For the past 17 years, Ed Steger, president of the National Foundation of Swallowing Disorders, has battled an invisible disorder. He appears healthy, leading to instances where people absentmindedly ask him to meet for lunch. “I may meet them, but lunch is not something I can do,” Steger said. When he does gather with friends and family at a restaurant, his unseen condition still stands in the way. If he does not order anything, the waitstaff typically repeatedly ask him if he would like something to eat. Steger has learned to order food, although it will go untouched, so that he can enjoy his company uninterrupted. “This is kind of a trick of the trade,” he said.
Steger has missed more than 10,000 meals since being diagnosed with severe dysphagia, or swallowing difficulty, in 2007. His story begins with a different, less invisible disease: cancer. To treat squamous cell carcinoma in his oral cavity, Steger underwent eight chemotherapy regimens, 36 radiation treatments, and six surgeries, including a salvage surgery that removed parts of his tongue, jaw bone, epiglottis, and soft palate. While this intervention stopped his cancer from recurring, it also left him unable to swallow normally. To adapt, Steger learned a specific swallowing maneuver (“It’s not a social swallow,” he said) and transitioned to an almost completely liquid diet.
People commonly experience swallowing difficulty following treatment for head and neck cancer. While surgical tumor resection may result in an immediate impairment, radiation toxicity leads to progressive muscle weakening, tissue scarring, and potential nerve dysfunction in the swallowing structures, causing swallowing function to deteriorate over time. The tongue represents one of the major targets for damage and the most critical anatomical components for swallowing. The tongue not only pushes chewed food from the mouth to the throat, but it acts as a pump that creates the force needed to propel the bolus into the esophagus. “Any therapy that helps strengthen the tongue and that helps improve its pump ability should be helpful for swallowing,” said Marlis Gonzalez-Fernandez, a swallowing disorder specialist at Johns Hopkins Medicine. “It's something that we [take] for granted until it's affected seriously.”
Current treatment for tongue dysfunction usually entails performing lingual exercises, but this approach does not sufficiently restore the muscle mass or range of motion of the tongue. Researchers at the University of California, Davis (UC Davis) recognized that regenerative cell therapy could provide a better solution, and that the tongue offered an intuitive, accessible platform. Building off a decade’s worth of research, they are now investigating tongue injections of autologous muscle-derived cells as a treatment for dysphagia in a Phase 1 clinical trial and partnering with researchers at the University of California, San Francisco (UCSF) to conduct a Phase 2 clinical trial. The team hopes that the therapy will help strengthen the tongue, improve swallowing function, and ultimately relieve the immense physical and mental burden associated with dysphagia.
Coming back stronger
The human body possesses an innate ability to repair its own muscle. When skeletal muscle undergoes small tears due to exercise or injury, satellite cells that reside on the outside of the muscle fiber spring into action. These progenitor cells, which serve as precursors to functional muscle cells, respond to signaling molecules released at the site of the injury. They differentiate into mature muscle cells and fuse with existing muscle fibers or create new muscle fibers to regenerate the muscle. The satellite cells also self-renew, proliferating in their undifferentiated state to maintain a reserve of cells that can repair the muscle the next time it is injured. However, more severe or permanent damage to the muscle tissue interferes with this natural healing process.
One strategy for repairing this damage is injecting muscle-derived cells from healthy skeletal muscle. During the injection, the needle creates microinjuries in the muscle similar to those caused by exercise, initiating the biological cues that trigger the satellite cells’ regenerative response. The muscle-derived cells also secrete growth factors that help promote the development of nerves and blood vessels to form functional muscle tissue.
As the research team at UC Davis began exploring this approach to treat dysphagia, they needed to ensure that the transplanted cells could survive and successfully integrate into the tongue tissue. When they surgically removed a portion of the tongue from immune deficient mice and injected human muscle-derived stem cells, they observed that the cells remained viable throughout the 12-week study period (1). Similarly, in a sheep model featuring nerve injury in the tongue, they found that muscle-derived stem cells collected from the sheep’s own sternocleidomastoid muscle survived and fused with the muscle fibers in the tongue upon injection (2).
