@reginaldp Thank you for drawing our attention to the paper by Kadri et al. (2023). It’s a brilliant find and deserving of the @Wilba32 award. So important that it’s published in Nature, IMO a rocket with a major payload that should be viewed in conjunction with Dr. Perin’s recent talk. The reply function sometimes doesn’t work, so I re-posted the links to the papers (first two) you referred to below and also to Dr Perin’s talk (26 min mark) on YT.
TLDR: This is a long post, so I put the main points below to serve as a summary and links to the papers I referred to so anyone can make up their own mind or make any corrections. A couple are behind a paywall.
In this post I discuss:
The complex interaction between the innate and adaptive immune system.
How it’s about more than inflammation, an anti-fibrotic effect brought about by the cells’ immunomodulatory action.
How the microenvironment of the host is crucial in determining response and thus there’s a need for biomarkers to identify responders.
Patient selection is key but it may not be so simple that some will benefit and some won’t. More than timing of delivery, patients’ ability to respond could be enhanced or even provided.
Biomarkers which could identify who is at risk of fibrosis; this is important for early detection of lung GvHD, which is difficult to diagnose and treat.
Biomarkers to Identify Responders
Kadri et al. (Nature, 2023) say, “An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness.”
Relevant to us, authors say:
“ In vitro, in coculture experiments with remestemcel-L, the FDA accepted MSC expression of tumor necrosis factor receptor type I (TNFR1) at a threshold level and inhibition of mononuclear cell expression of interleukin 2 (IL2) receptor α (CD25) as markers of potency and activity. However, these markers have failed to predict patient responsiveness and may rather be functional characteristics of cells with established MSC morphology and phenotype”.
Authors cite, however, a study with refs to studies which got conflicting results; in their letter to the editor of Nature (2012), Dander et al report on a very thorough study of 10 patients (children and adults) suffering from acute, overlap or chronic GvHD. They found IL-2Ra and TNFRI correlated highly with complete response, partial response and no response. Authors say even partial responders could taper immune suppression, which is very important due to high risk of infections.
My basic understanding of chronic GvHD is that it differs from acute in that it is more B cell driven and therefore more akin to an autoimmune condition; however, of the very small but IMO landmark phase 2 trial in 11 patients suffering cGvHD conducted in Sweden (NCT01522716), Kadri et al. say:
“In our study, not only B-cell frequencies but also naïve T-cell frequencies (with a high proportion of newly emigrant CD31+ cells) were elevated prior to treatment in the responders”
Reporting on this trial, Boberg et al. (2020), say:
“We performed a broad range analysis of cytokines and chemokines before, and 1 month and 5 months after the first MSC infusion (infusions 1, 2, and 6). The levels of the chemokines CXCL9, CXCL10, CXCL12, and the cytokines TNFα and IL-6 were similar in both patient groups before the first infusion. All of them increased in nonresponders during the first 5 months of treatment, while remaining stable in responders. The chemokines CXCL2 and CCL2 decreased in responders (Figure 3A). CXCL10 changes were completely segregated between the groups, increasing in all nonresponders, but in none of the responders, 5 months after the first infusion (Figure S5). The increase in inflammatory environment in nonresponders coincided with the progression of cGvHD symptoms and consequently the patients were classified as nonresponders after 6 months of treatment.”
Authors therefore propose CXCL9 and CXCL10 as early biomarkers for responsiveness to MSC treatment.
(If I understood correctly, this resonates with what Dr. Perin said about the innate and adaptive immune response. He mentioned IL-6 and the role of chemokines and cytokines, saying it’s about more than inflammation.)
Boberg et al. say the Swedish trial had similar findings to the study by Galleu et al. (2017). Galieu et al. focus on the immune status of recipients. Although only 1 patient out of 16 suffered cGvHD, the authors don’t differentiate between acute and chronic, discussing “GvHD”.
Galleu et al. found cytotoxicity was markedly different between responders and non responders and stressed the importance of the host immune system. The authors say patients should be ratified for MSC treatment according to their ability to kill MSCs and (if I understood correctly) even propose that those who don’t have the ability could be treated in order to provide this ability!
Biomarkers Correlated with Fibrosis
The Swedish trial should get the attention of physicians IMO because, despite the small number of patients, it’s so rigorous as to rule out any kind of bias. Very impressive results were achieved in patients who had been heavily pretreated and were refractory to first and second-line therapies.
The trial showed biomarkers correlated with biopsies of skin: “sclerosis remained unchanged in responders but progressed in nonresponders.”
This is huge IMO because it's clear evidence of an anti-fibrotic effect. (Dr Perin said the cells not only reduced inflammation but also had an “anti-atherosclerotic” effect. Atherosclerosis is associated with vascular fibrosis.)
Boberg et al. stress the importance of repeated infusions. They make a comparison with ECP (which actually failed its PE in a RCT) and is a very burdensome therapy requiring patients to attend hospital regularly over long periods, sometimes even years.
The Swedish trial had a very long follow-up and responders continued to improve over time, supporting what our CEO immunologist said many years ago about cells setting off a healing cascade.
