Abstract 4060: Selective Neoantigens Peptide TILs (snapTILs): A next generation tumor infiltrating lymphocytes (TIL) therapy platform
Authors: Halder Tithi Ghosh , Rheinschmidt Shelby , Adamson Sydney , Larson Anna , Bargenquast Taylor , Rodriguez del Villar Ryan , Ng Serina , Gutowsky Kate , Weston Alexis , Thode Trason , Kaadige Mohan , Kelley Erin , Soria-Bustos Jorge , Giron Jorge , Altin John , Soldi Raffaella , Sharma Sunil 
Published: April 2023

Background: Immunotherapies using autologous tumor infiltrating lymphocytes (TILs) have become effective treatment modalities for several patients with solid tumors, yielding a response rate of around 49% in patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TILs from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of these administered TILs recognize tumor antigens and most are non-mutated public antigens. Moreover, expression of these antigens on normal cells can trigger central and peripheral tolerance mechanisms. Against this background, cancer neoantigens derived from private mutations represent an ideal class of cancer antigens to target because they are highly tumor specific by nature, therefore reducing the potential induction of central and peripheral tolerance. We recently developed a new technology to enrich TILs with predefined neoantigen specificities, which we termed Selective Neo Antigens Peptides TILs (snapTILs). Here we describe the efficacy studies of a melanoma and pancreatic cancer patient’s snapTILs done in autologous settings both ex vivo and in vivo.

Methods: Our workflow consisted of a multistep process performed on a patient-specific basis. Briefly, mutations were called by whole-exome sequencing of tumor vs. normal DNA to generate a peptide library. The peptides were further filtered using an in-silico prediction algorithm and our proprietary peptide-MHC binding assay. Selected peptides were then incubated with TILs isolated from the patient’s tumor biopsy, resulting in TIL population enriched of T cells that recognize the neopeptides (snapTILs). After rapid expansion, snapTIL efficacy was tested by checking their ability to infiltrate in patient-derived tumor organoids, their activation status (IFNγ), cytotoxicity (Granzyme B), and T-cell exhaustion markers. Lastly, snapTILs in vivo efficacy was tested in human melanoma and pancreatic cancer xenograft models using hIL-2 transgenic mice.

Results: Our initial data showed that the levels of infiltration of snapTILs into tumor organoids was significantly higher compared to IL2-stimulated TILs in both cancer models. Also, snapTILs recognized tumors with great specificity as they showed significantly less infiltration in organoids generated from generally uninvolved tissues from the same patients. Moreover, snapTILs were found to be more cytotoxic in nature than the IL2-stimulated TILs in terms of IFNγ and Granzyme B secretion after coculture with autologous tumor cells. Our in vivo data confirmed these observations by showing 70% tumor growth inhibition in highly immunogenic melanoma and 50% tumor growth restriction in a poorly immunogenic pancreatic tumor model. In conclusion, our approach proves the potential for personally tailored immunotherapies to yield more effective and safer cancer treatments using snapTILs.

Citation Format: Tithi Ghosh Halder, Shelby Rheinschmidt, Sydney Adamson, Anna Larson, Taylor Bargenquast, Ryan Rodriguez del Villar, Serina Ng, Kate Gutowsky, Alexis Weston, Trason Thode, Mohan Kaadige, Erin Kelley, Jorge Soria-Bustos, Jorge Giron, John Altin, Raffaella Soldi, Sunil Sharma. Selective Neoantigens Peptide TILs (snapTILs): A next generation tumor infiltrating lymphocytes (TIL) therapy platform. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4060.