When the researchers examined the sheep tongue in closer detail, they observed that the muscle fibers that incorporated the cells showed an increase in diameter, demonstrating the treatment’s ability to build tongue muscle. They also found that injecting the muscle-derived stem cells enhanced the contractile force of the tongue and the pressure at the base of the tongue, suggesting that muscle growth at the cellular level could lead to functional improvements in tongue strength and swallowing.
Encouraged by these promising results, the team launched a Phase 1 clinical trial to evaluate tongue injections of autologous muscle-derived cells in humans (3). They collaborated with the regenerative medicine company Cook MyoSite to manufacture the cell therapy product, which has also been used to treat stress urinary incontinence, fecal incontinence, and underactive bladder. The clinicians first perform a biopsy to collect a sample smaller than the tip of the pinky from the patient’s quadricep muscle, one of the largest and strongest in the body. “These patients are typically patients that for a period of time are not able to eat very well, so they're patients that are a little bit frail in terms of muscle mass to begin with, so taking it from the thigh muscle would be the most logical choice,” said Ron Jankowski, the vice president of regulatory and scientific affairs at Cook MyoSite.
The biopsy sample is shipped to the Cook MyoSite facility in Pennsylvania, where scientists isolate the satellite cells and expand them in cell culture, using specific conditions to maintain the cells as undifferentiated muscle precursors. “Keeping them in that state that's going to lead to regeneration when you put [them] back into the target location, that's the secret sauce. That's the tricky part,” Jankowski said. Once they have produced millions of cells, Jankowski’s team cryopreserves the cell therapy product and ships it back to the clinical trial sites in California, where it is stable for at least six months while frozen.
In the ongoing Phase 1 clinical trial at UC Davis, the investigators have injected the cells into the base of the tongue in approximately 20 people with dysphagia resulting from oropharyngeal cancer treatment toxicity. While some patients reported pain and swelling at the injection and biopsy sites, and one patient developed a minor, transient hematoma in the thigh following the biopsy procedure, the researchers have not observed any significant safety concerns. With such a small sample size, the study was not designed to evaluate efficacy, but the team looked at preliminary trends in the effects on tongue function. “Developing the outcome measures was a really challenging topic, mainly due to the fact that this is the first time anything like this has been attempted in this patient population for this indication,” said Johnathon Anderson, a translational stem cell researcher at UC Davis and the project manager for the clinical trial.
The researchers measured tongue strength using the Iowa Oral Performance Instrument (IOPI), where the patient holds a small balloon on top of the tongue and presses the tongue to the roof of the mouth as hard as they can while the instrument measures how much pressure the tongue generates. In the 17 patients tested so far, they observed an average increase in tongue strength of 15 percent one year after the injection of the muscle-derived cells compared to their baseline state.
“In part, you're really hoping to prevent progression [of dysphagia]. So, if the patients stay the same with stem cell therapy, that's a victory,” said Clark Rosen, an otolaryngologist and the lead investigator at the UCSF site. Anderson added, “But what we saw is actually not just the patients staying steady state; we actually saw an increase in their tongue strength. …If that trend holds true for the later phases of the trial, that would be actually phenomenal for the field and would just be a huge win for the patients.”
It's a journey
The team is now conducting a double-blind, placebo-controlled Phase 2 clinical trial at UC Davis and UCSF to evaluate the efficacy of autologous muscle-derived cell therapy for dysphagia following treatment for oropharyngeal cancer (4). The patients who receive the placebo will be offered the active cell product after the treatment groups are unblinded.
In the Phase 1 trial, the researchers tested two doses, 150 million cells and 300 million cells, and observed a slightly greater increase in tongue strength with the higher dose. They therefore decided to use the 300 million cell dose in the Phase 2 trial, but to divide it into two separate administration sessions that take place four to six weeks apart. Spacing the injections out enables the cells to be distributed across a larger area of the tongue and allows for a fresh wave of microinjuries that support the cells’ regenerative activity.
