Review of 4 cell therapy types under study for COVID-19

This is a post by Mina Kim, a UC Davis student intern for The Niche blog, about the main types of cellular therapies being studied clinically for COVID-19.

During the novel coronavirus pandemic with millions of COVID-19 cases, the development of safe and effective treatments for patients is vital. Cellular medicine treatments are one of the most common approaches currently being studied in clinical trials by biotech companies and other researchers for COVID patients. 

Four of the major cell therapies that are presently undergoing trials for COVID-19 are mesenchymal stem/stromal cells (MSCs), natural killer (NK) cells, cardiosphere-derived cells (CDCs), and chimeric antigen receptor (CAR) T cells.

In today’s post I will give an overview of each of these cellular therapies including their rationales and potential risks or hurdles. I’ve also made a helpful infographic that I’ve  included below in this post.

Mesenchymal Stem Cells (MSCs)

The most studied type of cellular treatment for COVID-19 is based on MSCs. As stem cells, MSCs are known to self-renew and differentiate into a few specialized cell types. In addition, there is excitement about the molecules they secrete (the MSC “secretome”) potentially being therapeutic. They are mostly isolated from bone marrow, umbilical cord or other birth-related tissue, and fat tissue. 

As for the hypothetical benefits of administering MSCs to COVID-19 patients, studies suggest that MSC therapies might be able to reduce inflammatory cell infiltration in lung tissue, improve lung structure and function, and reduce over activation of the immune system. More specifically, a study proposed to infuse umbilical cord-derived MSCs into COVID patients with acute respiratory pulmonary inflammation. These MSCs are proposed to have the ability to repair damaged organs like the liver and kidney in several animal and human trials. The specific mechanisms of the treatment are continuing to be studied, but a publication from the European Respiratory Society mentions that the mechanisms could include the ability of the MSCs to modulate apoptosis and phagocytosis by immune cells. 

An issue concerning MSC treatments being studied for COVID-19 is that the cells are mostly allogeneic, meaning that they come from donors. Allogeneic cells may be rejected by the patient’s body because they are seen as foreign, resulting in getting attacked by the patient’s immune system. There is some debate as to whether stem-like cells such as MSCs may not trigger an immune response even in unmatched hosts, but this issue is still being studied. Allogeneic cells may also pose risks by having the potential to negatively impact the immune system.

Natural Killer (NK) Cells

Natural killer (NK) cells are essential to our immune systems. They are a type of white blood cell that supports the immune system by identifying and killing stressed and aberrant cells. As such, NK cells were originally tested clinically mainly to try to target cancerous cells. 

Due to the NK cells’ abilities to attack infected cells, hypothetical benefits in a COVID-19 context include enhancement of the immune system as well as possible targeting and removal of SARS-CoV-2, the novel coronavirus that causes COVID-19.

Celularity, a cell therapeutics company that utilizes NK cells derived from stem cells in the placenta, has received FDA IND clearance to administer their CYNK-001 immunotherapy to COVID-19 patients in a trial. They propose that CYNK-001 could limit the SARS-CoV-2 virus from spreading in the body and prevent worsening of the disease. This hypothesis is based on some studies that indicate activation of NK cells during viral infections and that some especially sick COVID-19 patients may have lower numbers of NK cells.

A potential risk for NK cellular therapy stems from its ability to boost the immune system; this feature can be dangerous since cytokine storms have been shown to occur in some COVID-19 patients, worsening their conditions and sometimes being fatal. Additionally, NK cells are allogeneic, posing another risk of allogeneic cells being rejected by the patient’s body and being attacked by the patient’s immune system. Similarly, repurposing of NK cell treatments presents an issue as they are originally intended to be administered for cancer so in the new COVID-19 clinical trial context there could be new challenges or risks.

Cardiosphere-derived Cells (CDCs)

CDCs are cardiac cells (made from different heart cells) that are developed in the lab. Initially intended to treat cardiac diseases, CDCs have been shown to produce diffusible factors that encourage proliferation of heart cells and activation of progenitor cells. 

Previous studies of CDC treatments on patients with heart and muscle-related diseases have shown some immunomodulatory and anti-inflammatory effects of CDCs. Immunomodulation could be a vital basis of treatment for COVID-19 patients, especially ones with an overactive immune response distinguished by cytokine storms. 

CAP-1002 is a cell therapy produced by clinical-stage biotechnology company, Capricor, that utilizes allogeneic CDCs. Originally, CAP-1002 was developed as a treatment for Duchenne muscular dystrophy, which is now in the late-stage of clinical development. The main COVID-19-related interest in CAP-1002 is its immunomodulatory properties that the firm says have shown favorable immune responses, specifically to cytokine storms.  

One possible risk for CDCs relates to repurposing issues: CDCs are made to treat the heart and also skeletal muscles. There is also the issue of CDCs being allogeneic, so they could potentially be rejected by the patient’s body. 

Chimeric Antigen Receptor (CAR) T Cells

CAR-T cells are designer T cells with specific receptors that in a simple sense act like magnets for cancer or virus-infected cells. These engineered cells have been intended primarily to treat blood cancers. 

In terms of COVID, scientists at Duke-NUS discussed the possibility of T cells to be redirected into targeting the coronavirus. They anticipate CAR-T cell immunotherapy to control the SARS-CoV-2 virus. 

However, there is uncertainty and skepticism towards CAR-T cells, which have gained momentum in the field of cancer, for the use of infectious diseases like COVID. The CAR-T treatment for cancer (eliminating a tumor) is potentially much more direct than for infections (many vital organs infected). One other particular risk for CAR-T cell therapy is its association with toxicity and cytokine release syndrome. Cytokine release syndrome can ensue as an adverse effect of certain immunotherapies, severely harming the patient as an inflammatory response. As mentioned above, release of cytokines could worsen COVID-19. Further, another concern is that CAR-T cells are allogeneic so they can be seen as foreign and rejected by the patient’s body.

More General Cell Therapy Risks and Challenges

Though there appear to be several potential treatments rising since the coronavirus outbreak, we must still be cautious about these studies and in some cases the hype surrounding multiple therapies. After all, there are no FDA approved medicines or treatments for COVID-19. 

Unfortunately, with the hype of prospective treatments comes the danger of misleading the public and political leaders about unapproved products. In particular, many unlicensed and unapproved (by the FDA) stem cell interventions have been promoted by businesses that make vague and over-enthusiastic claims about their products. Not to mention, there is still a lack of data from trials with COVID-19, and even these studies experience limitations such as difficulty recruiting control group patients and randomizing patients. 

Looking Ahead

It is difficult to predict which, if any, cellular therapy of the four types discussed in this post might be most helpful for COVID-19 patients and also be safe. Beyond the cells themselves, some studies are also testing exosomes secreted by the cells as potential COVID-19 therapies.  In addition, a vast number of non-cellular approaches are being tested for COVID-19 and some of these, such as steroids which have already shown promise, may end up being proven to be more helpful overall than cellular medicines. 

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Paul Knoepfler also contributed to this piece.