Developing a pre-clinical human pancreatic cancer model to test novel immunotherapies.

Essential background (up to 500 words including key references)

There is a high unmet medical need to develop new therapies for the treatment of pancreatic cancer (1). Drugs which engage the immune system (immunotherapies) have shown a survival benefit in lung cancers and melanoma, but there remains no approved immunotherapy specifically for the treatment of pancreatic cancer (2, 3). Developing preclinical models of pancreatic cancer, particularly human models that can replicate the complex interactions between cancer cells and the immune system has the potential to aid understanding of the biological mechanisms that propagate pancreatic cancer as well as support the development of candidate drugs more likely to improve outcomes for patients (4).

A pivotal event in the initiation of pancreatic ductal adenocarcinoma (PDAC) is the acquisition of somatic gain of function mutations in KRAS (1). Activated KRAS binds to effector proteins for example PI3K or PAK4 that transduce signals regulating cell survival, proliferation, and differentiation. Somatic gain of function mutations for example KRASG12D lead to constitutive oncogenic signalling and dysregulated tumour cell growth (5).

KRAS has historically proved a challenging target for therapeutic intervention. As an intracellular protein, KRAS is inaccessible to conventional monoclonal antibodies, while the lack of an amenable mutant-specific binding pocket has hindered attempts to develop selective small molecule antagonists (6). Recently, inhibitors capable of binding irreversibly to KRASG12C, have demonstrated promising clinical anti-tumour activity in colorectal and lung cancers that harbour KRASG12C mutations. However, pancreatic cancers are much more frequently driven by KRASG12D mutation.

Alongside the development of direct inhibitors of KRAS, inhibitors of the KRAS signalling pathway e.g., PI3K or PAK4 inhibitors and T cell receptor (TCR)-based therapeutics (7-9) are also in preclinical and clinical development. TCR therapeutics, unlike antibodies, which primarily bind to intact cell surface expressed proteins, can access mutated or dysregulated intracellular proteins by exploiting TCR recognition of peptides presented by human leucocyte antigen (HLA) class I on the cancer cell surface.

For example, a T cell clone specific for a KRASG12D peptide presented in the context of HLA-C*08:02 has been successfully utilized in immunotherapy to suppress tumours in a patient (10). Immunocore have recently isolated a human TCR specific to a KRASG12D presented in the context of HLA-A*11 (HLA-A*11-KRASG12D). Using the affinity enhanced TCR as the targeting arm, a bispecific T cell engaging ImmTAC molecule (11), mediates selective T cell targeting of HLA-A*11+ cancer cell lines expressing KRASG12D.

This work highlights the sensitivity of the TCR:pHLA system and implies that soluble high affinity TCR bispecifics may have the potential to treat neoantigen driven cancers (12). Aim of the investigation (up to 150 words)

This project aims to build on the work already achieved by Immunocore to develop PDAC organoid models for pre-clinical testing of lead TCR bispecifics. The project will not only test the developed modalities as mono therapy but will also test the efficacy of combining with PAK4 or PI3K inhibition to identify optimal strategies to treat PDAC.