The Kershaw Laboratory is involved in the development of effective immunotherapies for cancer.
We use novel in-house-derived strategies and new ways of using existing immunomodulatory reagents. Using these approaches in in vivo tumour models, we seek to determine the cellular and molecular mechanisms of immune-mediated anti-tumour effects. In these studies, we also gain insight into the limitations to the approaches. Armed with this knowledge, we can design new, more effective approaches. We also seek to translate the most promising therapies into the clinic here at Peter Mac and will use information gained from these clinical studies to further optimise treatment strategies. The research interests of the lab can be divided into two main areas: laboratory research and clinical/translational research. Laboratory research includes formulation of concepts and their characterisation in vitro and in in vivo models of cancer. The clinical/translational aspects include process and protocol development, and immune monitoring of patients.
Adoptive immunotherapy and vaccines
While immunotherapy can eliminate substantial burdens of some leukaemias, the ultimate challenge for most cancers remains the eradication of large solid tumours. We have generated dual-specific T cells expressing a chimaeric antigen receptor specific for Her2 and a T cell receptor specific for the melanocyte protein (gp100). Injection of T cells, together with recombinant vaccinia virus expressing gp100, can induce durable complete remission of a variety of Her2+ tumours in an immunocompetent in vivo setting.
Vaccinia virus induces extensive proliferation of T cells, leading to massive infiltration of T cells into tumours. There is resistant to tumour rechallenge, indicating immune memory involving epitope spreading. Toxicity against brain is sometimes observed, associated with infiltration by T cells, but is only transient. This work supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Future work in this area seeks to extend the approach to more types of cancer and the metastatic setting.
Understanding the tumour microenvironment
Advanced stages of cancer often involve multiple tumours in different locations in the body. These tumours are associated with a microenvironment that can influence tumour responses to immunotherapy. Whether tumours and their disparate microenvironment can interact together at a distance in a multiple tumour setting, through a form of cross-talk, and affect their responses to immunotherapy has never been previously described.
Our work investigates the cross-talk between two tumours with disparate microenvironments in in vivo models. We demonstrated that immunosuppressive visceral tumours could influence distant subcutaneous (SC) tumours to render them resistant to immunotherapy. We have observed distinct modifications in the SC tumour microenvironment following cross-talk with kidney tumours that exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumour is present, the SC tumours are highly infiltrated with M2 macrophages and have a reduced T cell and natural killer cell effector immune profile.
This work emphasises the potential negative effect that a tumour and a strong immunosuppressive microenvironment can exert on distant tumours that would normally be treatment responsive. Continuing work in this field may lead to a greater understanding of the tumour microenvironment and to a new vision of the prioritisation in the treatment of advanced metastatic cancer.
Investigating genetic modification of immunity
The recent success of chimaeric antigen receptor (CAR)-modified T cells as a form of cancer therapy has underpinned the push for immunotherapy to be a front-line approach in the treatment of cancer. We have previously reported the vav-CAR model, in which all haemopoietic cells expressed a CAR against the tumour antigen Her2 (ErbB2, ERB). In this work, we characterise the function of leukocytes, including natural killer (NK) cells, macrophages and CAR T cells, in the vav-CAR model, and determine the ability to respond to Her2-expressing tumours.
We have demonstrated the anti-tumour functions of leukocytes, including antigen-specific cytotoxicity and cytokine secretion. The adoptive transfer of CAR T cells provides a greater survival advantage in the E0771ERB tumour model compared to controls. In addition, CAR NK cells and CAR T cells also mediated similar levels of survival in the RMAERB tumour model. When challenged with Her2-expressing tumours, an effective immune response was mounted, resulting in tumour rejection and long-term survival. This was shown to be predominantly dependent on both CD8+ T cells and NK cells. However, macrophages and CD4+ T cells were also shown to contribute to this response. Overall, this study highlights the use of the vav-CAR model as a unique tool to determine the anti-tumour function of various immune subsets, either alone or when acting alongside CAR T cells in adoptive immunotherapy.
Devaud C, John LB, Westwood JA, … Schwendener RA, Darcy PK, Kershaw MH (2015). Cross-talk between tumors can affect responses to therapy. Oncoimmunology.4(7):e975572.
In this study, we make the novel observation that concomitant tumours in immunosuppressive sites can reduce the efficacy of immunotherapy against normally responsive tumours.
Devaud C, Westwood JA, John LB, ... Darcy PK, Kershaw MH (2014). Tissues in Different Anatomical Sites Can Sculpt and Vary the Tumor Microenvironment to Affect Responses to Therapy. Molecular Therapy.22(1):18-27.
Here we describe, for the first time, the impact on the tumour microenvironment around the site of tumour implantation.
Kersham MH, Westwood JA and Darcy PK (2013). Gene engineered T cells for cancer therapy. Nature Reviews Cancer.13(8):525-41.
Here we provided a summary of adoptive immunotherapy and perspective on the future of genetic engineering of immune cells for cancer.
Ritchie DS, Neeson PJ, Khot A, ... Darcy PK, Kershaw MH, Prince HM (2013). Persistence and efficacy of second generation CAR-T cell against the LeY antigen in acute myeloid leukemia. Molecular Therapy.21(11):2122-9.
This is a report of a first-in-human study performed in Melbourne, resulting from our developmental and preclinical work over the past 15 years.
John LB, Howland LJ, ... Kershaw MH*, Darcy PK* (2012). Oncolytic Virus and Anti-4-1BB Combination Therapy Elicits Strong Antitumor Immunity against Established Cancer. Cancer Res.72(7):1651-60. (* equal corresponding author)
In this work, a novel combination of oncolytic vaccinia virus and an immune agonist antibody was used to stimulate innate and adaptive immunity against tumours.
BSc (Hons) and PhD opportunities often exist within the lab in one or more of the above areas. Students should contact A/Prof Mike Kershaw for details.