The investigators are evaluating tongue strength using the IOPI for the primary efficacy outcome measure and incorporating several secondary outcome measures related to swallowing function. One of these is the penetration-aspiration scale rating from swallowing fluoroscopy, where the patient ingests a substance labeled with an X-ray-based imaging marker that allows the researchers to visualize the path of the swallowed material on video. “[Patients] can’t safely move food and liquid from the back of their throats down into their esophagi, and so things get stuck, or worse, more seriously, get into their larynx and airways and lungs and they develop pneumonia,” Rosen said. “What the penetration-aspiration scale quantifies is how much and how often and how deep does ingested food or liquid go into the airway?”
The researchers are also performing high-resolution manometry, where they pass a probe lined with pressure sensors through the nose and into the esophagus to measure the force of contraction in different regions of the throat as the patient swallows water. Additionally, they are assessing patient-reported experiences and symptoms of dysphagia using a validated survey tool.
The team has encountered some hesitation when recruiting clinical trial participants with complex medical backgrounds. “Some patients do have fears of stem cells causing cancer,” Anderson said. “When we think of stem cells, one of their properties is they have the ability to proliferate if they're triggered to do so. And that starts to become reminiscent of cancer, which is basically unchecked, uncontrolled proliferation of the cells.”
While certain stem cell therapies have demonstrated an ability to form tumors in mouse models, the researchers reassure the patients that this concern has not materialized in clinical settings (5). Importantly, there have been no instances of tumor development or recurrence in more than 700 people treated with Cook MyoSite’s autologous muscle-derived cell product for multiple indications.
For those that proceed with the trial, the response has been generally favorable. The team recently secured FDA approval to administer a second round of injections to the Phase 1 trial participants after receiving positive feedback and requests for additional treatment. For many patients, even the hope of a therapeutic for dysphagia signifies progress. Often, “healthcare providers look at them and say, ‘This is what happens when you have radiation. Be grateful that you're cured of cancer, but I don't have much to offer you [for] swallowing function,’” Rosen said. “I hear from our patients regularly, ‘Thank you for doing this study. I'm glad that someone's investigating this area because I've been hearing for years and years that nothing could be done.’”
While the current study population represents only a fraction of dysphagia patients, the team hopes that, if successful, the treatment can be explored for other types of swallowing impairments. “That's where the results of the video fluoroscopy and the manometry will be really helpful,” said Gonzalez-Fernandez, who is not involved in the clinical trial. “We need to understand well what physiologic change is prompted by this treatment, so then we can target other diseases where that same change in physiology could potentially be helpful and study it in those groups.” She also envisions that autologous muscle-derived cell therapy could be applied to swallowing apparatus muscles beyond the tongue that are weak or dysfunctional in certain patients.
Steger is not a candidate for the current treatment due to the extensive surgical damage to his oral cavity. But as a dedicated patient advocate, he hopes that the trial will yield a positive outcome. While ideally there will come a day when patients no longer have to choose between saving their lives and preserving the quality of their lives, Steger expresses no regrets about his treatment history. “I did have a choice in 2006 to not have surgery, but at the time, I wanted to see my 12-year-old daughter grow up, and so I decided to do everything I could to make that happen,” he said. “I’m glad that I’ve been able to take this journey.”
- Kuhn, M.A., Black, A.B., Siddiqui, M.T., Nolta, J.A., & Belafsky, P.C. Novel murine xenograft model for the evaluation of stem cell therapy for profound dysphagia. Laryngoscope 127, E359-E363 (2017).
- Plowman, E.K. et al. Autologous myoblasts attenuate atrophy and improve tongue force in a denervated tongue model: a pilot study. Laryngoscope 124, E20-E26 (2014).
- Clinical Trials. Autologous muscle derived cells for gastro-intestinal repair (AMDC-GIR) for tongue dysphagia.
- Clinical Trials. Autologous muscle derived cells for treatment of tongue dysphagia.
- Wang, Z. Assessing tumorigenicity in stem cell-derived therapeutic products: a critical step in safeguarding regenerative medicine. Bioengineering 10, 857 (2023).