Immunotherapies should work more broadly - why don’t they?
Solid tumours are the leading type of cancer causing 1 in 6 deaths globally. While many solid tumours have promising treatment strategies available to patients if diagnosed at an early stage (usually Stage I-III), once tumours advance to a metastatic stage (Stage IV), treatment options are often scarce or only able to mitigate symptoms.
Immunotherapy has revolutionised the treatment of many solid cancers. Simply said, immunotherapies are a new group of treatments that leverage a person’s own immune system to fight cancer. The most promising types of immunotherapy so far are chimeric antigen receptor (CAR) cell therapy and immune checkpoint inhibitor (ICI) therapy. Traditional CAR-based therapies use a patient’s own immune cells (most commonly T or NK cells), modulate them with a virus to “teach them” how to target and attack tumour cells, and then reinfuse them back to the patient to deploy these newly acquired anti-tumour skills. These expensive and time-consuming treatments have had incredible success in blood cancers such as leukemias but only limited success in solid tumours thus far. Immune checkpoints are the brakes (or off-switches) of the immune system, which help prevent self-attack of healthy tissue (autoimmunity). However, tumours learn to exploit this mechanism and heavily arm themselves with checkpoints to evade destruction by the immune system. Current ICI therapies aim to block such checkpoint signals to allow the reactivation of the immune system and the elimination of cancer cells.
Despite exceptional clinical successes of ICI treatments in cancer types like lung cancer or melanoma, average response rates in patients vary enormously and can range from 10-80%, leaving large numbers of patients without any meaningful treatment options. But why is that? Is there a way to increase the number of patients benefiting from existing therapies? How can we modulate solid tumours to make them susceptible to the benefits of immune-modulating therapies?
The elephant in the room: solid tumours are complex and redundant
The complexity of the tumour microenvironment (TME) can be likened to a symphony. Each individual component, such as cancer cells, blood vessels, immune and stromal cells, and the structural matrix, plays its own unique role. Still, when they all come together, they create a complex and dynamic system, much like how individual instruments in an orchestra come together to create a harmonious and intricate piece of music. Remove one instrument and the symphony may still play, but start affecting multiple important instruments and the tune falls apart - such is the case for immune-suppressed solid tumours that do not respond to ICI. While much effort has been directed towards improving clinical response rates - for example by identifying predictive biomarkers to improve patient selection - these efforts predominantly aim at identifying singular factors and thus largely ignore the multi-factorial components underlying immune suppression. The even bigger challenge, from a therapeutics perspective, is the large cohort of solid tumour types that currently are not even considered for ICI treatment.
Turning immune suppression upside down
The current state-of-the-art methods for removing problematic cell types within the TME focus on blocking their recruitment or function within the TME, or depleting them altogether. In most cases, the targets used to achieve this also trigger unwanted effects - either on beneficial cell types within the tumour, or in healthy, non-cancerous tissues in the body. These side effects can range from tolerable to life-endangering and have in some instances led to clinical trials being halted or suspended.
Substantial scoping efforts at DSV have led us to develop a multi-pronged therapeutic approach to reprogramme the phenotype of problematic cells in the TME. Our technology will not only revert the immuno-suppressive phenotype but will create the environment for immune-mediated tumour elimination. Our efforts have culminated in a novel approach with great potential therapeutic benefit across a wide range of different tumour types, which would be available as an off-the-shelf product as opposed to costly and poorly scalable personalised approaches. On one hand, this therapy will remodel immune-suppressed tumours to enable them to benefit from existing immunotherapies while on the other hand, it will allow solid tumours that were never before eligible for immune-modulating therapies to be susceptible to such treatments.
The opportunity here is enormous and is one that we are actively working on at Deep Science Ventures together with our venture build partners Cancer Research Horizons. Dr Elisa Arthofer joined us 9 months ago with the broad goal of finding ways to transform outcomes for immune-suppressed solid tumours. Elisa is now seeking a co-founder to build a company around this technology of enabling immunotherapies for solid tumours. If you are an entrepreneurial-savvy scientist with expertise in therapeutic nucleic acids and have insights into (non-viral) therapeutic drug delivery, plus are highly driven to start a company from the get-go, we want to hear from you! Please see more details on the role and the application process in the job description.