Case Study


Figure 3


A CANscript test was run on a patient with HNSCC. While several ‘equivalent’ therapeutic options were predicted to


confer a response, the clinician opted for the Tx4, a less toxic choice. The patient


presented with complete response after six treatment cycles


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rates as low as 20% and median survival around 5-6 months (https://www.ncbi.nlm. nih.gov/pubmed/28536670). While conven- tional platforms for personalised medicine typically report on one output, such as muta- tional load or driver mutations, CANscript has the unique ability to compare treatment regimens against each other and enable a clinician to base ‘equivalent choices’ around likelihood of systemic toxicity. For example, Mitra tested a panel of


eight ‘equivalent choice’ regimens being considered by the ordering physician for a case of advanced HNSCC. CANscript pre- dicted five potential responding treatments, with the best response coming from a toxic regimen (Tx1). The clinician opted to treat the patient with Tx4, an equivalent choice that is known to have reduced systemic toxicity. After six cycles of treatment, the patient presented with a complete response (Figure 3).


These known limitations prompted


Mitra to engineer an ex vivo tumour plat- form termed CANscript™, where thin tumour sections with conserved cellular and microenvironment heterogeneity are transiently held viable in tissue culture wells coated with grade-matched tumour matrix proteins. Within CANscript, the patient’s fresh


autologous blood plasma provides endoge- nous growth factors and cytokines, which enables an activated immune compartment (Figure 1). Mitra has used this platform to train a computer algorithm that is matched to clinical response of treatment. To do this, Mitra employed ‘machine learning’, a


subfield of computational mathematics that enables computers the ability to learn ‘clinical response’ without being explicitly programmed. Using this 21st century approach, an algorithm has been optimised by ‘scoring’ the tumour’s reflex to multiple different clinical treatments. This ‘M-score’ is scaled on a range of -0-100 where a cut- off of 25 separates ‘responders’ from ‘non- responders’ (Figure 2). Including training and validation this


algorithm, Mitra has provided clinical pre- dictions on more than 2,000 patients. Within seven days from tissue arriving at a Mitra laboratory, a patient’s response to clinical therapies, including biologics, tar- geted kinase inhibitors, immuno-modulators and cytotoxic chemotherapies is reported to the clinician with a positive predictive value (PPV) near 90% and a negative predictive (NPV) value near 99%.


Use case: separating out toxicity among equivalent choices Refractory,


Figure 4:Multiplex immunohistochemistry is used to help characterise the entire tumour microenvironment


Drug Discovery World Spring 2018


Helping to revolutionise the age of immunotherapy The recent discovery that tumours co-opt immune check-points as a mechanism of escaping immune surveillance has led to a renaissance in immunotherapy and revolu- tionised cancer


treatment options.


However, durable response rates remain variable, even in patients where immune activity is high. This suggests that inherent patient-specific biology is likely driving responses, which is thought to be depen- dent on the unique immune landscape of each individual patient. Not only is immu- nity an essential component to tumour biology, the spatial organisation of immune cells within the tumour, such as cytotoxic T-cells, contribute to the effect of therapy (Figure 4). Mitra is meeting these challenges, which


recurrent or


metastatic head and neck squamous cell carcinoma (HNSCC) is highly aggres- sive, with overall response


plague personalised cancer medicine, and is uniquely positioned to interrogate tumour- immune biology using the CANscript plat- form. By preserving the intrinsic spatial heterogeneity of immune cells within the tumour, and incorporating the active immune cells from each individual patient, the complete biology of the patient is recre- ated outside the body. With this advantage, Mitra is positioned to integrate emerging therapeutics that may hold the promise of a cure in the future.


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