The Current State of Chronic GvHD
The other paper Reg provided a link to by Vadakkel et al. (2024) discusses the current state of cGvHD. I couldn’t find mention of MSCs as a novel treatment (just discussion of the various nibs and rocks). Authors talk about “polypharmacy”, the cost of medication and medication intolerability as reasons for nonadherence, and that managing cGvHD requires a multidisciplinary approach. Steroids are the mainstay therapy which are associated with multiple AEs.
Authors say:
“In the long term, cGVHD-directed therapy should achieve a state of immune tolerance that allows for successful withdrawal from immunosuppressive therapy without relapse.”
This was achieved on the Swedish trial. Boberg et al. say:
“With a median follow-up time of 76 months (range 34-99) from inclusion, two patients have discontinued all systemic immunosuppression, and two are free of steroids and tapering calcineurin inhibitors”.
Vadakkel et al. say Reach3 showed Ruxolitinib efficacy even in late stages of therapy. Perhaps I overlooked something but I didn’t see that myself. The report published in the NEJM says the dose of glucocorticoids decreased over time in both groups with a “slightly greater decrease with Ruxolitinib”, which the graph in the supplementary index confirms. I couldn’t find anything about anyone being steroid-free or able to come off immunosuppression, or any clear discussion of an anti-fibrotic effect, despite Rux being known to do the best job in skin.
(Also, 50% of the treatment group discontinued, 63% of those due to lack of efficacy or AEs.)
Biomarkers to Identify Risk
Vadekkel et al. stress the importance of early treatment for cGvHD. In addition to identifying who will respond, surely it would also be valuable to identify who is at risk? This is particularly important for lung GvHD because its onset can be insidious and difficult to diagnose and treat.
Logan et al. (2023) say prompt diagnosis is necessary in order to avoid invasive biopsies which often reveal late-stage lesions. (One patient on the Swedish trial went on to lung transplant; in a study in MSCs for cGvHD cited by Kadri et al, Bronchiolitis Obliterans was excluded because authors say it is irreversible.)
In both the Swedish trial and Reach3 I couldn’t see a response for lung. If such fibrosis can't be reversed, then progression may be stopped. If not organ-specific biomarkers, then perhaps ones specific to fibrosis could identify patients at risk?
Logan et al. propose biomarkers to identify patients at risk of GvHD. Prior acute was not a clinical covariate in the present study. For lung, they propose early detection of MMP3, a proteolytic enzyme that degrades components of the extracellular matrix, which has been involved in lung fibrosing diseases.
Cheng et al. (2022) discuss stem cell-based therapy for pulmonary fibrosis. They provide references to an extensive body of literature on animals and humans which supports the therapeutic efficacy of MSCs in ALI (acute lung injury) and PF. Authors say there is a paucity of available pharmacological therapies for PF and that “to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF.” They say it's a very complex disease:
“Although some progress has been made to understand the innate and adaptive immune responses in PF, our grasp of the immune dysfunctions in the pathophysiology of lung diseases is still elusive.”
Authors say:
“Tregs may exert both anti- and pro-fibrotic roles, which depending on the balance of Th1/Th2 cells in lung” (I think that’s a typo and should be “depend on”.)
In this post 72160307 JB1975 says, “in the GVHD milieu you want MORE regulatory T cell activity and LESS helper T cell activity”. I’m unclear on this. I’m interested to learn more and how anyone can be so sure. Do we fully understand the complexity of the adaptive and innate immune response in any particular condition of immune dysregulation and at every stage of it? If it’s fully understood, then why did Dr. Perin say that Covid has taught us about the adaptive and innate immune response? Obviously, you want repair but for it not to be over exuberant.
Cheng et al. (as do Boberg et al.) stress the importance of repeated infusions. That reinforces the impressive results of our Dream trial with a single dose. Top cardiologist Valentin Fuster IMO didn’t appear to think the trial had failed. He sounded very impressed and raised the possibility of further dosing (though I concede it’s more invasive than IV). I also wonder about IV delivery of the more potent MPCs for PF?
Conclusion
Obviously the product characteristics are important but I suspect ours have been consistent for a long time and that detractors have deliberately focused attention away from something very important - the immune characteristics of the individual. GvHD is said to be challenging to treat because it’s a heterogeneous condition; however, by focusing on grades C and D with gut involvement, perhaps MSB’s target group is more homogenous?
Regardless, GvHD001 met its PE and the FDA don’t dispute efficacy; however, the strong evidence of the importance of the host immune system has implications for the RCTs which failed their PE overall but had success in prespecified subgroups. IMO they should be viewed in a new light.
Further, with ref to HF, Dr. Perin mentioned fluid in the lungs. He didn’t say this but it made me wonder about Entresto. One of its side effects is that it can impair kidney function. If this causes fluid build up in the lungs then that could lead to hospitalisations.
At the very least, approval should also be granted for end-stage HF soon, particularly given what’s gone on these past three years. Putting in an LVAD is a very invasive procedure and known to raise IL-6 level. Just how potent are the MPCs if they can not only survive in such an aggressive milieu but achieve vascular repair?
(20min delay)