Paul Neeson Lab

Despite advances in therapy options over the last decade, melanoma remains a lethal disease. Early melanoma (stage I or II) which is still confined to skin is managed by surgical resection, but recurrence can occur, often to other organs. Understanding the mechanisms which leads to this process is critical in order to know which patients which need further therapies after surgery. Tissue-resident memory T cells (TRMs) are critical for immune control of melanoma. In this project, we hypothesised that the abundance of TRMs can serve as a predictor for favourable prognosis in individuals with early-stage or metastatic disease.

 

Renal cell carcinoma (RCC) and prostate cancer (PrCa) have contrasting immunogenicity and responses to immunotherapy (IO). We are exploring the effects of radiation (eg. radiotherapy or radionuclide therapy) on both RCC and prostate cancer TME using in vitro and in vivo models, as well as examining biospecimens from patients treated with radiation-IO in clinical trials. These projects encompass mechanistic studies in pre-clinical models all the way to clinical translation. We are using this information to define targets for novel engineered IO, and also stratify patients for the correct type of combination treatment and improve clinical outcomes.

Chimeric antigen receptor (CAR)-T cells have poor efficacy in solid tumours. We are developing a series of strategies to address this issue including (1) progenitor memory CAR-T cells with enhanced in vivo persistence (2) switch CAR-T cells resistant to the suppressive TME (3) a novel single CAR targeting multiple epitopes in a protein complex (4) tumour-specific delivery of bispecific chimeric engagers (5) combination therapies with TME-altering neoadjuvant treatments. We are now exploring the feasibility of in vivo CARs (eg targeted mRNA-LNP) in order to translate our findings into real world practise for patients with refractory cancer.

The Neeson lab is exploring unique molecules on T cell lymphoma for CAR-T cell therapy. We are now screening novel epigenetic drugs which regulate target molecule expression levels and creating ‘universal donor’ CAR-T cells using gene editing technology. Taken together these strategies will be tested in vitro and in pre-clinical models of T cell lymphoma. In multiple myeloma (MM) we are developing switch CAR-T cells to target CAR-T cell resistance mechanisms and convert T cell suppression into activation. We have also identified novel molecular targets for CAR-T cell attack of MM in conjunction with proteasome inhibitors.

High-risk extracranial solid paediatric cancer outcomes are grim, necessitating improved treatments without long-term side effects. To address this, our strategy involves studying and reversing the immunosuppressive TME of solid tumours (neuroblastoma, osteosarcoma and PFA-E). To do this, we derive multi-dimensional data to identify mechanisms of immune suppression and low tumour immunogenicity. We will combine progenitor memory CAR-T cells with TSTEM-like properties (developed at PMCC) with novel anti-cancer drugs (collaboration with Children Cancer Institute) which inhibit tumour growth in preclinical models of paediatric cancers and rewire the immunosuppressive TME. If successful, this approach could revolutionize extracranial solid paediatric cancer treatment.