclusion of manufacturing, the mean yield per patient was 1.6±0.3bn NPTs across runs (N=9) completed by the time of data cutoff. Characterization tests revealed the NPTs were consistently 80-90% CD8+ and 10-20% CD4+ T cells, of which 97% (range 64.9-99.8%) were effector memory and 1% (range 0.1-32.3%) central memory. The median purity at release was 98% with 82% viability. By functional assessments, the NPTs retained specificity for 91% (range 82-100%) of their intended neoAg targets (N=4). Administratable doses were successfully manufactured for 100% of patients to date.
Conclusions: NPTs can routinely be manufactured in a GMP setting to treat patients with solid tumors. By expanding fresh, non-exhausted NeoAg-specific T cells with known tumor specificity from the periphery, GEN-011 has the potential to provide clinical benefits of TIL with greater accessibility and minimal irrelevant T cells. The TiTAN trial is ongoing.
Citation Format: Harshal Zope, Rounak Nande, Manish Jain, Charley Hubbard, Louisa Dowal, James Foti, James Loizeaux, Crystal Cabral, Daniel B. DeOliveira, Guohan Yang, Mercay Reuter, Jessica Baker Flechtner, Raymond Stapleton. The PLANET manufacturing process reproducibly generates high-quality neoantigen-targeted peripheral T cells (NPTs) for adoptive T cell therapy in the TiTAN clinical trial [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 2745.