Inducible apoptotic mesenchymal stem cells for the treatment of inflammatory conditions
Professor Francesco Dazzi
Dr Barry Porter
Stem cell therapies have the potential to address a variety of clinical unmet needs in many key disease areas, such as inflammatory disorders and regenerative medicine. For example, acute graft-versus-host disease (GvHD) in bone marrow transplant patients is a serious and potentially life-threatening condition. As first-line treatment, immune suppression with steroids has shown limited efficacy, however, the recent introduction of mesenchymal stem cells (MSCs) as immune modulators has had some success in steroid-refractory patients. The difficulty lies in the variability of the clinical responses and has led to large clinical trials with ambiguous or often conflicting results.
Ground breaking research by Professor Dazzi has demonstrated that immune suppression achieved by MSC therapies only arises when they undergo programmed cell death (apoptosis). This occurs in vivo, after live MSCs have been administered to patients, where apoptosis is triggered by the patient’s own cytotoxic immune cells. Importantly, the team also confirmed that MSCs can only be efficacious in providing immune suppression if a patient’s cytotoxic immune cells are present in adequate levels; patients without competent cytotoxic cells do not respond to live MSC therapies. This is an important finding and explains why MSC therapies do not work in all patient populations. This association has been confirmed in patients affected by Graft v Host Disease undergoing MSC infusions. Those exhibiting a high killing activity against MSCs are those who respond to the MSC infusion, whilst the killing activity is much lower in non-responders.
Caption: Clinical responses correlate with patients’ killing activity against MSCs
One application of this observation is the stratification of patients for treatment based upon their ability to kill MSCs and hence are more likely to respond positively to MSC therapies. To this end, a separate but complimentary project is underway to refine a simple biochemical assay that can determine a patient’s cytotoxic cell load and hence their likely ability to respond to MSC therapy. This current project is an extension of this discovery, involving the direct use of apoptotic MSC preparations (apoMSCs) eliminating the need for a patient’s own cytotoxic cells. This approach would revolutionise MSC therapies that could be efficacious in all patient populations irrespective of their cytotoxic abilities. Data has been generated using these in vitro-generated apoMSCs and has shown clear immunosuppressive results in preclinical models of both asthma and GvHD.
Caption: MSCs made apoptotic in vitro (apoMSC) are immunosuppressive in preclinical models of both asthma (A) and GvHD (B).
Work is underway to fully characterise these apoMSC preparations and will confirm their efficacy when administered either in a state of apoptosis or have been modified to allow the induction of apoptosis in vivo.
Given the variability of current MSC therapy in clinical trials and the evidence that this is partially due to a patient’s own variable cytotoxic cell killing ability, the use of apoMSCs that require no further activation would be a ‘one size fits all’ therapy that could benefit all patients.
The Project is currently seeking licensees or partners to fund and support development of the novel MSC preparation and workup to IND.
We are also considering seeking investment to create a company that could exploit all aspects of the intellectual property including both the novel MSC preparation as a pan-MSC therapy as well as the diagnostic and its use as a companion diagnostic for current MSC therapies.
A UK priority patent application was filed on 06/11/2017 (GB1718320.3).
Galleu et al., Sci. Transl. Med. 9, eaam7828 (2017) 15 November 2017. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.