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post treatment. More than one-third of oncology trials were using biomarker-based immunotherapy as of late 2017, according to the IQVIA Global Oncology Trends 2018 report. In concept, biomarkers are small and large molecule signatures that can be used to determine whether a drug has a likelihood of success in a given patient. Biomarkers are obtained from patient biological samples, main- ly blood and biopsies, and then analysed for an individual patient. Healthcare professionals then use biomarker profiles to make treatment decisions. On the furthest (and most expensive) end of the biomarker spectrum is the use of PDXs in a mouse model, making the mouse an avatar in which to test the efficacy of a therapy tailored to an individual based on the unique make-up of his/her tumour. Champions Oncology, a US-based contract research organisation, employs a similar approach, develop- ing custom PDX models based on highly specific characterisation of tumours and tumour subtypes. While there is significant potential for this work to improve clinical decision-making, a current draw- back is that no mechanism for coverage under tra- ditional health insurance exists as of yet, and broad implementation thus far has been limited due to cost prohibitions.


The case for cancer vaccines Using vaccines for disease prevention or treatment is another emerging area of focus in oncology, encompassing off-the-shelf vaccines and those tai- lored to an individual patient’s genetic make-up. Typically, cancer vaccine development requires extensive screening to identify unique tumour anti- gens and then further engineering them for efficient presentation to the adaptive immune system via major histocompatibility complex (MHC) pro- teins. Similar to checkpoint inhibition, a key lim- iter in leveraging animal models for efficacy testing requires genetic humanisation to ensure appropri- ate downstream activity and function. In humans, the MHC machinery is known as the human leuko- cyte antigen (HLA) programme. HLA and MHC function similarly in mice and humans, but have diverged through evolution, leading to subtle but meaningful differences in the way murine MHC and human HLA present antigens in vivo. Using mouse models that express HLAs, researchers have begun to study human response to antigens in vivo. In silico modelling typically is used first to identify the peptides that bind to target HLA supertypes; then in vivo immunogenicity is confirmed in HLA transgenic mice, followed by development of a vac- cine that incorporates the appropriate epitopes3. Though the field of cancer vaccines is still rela-


Drug Discovery World Spring 2019


tively young, several early successes have been achieved in the clinic and the lab. Inovio Pharmaceuticals recently announced a second patient in remission from HPV-related head and neck cancer in a Phase I trial after treatment with a DNA vaccine and a PD-1 checkpoint inhibitor4, while researchers from the Scripps Research Institute, working with other investigators, devel- oped a vaccine that demonstrated efficacy in a mouse model of melanoma when combined with a PD-L1 inhibitor5. Given the growing trend toward combination therapies, it is perhaps not surprising to see leading players such as BMS and Merck now collaborating on trials that combine established PD-1 checkpoint inhibitors with investigational cancer vaccines for a variety of tumour types. In keeping with the precision medicine trend,


cancer vaccines are likely to take a more person- alised approach in the future. Already there is interest in exploring how machine learning could be used to assess where the greatest risk of cancer exists in a given class of patients, then tailoring a vaccine accordingly. For example, the Epstein Barr virus has been associated with certain forms of lymphoma, prompting researchers to investigate whether tumour cells that produce proteins associ- ated with the virus could be targeted by a T-cell- based vaccine capable of killing cancerous cells.


The microbiome-cancer link While the microbiome is often associated with dis- eases of the gut, mounting evidence indicates the microbiome plays a role in a wide range of dis- eases. Several investigations are under way to explore the potential link to cancer, including a recently-announced $25 million study funded by Cancer Research UK to investigate the connection between the microbiome and colorectal cancer. Fourteen investigators in six countries will use ani- mal models and organoids to assess a potential relationship, while also examining the effect of col- orectal cancer treatments on patient microbiota. Several studies have already shown a link


between the microbiome and various cancer types. New York University researchers demonstrated that the pancreas has its own microbiome capable of driving immunosuppressive conditions in a mouse model and increasing disease progression. When the KC mouse model of pancreatic oncoge- nesis was derived as germ-free, the mice were pro- tected against disease progression. A combination of microbial ablation and treatment with a PD-1 inhibitor reduced tumour growth, indicating that manipulating the microbiome can both limit dis- ease progression and enhance treatment6.


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