Righi, Matteo; (2021) Enhancement of Adoptive Cell Therapies via novel engineered Chimeric Cytokine Receptor. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chimeric antigen receptor (CAR) T cells therapy has proven to be extremely efficacious in leukaemia and lymphoma patients. However, these exceptional results did not translate to solid tumours. Although the lack of clinical efficacy in solid cancers could be attributed to multiple factors, data from the haematological setting suggest a strong correlation between CAR T cells expansion/persistence and a positive clinical outcome. Persistence of CAR T cells is especially difficult in solid tumours where there is an absence of widespread target availability that induces CAR turnover such as in the case of targeting CD19. To improve CAR T cells expansion and persistence studies have co-administered proliferative cytokines with CAR T cells therapy however, systemic toxicities have limited clinical efficacy. A more recent approach that limits the systemic toxicities of cytokine administration, hijacks the cytokine receptor signal pathways within the CAR T cells. Many of these approaches have demonstrated improvements in CAR T cells survival in pre-clinical models however, they are limited by the type and the quality of cytokine signal deliverable. I, therefore, sought to design a novel constitutively active synthetic chimeric cytokine receptor (CCR) with a more generalisable output, using the Fab heterodimerisation domain as receptor dimeriser structure. Expression of both IL2 and IL7 CCRs in T cells delivered a constitutive ligand-independent cytokine receptor signal that triggered T cells proliferation. The co-expression of a CCR with a CAR module enhanced CAR T cells ability to respond to multiple target re-stimulations. Furthermore, CCR co-expression boosted CAR T cells persistence in absence of cognate ligand through the induction of a constitutive proliferation in-vitro. Importantly, these CAR T cells were not immortalised by the CCR and would eventually succumb to cellular death in the absence of stimulation. In-vivo, CCR expression improved anti-tumour efficacy of the CAR and showed no signs of lymphoproliferative disease in an immunocompetent murine model. The lack of detected toxicity was in part due to restricting the CCR signals to the CAR T cells with no detectable effects on bystander, non-transduced T cells. Nevertheless, efforts were undertaken within this thesis to either attenuate the CCR signal or control the CCR signal with either the administration of small molecules such as the FDA approved JAK inhibitor Ruxolitinib or a soluble protein such as TGFβ or PSA. Finally, I showed that the CCR platform developed in this thesis is not only agnostic to the cytokine receptor; being capable of hijacking receptor families from the common gamma chain, common beta chain, IL12-like receptors, and others; but could be broadened to non-natural cytokine receptor pairs. In summary, this thesis reported the generation of a novel CCR structure that efficiently re-created different cytokine receptor signals. This new technology has a direct implication in the improvement of current CAR T cells therapies, especially in solid tumours. Moreover, the agnostic nature of the CCR platform can be also applied to other cell-based therapies.

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