460 Enrichment of neoantigen reactive tumor infiltrating lymphocytes (TIL) in gastric cancer
Year: 2024
Type: conference-abstract
Abstract: Background Tumor-specific neoantigens have been employed in cancer immunotherapies such as cancer vaccines and adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL).1–8 These protocols are used to enhanced immune response against solid tumors by enriching tumor specific immune cells. Gastric cancer is one of the most lethal cancers. The objective of this study is to determine the feasibility of using neoantigens to isolate tumor-specific TILs in upper gastric cancer (esophageal and stomach) and potentially increase anti-tumor response. Methods A total of 14 research samples gastric cancer patients were evaluated in this study. Tumors and PBMC samples were collected at Moffitt Cancer Center under an IRB approved study (Advarra Pro0043972). Tumor-specific neoantigens were identified using whole exome and RNA sequencing. Long peptides (25aa), designed to bind to autologous HLA molecules, were manufactured. TIL were expanded ex vivo from whole tumor digest in media containing high dose IL2 (pre-REP). Tumor neoantigens were pulsed onto antigen presenting cells (APC). APC were cocultured with bulk TIL and neoantigen-reactive TILs were isolated by FACS based on expression of OX40 and 4-1BB. Sorted TIL populations underwent rapid expansion (REP). Tumor-reactivity of the final product was validated by quantifying IFN-g and Granzyme B in co-culture supernatants. Results Utilizing small tumor samples (~0.06g a scale-down model of clinical TIL isolation prior to a rapid expansion protocol (preREP), TIL could be expanded from 12/14 (86%) of the available samples. Tumor-specific neoantigens were predicted (ranging from 130 to 321 peptides) for each tumor sample. Up to 192 individual peptides were synthesized to represent neoantigens for each sample, and in instances where >192 neoantigens were identified bioinformatics-based prioritization of peptide manufacture was performed. Neoantigen-reactive TILs, as measured by upregulation of OX40/4-1BB, were successfully enriched and expanded in a REP. Enriched TILs were tested and demonstrated significant reactivity against several individual neoantigens. Conclusions This study utilized a scaled-down research model of clinical TIL isolation and demonstrated successful TIL expansion from gastric tumors. Additionally, the use of tumor-specific neoantigens allowed the enrichment of TIL, which maintained neoantigen reactivity after TIL rapid expansion. This data support previous studies performed in melanoma patients and demonstrate that reactive TIL enrichment protocols represent a promising venue to enhance adoptive cell therapy with TIL for solid tumors. References Agnarelli A, Vella V, Samuels M, Papanastasopoulos P, Giamas G. Incorporating immunotherapy in the management of gastric cancer: molecular and clinical implications. In Cancers 2022;14(18). https://doi.org/10.3390/cancers14184378. 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Institution: Moffitt Cancer Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4404065288