News Hub

Madhavi Lakkaraja, MD, MPH
Fred Hutchinson Cancer Center, University of Washington School of Medicine
United States

From ISCT 2025 Roundtable Session: Cell Therapies to Manage GVHD - Learning From Pivotal Approvals

1. How the Biology of Acute Graft Versus Host Disease (GVHD) Makes It Amenable to Specific Treatment With a Focus on Mesenchymal Stromal Cell (MSC) Therapy

Introduction of GVHD and how MSCs have been useful for management of GVHD

Acute GVHD (aGVHD) mainly comprises of T cell alloreactivity and tissue damage. When host tissues are injured by chemotherapy/conditioning, the injury triggers an inflammatory cascade including trafficking of T cells to sites of injury as well as activation of antigen presenting cells (APCs). Activated APCs up-regulate presentation of minor and major self-antigens. Donor T cells recognize these disparate antigens as foreign on APCs as well as other tissue presenting these antigens leading to GVHD. 

Typically, agents used for treatment of GVHD focus on down-regulation of T cells. However, the immunity of GVHD is broader than T cell activation alone. MSCs can release multiple immune suppressive factors such as indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2).  They suppress activated alloreactive T cells but have additional immune suppressive functionality against both adaptive and innate immune cells. Preclinical and correlative studies have demonstrated that MSCs can be activated by specific inflammatory profiles in the host – especially interferon gamma and TNF-alpha.  The inflammatory signature of GVHD can potentially improve the in vivo functionality of MSCs. Consistent with this is the finding on clinical trials that patients treated earlier in the course, and for more severe manifestations of GVHD had superior outcomes. Over a 6-year follow up only 14% died of aGVHD – with the ones who responded early were cured of aGVHD.

The side effect profile of MSCs is favourable compared to that of other agents, so MSCs are appealing for first line treatment of steroid refractory GVHD especially in the pediatric setting. Biomarkers are an additional tool to identify patients at high risk of mortality from GVHD.  Pre-treatment ST2 and REG3α was assessed on the Mesoblast prospective study to generate a MAP score. High MAP scores correlate with grade 3 to 4 GVHD. Patients were matched with patients from the MAGIC study. It was noted that patients with a high risk MAGIC score (above 1.9) not treated with MSCs had 10% response and 1-year survival was 10% compared to those on the prospective trial, who had survival of 60% (comment by Mesoblast). 

Q: "Are there specific characteristics of non-responders to MSCs that could inform the field?"

The amount of inflammatory environment predicts response. MSCs need an optimal level of inflammation to respond. If inflammation is higher, then one needs a higher dosing of MSCs to work, and if there is no inflammation, cells won’t work (comment by Mesoblast).

In studies of COVID where MSCs were used, younger patients with COVID did better than adults who had several chemokine's. In addition, patterns of gene expression were higher in younger patients who got MSCs and they also responded better to steroids. Thus, degree of inflammation trigger may be different in older patients and may need different dosing of MSCS. 

Q: "Was there 'efficacy' in all types of acute GVHD? Hepatic GVHD?"

Very few patients have isolated liver GVHD. MSCs have been given in patients with liver and GI GVHD and liver GVHD has responded faster than GI GVHD, thus giving room for using hepatotoxic medications. 

Q: "Is there experience with MSCs in the Post Transplant Cyclophosphamide (PT-CY) setting?"

A lot of pediatric data for MSCs was in pre-post-HCT Cy era. Rates of aGVHD have decreased with increasing use of T cell depleted based transplant platforms (specifically Post-Transplant Cyclophosphamide). 

Q: "How does that change potential use and efficacy of MSCs? Is acute GVHD after PT-CY based GvHD prophylaxis similarly amenable to treatment with MSC?"

The frequency of aGVHD is lower in pediatric than adult transplant recipients and is especially low after T cell depleted transplants. That said, aGVHD occurring after either in vivo or ex vivo T cell depletion is more frequently severe (Grade 3 and 4) and steroid refractory than after conventional transplant. Patients enrolled on the Phase 3 trial included recipients of  ex vivo- T cell depleted transplant. The response to MSCs in these patients was similar to that seen in recipients of conventional HCT.

In the expanded access experience there was experience in children who had received PT-CY based GVHD prophylaxis and had steroid refractory grade 3 to 4 aGVHD. Responses to MSCs were very good in this setting. There is an upcoming trial in adults for Grade 3 to 4 aGVHD refractory to both steroids and ruxolitinib.  

