Dr Ernest Moles Meler

Jan 2023 - date. mRNA nanomedicines for brain cancer therapy.

DIPG is the deadliest of all paediatric cancers (<1 year life expectancy) and remains incurable. Chemotherapy has been vastly unsuccessful due to the limited penetrability of conventional drugs into the brain, and radiotherapy only provides a short delay in tumour growth. CAR T cell therapy is an active treatment whereby T cells are extracted from the patient and genetically reprogrammed in the laboratory to attack the cancer cells. Recent preclinical and clinical studies have demonstrated the therapeutic potential of this approach to treat DIPG. However, high costs, delays in production, along with recurrent neurotoxicity linked to the permanent changes currently introduced in the T cells have severely hampered the clinical applicability and availability of this approach. IVT mRNA delivery using injectable NPs now offers the unique opportunity to circumvent these limitations by reprogramming the T cells directly in the patient in a transitory and precisely controlled manner, improving therapeutic potency and treatment availability, whilst reducing toxicity and costs of production. The main objective of this project, supported by a Moderna global fellowship awarded to Dr. Ernest Moles, is to the investigate the efficacy of IVT mRNA technology for the in vivo controlled reprogramming of T cells to recognize and precisely treat brain DIPG tumours. This approach is explored as an alternative treatment modality to conventional CAR T cell therapy by which we expect to achieve a potent cancer remission whilst reducing side effects, and advance towards the goal of providing a cure against this incurable cancer.

2019 - date. Development of RNAi nanomedicines for treatment of high-risk neuroblastoma.

High-risk neuroblastoma has a poor survival due to treatment failure and off-target side effects of therapy. Small molecule inhibitors have shown therapeutic efficacy at targeting oncogenic cell cycle dysregulators, such as polo-like kinase 1 (PLK1). However, their clinical success is limited by a lack of specificity, causing off-target toxicity, and difficulties in delivery to the cancer cells. Herein, we investigated a new treatment strategy whereby a bispecific antibody with dual recognition of methoxy polyethylene glycol (PEG) and a neuroblastoma cell-surface receptor, epidermal growth factor receptor (EGFR), is combined with a PEGylated small interfering RNA (siRNA) nanoparticle, forming BsAb-nanoparticle RNA-interference complexes for targeted PLK1 inhibition against high-risk neuroblastoma. Therapeutic efficacy of this strategy was explored in neuroblastoma cell lines and a xenograft animal model. Using ionizable lipid-based nanoparticles as a low-toxic and clinically safe vector for siRNA delivery, we identified that their complexing with EGFR-PEG BsAb resulted in unprecedented improvements in cell targeting (1.2 to >4.5-fold) and PLK1 silencing (>2-fold) against EGFR⁺ high-risk neuroblastoma cells, and enhancements correlated with EGFR expression on the cells (r > 0.94). Through formulating nanoparticles with PEG-lipids ranging in diffusivity, we further identified a highly diffusible PEG-lipid which provided the most pronounced neuroblastoma cell binding, PLK1 silencing, and effectively suppressed cancer growth in vitro in high-risk neuroblastoma cell cultures and in vivo in a tumor-xenograft mouse model of the disease. Together, our findings are of major relevance in the advancement of precision medicines for treatment of high-risk neuroblastoma. Research was conducted independently and in collaboration with the University of Queensland (Prof. Kris Thurecht - Centre for Advanced Imaging).

2017 - 2023. Development of targeted nanomedicines for treatment of high-risk paediatric leukaemia.

High-risk childhood leukaemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukaemia cells. This liposome targeting system follows a “mix-and-match” principle where BsAbs were selected on the specific receptors expressed on leukaemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukaemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukaemia. BsAb-assisted improvements in leukaemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukaemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukaemia

Research was conducted independently and in collaboration with other team members and research groups at CCI (Prof. Richard Lock - Leukaemia Biology group; Prof. Michelle Haber – Experimental Therapeutics group), University of Queensland (Prof. Kris Thurecht - Centre for Advanced Imaging), UNSW (Prof. John Pimanda), St Vincent's Centre for Applied Medical Research (Prof. David Ma). In a separate work following a similar approach, I have developed nanomedicines recognizing EGFR for targeted delivery of chemotherapy to non-small cell lung cancer (NSCLC). Outcomes are reported at published in the highly-regarded Science Translational Medicine journal (E. Moles, et al., Sci Trans Med, 15(696), 2023).