Paul Beavis

Immunotherapy of cancer has been a major breakthrough in the last decade, now being accepted as the fourth pillar of cancer treatment after surgery, chemotherapy and radiotherapy. Immunotherapy is most effective in cancers with a high mutational burden and high levels of immune infiltrate, while cancers with a low mutational burden and/or low levels of immune infiltrate are refractory. Our vision is to identify novel targets/ combination approaches that are effective in these refractory cancers.

research Projects

Targeting adenosine mediated immunosuppression

Tumours utilise multiple immunosuppressive pathways to suppress anti-tumour immune responses including well characterised immune checkpoints such as the PDL-1: PD-1 axis. One such mechanism is the production of adenosine by tumour cells and host immunosuppressive cells (Beavis et al. 2012), catalysed by the ectoenzyme CD73 (Figure 1). Our work has shown that expression of CD73 is a prognostic biomarker in cancer patients and has highlighted the significant role of adenosine in the tumour-mediated immunosuppression of NK cells (Beavis et al. 2013) and T cells (Beavis et.al. 2015). Adenosine suppresses the anti-tumour activity of NK cells and T cells principally through binding to adenosine A2A receptors, expressed following activation of these cells. Importantly, we led the way in revealing that blockade of A2A receptors increases the effectiveness of PD-1 blockade (Beavis et al. 2015).

Several pharmaceutical companies have now developed antibodies and/or small molecule inhibitors of the CD73-A2A axis and these are now in phase I clinical trials, including two phase I clinical trials that are being conducted at the Peter MacCallum Cancer Centre (https://clinicaltrials.gov/ct2/show/NCT02655822). Current work in this area is focused upon further characterising the mechanism by which A2A antagonists are effective at both the cellular and molecular level. We believe this will result in the identification of novel combination therapies, with the potential to further enhance the effectiveness of targeting this pathway in cancer patients.

Figure 1: Generation of adenosine in the tumor microenvironment, driven by ectoenzymes CD39 and CD73, leads to the suppression of multiple immune subsets.

Enhancing the efficacy of chimeric antigen receptor (CAR) T cells in solid tumours

The generation of Chimeric Antigen Receptor (CAR) T cells involves the transduction of a patient’s peripheral blood derived-T cells with a CAR that is able to directly recognise tumour antigens on the cell surface and infusing these back into the patient. CAR T cells have been proven to be highly effective in haematological malignancies and are now FDA approved.

In the Beavis laboratory, we are focused upon enhancing the effectiveness of CAR T cells in solid cancers since results in this setting have so far failed to recapitulate the striking successes seen in haematological cancers. The major themes of our research are to develop innovative strategies to overcome 1) Local immunosuppression of CAR T cells 2) Heterogeneity of tumour antigen expression and 3) Poor trafficking of CAR T cells to the solid tumours (Figure 2).

Figure 2: Research themes in the Beavis lab to enhance the efficacy of CAR T cell therapy

Theme 1: Local immunosuppression of CAR T cells

It has now been established that CAR T cells are subject to the same immunosuppressive mechanisms which limit the anti-tumour activity of conventional T cells. Our group was the first to show that targeting the adenosine A2A receptor could significantly enhance the efficacy of CAR T cells in solid tumours, particularly in combination with anti-PD-1 (Beavis et al. 2017). We are currently pursuing other targets that can enhance CAR T cell function by relieving tumour-induced immunosuppression and have developed CRISPR/Cas9 technology to achieve this (Giuffrida, Sek et al. 2021).

Theme 2: Engaging endogenous immunity to overcome antigen heterogeneity

A major obstacle to the success of CAR T cells in solid tumours is the heterogeneous expression of tumour antigens which can lead to relapse after treatment with tumour cells negative for the CAR antigen. Therefore our philosophy is that CAR T cells need to engage the endogenous immune system to be successful in treating solid tumours. Our recent work (Lai, Mardiana et al. 2020) has demonstrated that T cells engineered to secrete Fms-like tyrosine kinase 3 Ligand (Flt3L) can induce the proliferation of host dendritic cells, particularly conventional type I DCs (cDC1); a subset specialised in the cross-presentation of tumour antigens to activate host CD8+ T cells. Importantly, we showed the combination Flt3L armoured CAR T cells and immune stimulatory adjuvants can drive significant host CD8+ T cell epitope spreading to target non-CAR antigens (Figure 3). This work holds translational potential for enhancing CAR T cell therapeutic efficacy in clinical settings of solid cancers with heterogeneous tumour antigen expression.

Figure 3. a. Graphical illustration of Flt3L armoured CAR T cell therapy. CAR T cells target antigen-positive tumours and secrete Flt3L into tumours. Flt3L expands and recruits cDC1, which upon activation with immune adjuvants, increase the activation of host CD8+ T cells in the tumour draining lymph node. This enhances the proportion of host anti-tumour CD8+ T cells, which are able to target antigen-negative tumour variants. b. Adoptive transfer of T cells engineered to express Flt3L induces the oligoclonal expansion of host T cells. c. Treatment of E0771-OVA-Her2 tumor-bearing mice with Flt3L-secreting anti-Her2 CAR T cells and immune adjuvants significantly increase the number of host CD8+ T cells targeting non-CAR (OVA Tetramer+) antigens (Data from Lai, Mardiana et al. 2020).

Theme 3: Enhancing T cell trafficking

One of the major limitations of currently approved immunotherapies is that they are ineffective in patients where an immune cell infiltrate into the tumour is lacking (so called ‘cold’ tumours). We have recently demonstrated that the chemoattractant cytokines (chemokines) CXCL9 and CXCL10 are essential for the trafficking of T cells to the tumour site and, in turn, the therapeutic efficacy of immune check point blockade (Figure 4; House et al., 2020 Featured on the cover of Clin. Cancer Res.). It is for this reason that in the Beavis lab we are currently developing novel strategies designed to enhance immune cell trafficking into tumours. We have developed high-throughput strategies to identify gene targets and therapeutics to enhance T cell trafficking. We have now combined this work with our significant experience in CAR T cell biology to develop highly innovative strategies to reprogram the tumour microenvironment and promote both CAR and endogenous T cell trafficking to the tumour. This project has the potential to discover novel targets that could significantly enhance the effectiveness of immunotherapy in solid cancers.

Figure 4. A. Differential gene expression analysis comparing responders to non-responders in baseline biopsies from melanoma patients receiving combination nivolumab/pembrolizumab and ipilimumab. B CXCR3 blockade inhibits the therapeutic efficacy of dual anti-PD-1 and anti-CTLA-4 (P+C). C. T cell infiltrate in tumours was assessed 7 days post-therapy ± anti-CXCR3 by immunofluorescence staining. Data from House et al. 2020, Clinical Cancer Research.

Theme 4: Clinical Translation

The Peter Mac is a world leader in the CAR T cell field and was the first centre in Australia to run a CAR T cell clinical trial. Clinical trials investigating CAR T cells in solid cancers are ongoing at the Peter Mac (PI Ben Solomon, funded by Celgene-Bristol-Myers-Squibb) targeting the Lewis Y antigen. The Peter Mac is the home of the National Centre of Excellence in Cellular Immunotherapies, developed to provide world-leading discoveries in CAR T-cell and cellular immunotherapy. Therefore our research in this area has high potential for future translation.