Ben Aissa, Assma; (2021) Developing strategies for expansion and evaluation of the activity of Neoantigen Reactive T cells in non small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The advent of immunotherapy with checkpoint inhibitors constitutes a paradigm shift in the oncological therapeutic armamentarium in several solid tumours including NSCLC, with improved response rates and survival. However, despite better outcomes, most of the patients will have disease progression. Therefore, alternate treatment options are needed. Adoptive cell therapy with the transfer of ex vivo expanded autologous T cells showed promising results mainly in melanoma including in heavily pre-treated PD-1 resistant patients. Lung cancer is the leading cause of cancer-related deaths in men and women worldwide and is mainly related to cigarette smoking. NSCLC is characterised by a high tumour mutational burden (TMB) and high tumour infiltrating lymphocytes (TILs) but these cells are often dysfunctional due to chronic antigen exposure within the tumour microenvironment. Our work aimed to analyse the impact of immunomodulation on different checkpoint receptors (4-1BB, ICOS, PD-L1) on TILs number, phenotype, differentiation and TCR repertoire during the ex vivo co-culture of TILs and tumours cells in early stage NSCLC. Activation of 4-1BB or ICOS axis, blocking of PD-L1 pathway and combination of 4-1BB activation and PD-L1 inhibition were tested and revealed that co-stimulation of 4-1BB leads to the highest expansion of differentiated effector memory CD8+ T cells harboring features of exhaustion. In addition, upon 4-1BB activation alone or associated with PD-L1 inhibition, preliminary results of TCR sequencing suggested an increase of ubiquitous TCRs (present in every tumour regions) that may be tumour reactive. Generated PDXs and synthetised neoantigens allowed us to investigate TILs for tumour reactivity. We demonstrated the presence of neoantigen reactive T cells within the expanded T cells and 4-1BB co-stimulation allowed a more potent anti-tumour response compared to the absence of 4-1BB activation. In conclusion, TILs expansion was successful in early stage NSCLC and co-stimulation of 4-1BB enhanced CD8+ T cells proliferation and ubiquitous TCRs and might preferentially increase tumour reactive T cells.

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