Q: "Does treatment of acute GVHD with MSCs prevent subsequent chronic GVHD?"

The rate of cGVHD in responders ~ 10% 

2. Is There Experience in the Treatment of Acute GVHD That May Inform Repurposing of Cellular Therapies for Other Immune Mediated Disease?

There have been trials performed to demonstrate proof of concept in multiple disorders, but there is a need for large RCTs to see efficacy. 1-4 Additionally, concerns over the diversity of manufacturing contributes to product heterogeneity. Inconsistent trial design, patient heterogeneity and varied end points becomes a problem for clinicians and regulators.   

Q: "The approval happened after two prior denials by the FDA.  What can be said about this path to approval? What change with FDA interactions 2nd and 3rd interaction led to approval of MSCs?"

In every interaction with the FDA, updated data was presented.  From the beginning there was good clinical data. An expert advisory group also presented good efficacy data. However, the general view was that it was difficult to understand the mechanism of action of MSCs. The biomarker data was used to demonstrate that the severity of GVHD was associated with outcomes. In addition, details on the components of manufacturing process was presented in the meetings, which demonstrated that the product was potent and reproducible. An important piece was that the company understood the regulatory needs, and worked on standardization of the product used in trials and the same product was used in commercialization.

Q: "Having a drug approved in pediatrics for a disease that also occurs in adults and has the same diagnostic criteria is remarkable. Could this inform approvals for other diseases such as SLE or other autoimmune disease?"

Yes, maybe.  There was good clinical data from the beginning. An expert advisory group who presented good efficacy data. The company responded to concerns with a small cohort specific study and presented 5-year survival follow up data in children. 

3. Academic and Industry Based Models for Extending These Therapies to Patients in Need

There are two issues to be addressed – one is access of currently approved therapies and the other is how to support the next generation of therapies. 

The advantage of an industry-based product is the consistency of manufacturing, potency assays and product characterization.  These are things that will be very hard for academic based trials to achieve. However, as with other cell based therapies, there are academic centers that are producing MSCs to support their own clinical practice and that is likely to continue. As a worldwide community establishing clear paths for these different models is something that will likely evolve over the next few years. 

4. Access to Approved Product

Q: "Please specifically discuss the high price of this therapy in the US ($194k) and the price of a slightly different product in Japan (7k$)."

Cost depends on dosing, frequency, and details of product. Japan has first generation product developed 10 to 15 years ago (Prochymal). US has newer product (Rayanso) which is much more superior to the older product.  In addition, health care costs in the US are much higher. But also, one needs factor in decrease in hospital costs due to impact on ICU stay due effectiveness of the product, which also varies with region.

There are potential barriers to rapid access imposed by this high cost; with the competing issues of time sensitivity for treatment with the need to get payer approval for high cost agents. Mesoblast states that they are committed to making the product available to all patients in need. It is not clear how exactly this will be managed, and it will likely require different models at different centers. Mesoblast is currently working with different insurance companies (Medicaid, private insurance companies), to improve accessibility. Mesoblast is also working with specialty pharmacies to increase access (goal is to get cells in 2 days).

Q: "Currently, 14 doses treatment course per FDA label but if clinicians feel lower number doses create stability, is there any data re-exposure to see if GVHD is responsive or will be worse?"

CR is the best measure for response. There is no data if CR is noted sooner if there is need for more doses. However, with PR there is a need for more doses – to get CR. Clinical improvement is not adequate and patient needs to be in CR. Clinical course can be variable therefore needs all doses. Once patient attains CR, then treatment relapse is not typically seen. Given that the safety profile of MSCs is good would not stop treatment early. Furthermore, approval for the product is obtained upfront and reimbursement is not an issue. 

Q: "How can we support next generation products?"

The evaluation of the next generation of products depends on collaborative medicine and good collaboration between academia and industry. There is a need for larger trials exploring homogenous products and endpoints. Currently bone marrow derived MSC trials are ongoing in Europe.  

Q: "How can one keep the product consistency? Is there a way to accommodate that if the source material extends to, for example, cord blood?"

We need very sensitive and specific matrix of assays to keep product consistent.  These need to be paired with scientific rationale (identify attributes which are important and keep measuring them). This approach will be helpful whether in an academic or industry setting and whether seeking regulatory approval or not.  As an example, bone marrow derived and cord derived products need to be compared head-to-head. 

references

#CommunityFeature