Towards next‐generation TIL therapy: TILs enriched in neoepitope‐specific T cells

Abstract

immunology, immunotherapy, T cells The relationship between neoantigen recognition by T cells and the clinical success of cancer immunotherapy is beyond doubt. 1,2 Personalized neoantigen-based cancer vaccines and neoantigen-specific T-cell therapy represent promising cancer treatments. 3 Challenges yet remain to unleash the full potential of mutanome-based cancer immunotherapy. Among them, the identification and validation of clinically-relevant neoantigens require a complex , individualized and costly approach which only yields a limited number of neoepitope per patient. 4,5 We recently reported a novel method that enables the sensitive detection of tumour neoantigens in highly enriched in vitro-expanded tumour-infiltrating lympho-cytes (TILs). 6 This strategy, dubbed NeoScreen, is based on the early exposure of patients' tumours to private sets of selected neoantigens loaded on competent autol-ogous B cells. NeoScreen demonstrated a considerable enrichment in neoepitope-specific T cells by several orders of magnitude and increased by threefold the breadth of tumour antigens found with conventional methods, thus enabling the sensitive identification of rare patient-specific neoantigens. By increasing the frequency of existing tumour-specific T-cell receptor (TCR) clonotypes but also by recruiting additional clonotypes that can be newly detected with markedly enhanced sensitivity, NeoScreen This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. allows the generation of expanded TILs highly enriched in neoepitope-specific T cells. Of note, in the TIL adoptive cell transfer therapy (ACT) field, both the breadth and magnitude of neoantigen-specific T-cell responses, together with tumour mutational burden, correlate with clinical outcome. 7,8 Collectively , this suggests that NeoScreen-enriched TIL products represent attractive candidates for TIL ACT therapy. This perspective, however, raises important questions. One key component is the nature of tumour-rejection antigens to be selected and how to prioritize them (Figure 1), given that both neoepitope-and tumour-associated antigen-specific TILs were successfully enriched with NeoScreen. There is currently an armamen-tarium of computational tools to predict patient-specific tumour antigens-based, among others, on the affinity and stability of binding to cognate HLA alleles, immunogenicity, clonality, agretopicity or distance to self. 9,10 Furthermore, the spectrum of canonical and non-canonical antigens is also expanding, including, among others, canonical neoantigens derived from indels or gene fusions and non-canonical antigens such as post-translational modifications or long noncoding RNAs. 5,11,12 Clin. Transl. Med. 2023;13:e1174. wileyonlinelibrary.com/journal/ctm2 1 of 4 https://doi.