What role will investigators in the Mass General Brigham (MGB) system play in the growing field of gene and cell therapy (GCT)?

It’s a large and complex one that includes gaining insights into the mechanisms of disease, translating those insights into products that can help patients, and collaborating with industry, regulatory agencies and payers to ensure the treatments are available to all who need them.

That was a key message delivered by MGB research leaders during the three-day World Medical Innovation Forum sponsored by Mass General Brigham Innovation last week.

The virtual event convened thousands of participants from the fields of academia, industry, venture capital and regulatory fields, as well as patients who have benefited from the first wave of GCT treatments.

“As a leading academic medical center in the US and globally, patients depend on us to make discoveries to cure disease or at least change the course of their illness, said Ravi Thadhani, MD, chief academic officer for MGB.

“This is a challenge we accept, but this challenge comes with responsibilities,” he added. “We must be sensitive to the needs of our patients, transparent about the benefits and risks involved, realistic about expectations, address concerns about costs and equities and transparent about costs.”

Thadhani and other research leaders also emphasized the importance of keeping patients at the center of the GCT discover process.

Engaging patients is crucial for investigators to understand the natural history of disease—particularly in the case of rare and ultra-rare diseases—as well as what’s important to the patient, what risks they are willing to accept and what endpoints are important to them.

Day One

Day One began with discussions on gene therapy, with themes of safety, efficacy, technological limitations and economies of scale.

Given the unique nature of genetic disorders, there’s not going to be a one-size-fits-all approach to treatment, said Meredith Schultz, MD, Executive Medical Director and Lead TME for Novartis Gene Therapies. “Each application, each patient group, each disease is going to have its own nuances.”

While early successes have been promising, target delivery continues to be a challenge.

Most gene therapy trials are using first generation adeno-associated viruses (AAVs), noted Mathew Pletcher, PhD, SVP and head of gene therapy research and technical operations for Astellas.

“We haven’t perfectly optimized that system, which leads to a deficit in reaching our target tissue at our optimal dose range,” Pletcher said. “If we can better engineer our capsids and viruses to get our transgene into cells to make a difference—this means dosages are lower, increased safety, lower pressure on manufacturing capacity, and lower costs.”

The high cost of gene therapy treatments is another potential roadblock, panelists acknowledged.

“There is a real tension between the types of therapies we are introducing, and the way health systems are set up to reimburse,” said Julian Harris, MD, a partner at Deerfield and former government health care finance executive.

Day Two

Day Two took a deeper dive into the potential of GCT therapeutics to treat different diseases—from ultra-rare genetic disorders to highly prevalent chronic diseases such as diabetes.

Panelists discussed several potential future uses for mRNA vaccines, including developing multivalent vaccines (vaccines equipped with multiple antigens) to protect against SARS-CoV-2 variants and improving the efficacy of the annual flu vaccine by including antigens from multiple influenza strains.

The same platform could also be adapted to deliver gene therapies and personalized cancer vaccines, participants said.

“Messenger RNA is the message, and we just have to decide what message we want to deliver to the cell,” said moderator Lindsey Baden, MD, of Brigham and Women’s Hospital. “The promise of this technology could not be more front and center for all of us.”

Day Two discussions also touched on challenges and opportunities in CAR-T therapy.

Panelists agreed there is still significant interest in CAR-T, from expanding treatments to more types of blood cancers to streamlining the production process to lower costs and improve accessibility.

When it comes to targeting solid tumors with CAR-T cells, two key challenges are identifying antigens specific to the tumors (so the CAR-T do not attack healthy cells in the body) and learning how CAR-T cells function in the tumor microenvironment—and what strategies cancer cells might use to evade them.

“We are still early in understanding how to tackle solid tumors and it is going to take a lot of innovation, a lot of creativity, and a lot of investment to figure out how we can do this,” acknowledged Barbra Sasu, PhD, CSO of Allogene. “But patients are waiting.”

Day Three

Scientific panels on Day Three focused on GCT opportunities in regenerative medicine, stem cell therapies and neurodegeneration.

“Regenerative medicine—perhaps more than anything—has captured the imagination of scientists and doctors, because it provides the opportunity for a new modality that is truly transformative,” said Ole Isacson, MD, PhD, director of the Neurodegeneration Research Institute at McLean.

“Neurodegeneration implies a slope of clinical and phenotypical decline,” said Bob Carter, MD, PhD, chairman of MGH neurosurgery. “Is our goal here mitigation, or do we think there is an opportunity for reversal of some of these neurological phenotypes and symptoms?”

Looking Forward

Concluding remarks touched on the importance of continued collaboration, access, equity and keeping patients at the center of the GCT development process.

Thadhani reemphasized MGB’s commitment to ensuring access and equity in delivering these treatments to patients. “It’s our mission.”

“There’s a continued need for a pipeline of invention, a pipeline of investment and the continued development of new tools and treatments, added co-chair Luk Vandenberge, PhD, Grousbeck Family Chair for Gene Therapy at Mass Eye and Ear. “We all sense great optimism regarding the power of gene and cell therapies. We have heard the day-to-day impact they can have on patients.”