August 14, 2020

The Niche

Knoepfler lab stem cell blog

Interview with Sean Morrison on cellular therapies for COVID-19

Sean Morrison M.D.
Professor Sean Morrison, Ph.D.

To get at addressing what’s the real deal on the idea of cellular therapies for COVID-19, I did a short email Q&A interview with Dr. Sean Morrison.

Sean is Chair of the Public Policy Committee at ISSCR and Director of Children’s Research Institute at UT Southwestern. He was also President of ISSCR in 2015-2016, and during his tenure I interviewed him here on The Niche about the challenges and future of the stem cell/regenerative medicine field. You can read more about the Morrison lab here.

Here’s the interview.

PK: In the big picture, can you see potential roles for cellular therapies for COVID-19? Is there something unique they might be able to achieve that other approaches like anti-viral drugs could not?

I’m afraid I’m skeptical about cellular therapies for Covid-19. Some have suggested that transplantation of immune effector cells, such as NK cells, into patients might promote a more effective immune response. I worry it will take too long for the transplanted cells to engraft and mount an effective immune response against a virus that often kills patients within days of hospitalization. Others have suggested that mesenchymal stem cell (MSC) transplants might provide a benefit by attenuating the hyper-inflammation that occurs in late stage patients. While there has been some evidence that MSCs can attenuate pathological immune responses in some contexts, most clinical trials that tested this strategy failed. The other red flag is that all of the cell therapies I have seen proposed for Covid-19 have been repurposed from very different indications. To some extent that’s to be expected when dealing with a novel pathogen. However, it gives one pause when a cell therapy under development for cancer is suddenly touted as also having anti-viral activity. Immunologically, these are two very different problems that require very different kinds of pre-clinical testing.

There are things we can do. Social distancing is already making a big difference. Second, we need a national strategy for Covid testing on a much larger scale. That is the only way to achieve the goal of getting people back to work. I would draw people’s attention to Germany, which is rolling out widespread testing for anti-coronavirus antibodies to identify people with immunity to the virus. We need to find a way to do that on a national scale in the US. Finally, therapeutic recommendations should be based on data from clinical trials, not gut feelings. It doesn’t help when untested therapies are promoted as possible cures that should be widely adopted outside of clinical trials – it diverts resources in unproductive directions and has the potential to harm people.

PK: What unique risks might cellular and regenerative medicine therapies pose in COVID-19 patients as compared to traditional pharmaceutical drugs?

The cellular therapies proposed so far have sometimes been intended to increase immune activity and sometimes to decrease immune activity. The problem is that we don’t know whether patients would benefit from increased or decreased immune activation. Maybe it depends on the stage of disease. Perhaps increased immune activation would benefit early stage patients and decreased activation would benefit late stage patients. If we guess wrong, some of these cell therapies could make things worse. We need rigorous clinical trials to test new ideas. But there also has to be a sober consideration of the strength of the science supporting new ideas and of the potential risks and benefits.

PK: There are a few dozen registered small studies and trials utilizing allogeneic MSCs for COVID-19 based on the general premise of reducing overactive immune responses and/or inflammation. More such trials are going to begin shortly. As an immunologist, what do you think of this proposed overall MSC-immunomodulatory approach?

While there has been some evidence that MSCs can attenuate pathological immune activation in some contexts, most clinical trials that tested this strategy failed. As a result, I’m skeptical that MSCs will benefit Covid-19 patients. Allogeneic MSCs are probably rapidly eliminated by a patient’s immune system, particularly in the hyper-inflammatory environment within a Covid patient. Whether or not people disagree, the key thing is that advocates for this approach should test it in regulated clinical trials and publish their results. MSCs have too often been sold directly to patients as “cures” without systematic clinical trials to test for safety and effectiveness. Nobody should represent this approach to Covid patients as a therapy that is known to be effective.

PK: Exosomes, mainly derived from MSCs, are also being tested, in some cases via IV administration but in other cases via inhalation. Thoughts on exosomes for COVID-19?

