The Neeson Laboratory explores the human immune system responses to tumour development and to immunotherapy. We do this using patient samples from cohort studies or clinical trials. Having made observations in these samples, we then explore immunotherapy drug combination mechanism of action in model systems to provide new information for rational use of these drugs in the clinic.
Chimeric antigen receptor T cells
Chimeric antigen receptor (CAR) T cells have induced spectacular responses in patients with refractory B-cell malignancies. Despite the rapid transition and success of this form of therapy in the clinic, there are many aspects of CAR-T biology which remain unknown. We have two distinct projects in this area:-
1. CAR-T cells are known to eradicate large tumour bulk in patients to the point of molecular remission, yet very little was known about how CAR-T cells achieve this. Using pre-existing in vitro and in vivo models, this project will further explore how CAR-T cells can be optimally activated (endogenous TCR vs CAR or both), what signaling endodomains achieve the best tumour clearance and ongoing immunosurveillance.
2. CAR-T cell persistence in the peripheral blood of patients is associated with tumour regression and ongoing tumour control in B cell malignancies. It is thought that CAR-T persistence represents T cell memory. Using pathogen challenge models, formation of antigen-specific T cell memory required CD4+ T cells; however it is not known whether this is the case with CAR-T cells. Using an immune-competent mouse model this project will explore the role for CD4+ CAR-T cells in tumour clearance, CD8+ CAR-T cell persistence and whether increased numbers of CD4+ CAR-T cells play a role in CAR-T cell attack of normal tissue.
Davenport AJ et al Cancer Immunology Research 2015.
Immuno-Oncology: exploring the immune context of tumours and immune exhaustion
Immunotherapy clinical trials over the last 5 years have yielded spectacular results in patients with a wide range of solid tumours. Blocking antibodies to the immune checkpoints CTLA-4 and PD-1/PDL1 have produced the first wave of patient responses; there are many more types of immunotherapy drugs in clinical trials and in pre-clinical development. However, predicting which patients will respond to immunotherapy, and what type of immunotherapy is appropriate has proven difficult. To address these issues, we have developed a range of technologies to explore the immune context of human cancer including multiplex immuno-histochemistry, and immune gene expression profile and network analysis on primary or metastatic tumour FFPE sections. We also have ongoing development of a T cell TCR repertoire platform. We have a TIL (tumour-infiltrating lymphocyte) program to explore the immune context in fresh tumour samples from patients with solid tumours including melanoma, breast or prostate cancer and will be using mass cytometry to describe the tumour ‘immunome’.
This project will use these technologies to explore exactly what is the immune context of the primary tumour? How does the immune context change in the primary site in response to immunotherapy? What goes wrong with immune control when the tumour escapes at local or distant sites? Is this a tumour or immune intrinsic problem or both? This information will then be used to inform the design of ongoing immunotherapy clinical trials at the Peter MacCallum Cancer Centre.
- Prostate cancer: Scott Williams, Shahneen Sandhu, Declan Murphy
- Melanoma: Grant McArthur, Shahneen Sandhu, David Gyorki
- Renal Cancer: Shankar Siva
- Breast Cancer: Sherene Loi, David Gyorki, Steven David
- Lung cancer / Head and neck cancer: Ben Solomon
- Merkel Cell Carcinoma (Neuro-endocrine): Rod Hicks, Richard Tothill
- Gastric cancer: Alex Boussioutas, Rita Busuttil
- Colo-rectal cancer: Rob Ramsay
Multiple Myeloma is an incurable disease; however, immunotherapy is providing new dramatically response rates in patients with refractory disease. Elotuzumab (Elo) is a SLAM-F7 targeting humanised IgG1 antibody. (Elo)+Lenalidomide (Len) combination therapy of patients with refractory multiple myeloma induced 84% objective response, with 16% long term remission (Richardson PG et al Lancet Haematol 2015). Whilst SLAM-F7 is expressed on malignant plasma cells, it is also expressed on NK, T and B cells, dendritic cells and monocytes. It is not known whether all SLAM-F7+ immune subsets are targets for the Elo+Len effect or just the malignant plasma cells. This project aims to understand the Elo+Len mechanism of action in order to better design I-O drug combination therapy for patients with multiple myeloma and improve long-term outcome.
Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, Salgado R, Byrne DJ, Teo ZL, Dushyanthen S, Byrne A, Wein L, Luen SJ, Poliness C, Nightingale SS, Skandarajah AS, Gyorki DE, Thornton CM, Beavis PA, Fox SB, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Darcy PK, Speed TP, Mackay LK, Neeson PJ, Loi S (2018). Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 24(7):986-993
Lee B, Wong A, Kee D, Neeson P, Shackleton M, McArthur G, Sandhu S (2016). The use of ipilimumab in patients with rheumatoid arthritis and metastatic melanoma. Ann Oncol.27(6):1174-1177.
Beavis PA, Slaney CY, Kershaw MH, Gyorki D, Neeson PJ*, Darcy PK* (2016). Reprogramming the tumor microenvironment to enhance adoptive cellular therapy. Semin Immunol.28(1):64-72. *Joint senior author.
Neeson PJ, Hsu AK, Chen YR, Halse HM, Loh J, Cordy R, Fielding K, Davis J, Noske J, Davenport AJ, Lindqvist-Gigg CA, Humphries R, Tai T, Prince HM, Trapani JA, Smyth MJ, Ritchie DS (2015). Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib. OncoImmunology.4(9):e1038011.
Davenport AJ, Jenkins MR, Cross RS, Yong CS, Prince HM, Ritchie DS, Trapani JA, Kershaw MH, Darcy PK, Neeson PJ (2015). CAR-T cells inflict sequential killing of multiple tumor target cells. Cancer Immunol Res.3(5):483-494.
Shortt J, Hsu AK, Martin BP, Doggett K, Matthews GM, Doyle MA, Ellul J, Jockel TE, Andrews DM, Hogg SJ, Reitsma A, Faulkner D, Bergsagel PL, Chesi M, Heath JK, Denny WA, Thompson PE, Neeson PJ, Ritchie DS, McArthur GA, Johnstone RW (2014). The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound. Cell Rep.7(4):1009-1019.
Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Hönemann D, Gambell P, Westerman DA, Haurat J, Westwood JA, Scott AM, Kravets L, Dickinson M, Trapani JA, Smyth MJ, Darcy PK, Kershaw MH, Prince HM (2013). Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther.21(11):2122-1129.
Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA, Smyth MJ, Neeson P*, Ritchie DS* (2011). The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood.117(5):1605-1613. *Joint senior author.
PhD opportunities for students often exist within the lab in one or more of the above areas. Students should contact A/Prof Neeson for details.