Poster Presentation 30th Lorne Cancer Conference 2018

A preclinical platform for evaluating targeted therapy and immunotherapy combinations in BRAFV600E melanoma (#191)

Emily J Lelliott 1 , Carleen Cullinane 1 , Claire Martin 1 , Rachael Walker 1 , Jane Oliaro 1 , Nicole Haynes 1 , Grant McArthur 1 , Karen E Sheppard 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Immunotherapy and targeted therapy are standard of care in melanoma and there is great interest in combining these approaches. Evaluating the efficacy of such combinations requires preclinical models that are both immunogenic and sensitive to targeted inhibitors. Several syngeneic models have recently been developed using mouse melanoma cell lines with clinically-relevant genetic backgrounds, including the YUMM1.1 line (BrafV600ECdkn2a-/-Pten-/-). However, the suitability of this model as a preclinical tool in the context of standard-of-care clinical therapies has not been well characterised. We also found the line to be lowly immunogenic, limiting its potential as a platform for preclinical immunotherapy studies. Specifically, we found that YUMM1.1 tumours grown in immunocompetent C57BL/6 mice had low T cell infiltrate and grew at a similar rate to tumours in immunocompromised mice, indicating the line is poorly recognised by the immune system. We found the line expresses MHC Class I but likely lacks sufficient neoantigen expression to stimulate adaptive immunity. Hence we derived a new model, YOVAL1.1, by stably transducing YUMM1.1 to express ovalbumin (OVA) to enhance immunogenicity and allow tumour-specific T cell tracking in vivo. YOVAL1.1 showed high sensitivity to T cell killing in vitro and we observed a significant delay in tumour growth in C57BL/6 mice compared to immunocompromised mice. YOVAL1.1 tumours express high levels of MHC Class I, PD-L1 and CD80 and have significantly increased CD3+ immune infiltrate compared to vector-transduced tumours. We also found that YOVAL1.1 is sensitive to targeted therapies currently used in the clinic for melanoma, including BRAFV600E and MEK inhibitors. Importantly, the response and resistance of this model to targeted therapy recapitulates observations in human models and in the clinic. YOVAL1.1 is a transplantable model, which is both immunogenic and sensitive to clinical targeted therapies, and in which tumour-specific immune responses can be tracked in vivo. Together, this makes YOVAL1.1 a valuable and cost-effective platform to guide strategic development of combined targeted and immunotherapy approaches in BRAFV600E melanoma.