There is no reason to think that exosomes would provide any benefit to a Covid-19 patient. The scientific community is still struggling to understand precisely what exosomes are, what they do, and whether administration to a patient could have any effect. If people are able to develop well thought out scientific rationales for the use of exosomes in Covid patients, and compelling pre-clinical data, then this approach would have to be tested in regulated clinical trials. Nobody should represent this approach as a therapy that is known to be effective.

PK: Are there any new insights into why seemingly very similar patients have such extremely different experiences after infection with the novel coronavirus? Could it be the dose of exposure? Genetic factors?

We don’t know. Differences among people in pre-existing conditions certainly contribute. Genetic differences could play a role. There are all kinds of differences among individuals in their immune systems, some of which arise by chance and some of which are shaped by our prior infections/illnesses. We all have somewhat different T and B cell repertoires because the receptors that determine the specificity of these immune cells undergo random changes during development. Those random changes could make all the difference when confronting a novel pathogen. Some people may get lucky and just happen to have T cells and B cells that are good at combating this virus. Others may be unlucky. Layered on top of these differences are the effects of prior history. For example, people who received chemotherapy may have lost some of their protective immune cells. We still have a lot to learn about the biology.

The good news is that the scientific and medical communities have been mobilized. It will be incredibly inspiring over the next two years to watch as scientists dissect the biology of Covid-19 in incredible detail. There will be lots of unexpected new ideas and we will test many new potential therapies. We will ultimately develop an effective vaccine. This could be a turning point that stimulates the development of a new generation of anti-viral drugs. Physicians will figure out how to provide more effective supportive care to late stage patients. The mortality rate will decline over time. At some point we will think of Covid-19 in the same way as we used to think of other deadly viral pathogens, like polio, that were once major public health problems but that now no longer seem relevant to our daily lives.

PK: The FDA seems in a rapid-approval kind of mode for COVID-19-related investigational therapies, with some approaches and INDs being cleared in as little as a few weeks. Do you have any concerns about that or instead given the extreme risks of the pandemic do you feel such speedy approvals are sometimes going to be the way to go during the outbreak?

I have enormous respect for the FDA and the talented people who work there. Most Americans don’t understand how important the FDA is to ensure the safety and effectiveness of therapies sold to patients. In recent years, many states, and even the federal government, have passed Right-to-Try laws that were sold as a way of accelerating medical innovation and giving incurable patients wider access to experimental therapies. In fact, few patients are likely to ever benefit from these laws. The real intent of those laws was to undermine FDA regulation. I worry that the current environment may stimulate efforts by bad actors to use Right-to-Try laws as a pretext to deliver fake therapies to desperate patients.

I’m glad many organizations were able to launch clinical trials for diverse anti-viral agents so quickly during the current pandemic. The key thing is that these decisions to accelerate entry into clinical trials have to be based on credible data that provide a sound rationale for why patients might benefit. I do worry in the current environment that FDA may experience political pressure to accelerate approvals for some agents that are not supported by sound science. That would harm patients and divert resources from more promising approaches.

PK: Anything else you think important to add?

I hope this experience redoubles the nation’s commitment to science and medical research. The public strongly believes in the power of medical research but the general public doesn’t pay much attention to changes in science policy or funding. Most people rarely think about medical research. They assume it’s going on in the background and that it’ll be there to help them if they ever get really sick. But national policies that undermine medical research really do affect our ability to be there for people when they need us.

Medical researchers often find themselves defending meritorious work against restrictions that are imposed for political or ideological reasons. For example, the recent federal restrictions on fetal tissue research are already undermining work on anti-viral therapies – the same kind of research that led to the development of anti-viral vaccines and therapies that have saved millions of lives. Given the broad bipartisan support for this research over many decades it doesn’t make sense to undermine this research during a viral pandemic. I’m hopeful that the Covid experience will make people less tolerant of policies that undermine medical research. I’m hopeful that this will be a Sputnik moment for medical research, galvanizing public support for medical science and our dependence on it as a society.

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