Emily Whitehead was the world’s first child to receive CAR T-cell therapy in a clinical trial. She … [+]
Thirteen years ago, the first patients were treated in a landmark trial that is now recognized as one of the biggest breakthroughs in cancer treatment. The trial at Penn Medicine introduced the famous CAR T-cell therapy, in which patients’ own T-cells were genetically modified to hunt down and destroy their cancer cells.
Remarkably, more than a decade later, the researchers reported in Nature that several of those first patients are still alive and in sustained remission; the “living drug” remains active in their immune systems like a 24-hour guard long after their cancer has disappeared. One such patient is Emily Whitehead, pictured above, who was the first child to receive CAR T-cell therapy in a phase 1 clinical trial as treatment for her leukemia and is now still cancer free eleven years later.
That trial delivered thrilling proof of the power of cell therapy to cure – a word we don’t use lightly – cancer. There are now five FDA-approved CAR T-cell therapies, all indicated for hematologic malignancies like leukemia and lymphoma. Beyond cancer, cell therapy is seen as the next frontier with the potential to shift treatment paradigms for many other areas of unmet need, from autoimmune and infectious diseases to neurological disorders and diabetes.
But a stubborn gap has persisted between the promise and the reality. We have no proven cell therapies so far for solid tumors, which comprise 90 percent of cancer diagnoses, or for any of the other major disease areas — yet.
Today, however, we stand on the precipice of another sea change. Advancements in AI and machine learning, in combination with the biological and genetic insights gleaned over the last decade, are rapidly coalescing to enable the development of unprecedented technological solutions. Policy goals also now recognize the critical importance of ramping up cell therapy to meet its long-awaited potential. This spring, the White House formally articulated a national ambition to reduce the cost of cell therapy by 10-fold over the next 20 years. The stakes are high. If we fail to reach the goal, we risk cell therapy becoming a limited option that fails to reach many of those who stand to benefit.
At the same time, a debate persists among investors, founders, and researchers about how to prioritize two distinct scientific approaches: autologous and allogeneic cell transplants. Autologous cell transplants are bespoke treatments made from a patient’s own cells, while allogeneic ones are “off-the-shelf” and intended to be accessible to many patients at once. Each approach has its own costs and benefits.
More investors have been interested lately in allogeneic therapies because of their efficiency: many doses can be manufactured simultaneously from a single batch of induced pluripotent stem cells and banked. Case in point: there are more allogeneic cell therapies being developed than autologous therapies. Their mass distribution simplifies logistics and minimizes the time to each patient. Such therapies are currently in development for heart failure, Parkinson’s, and other diseases.
But there is a need for immunosuppression, even with human leukocyte antigen (HLA) matching. (HLA markers help your immune system recognize whether cells are foreign or part of your own body, and are important to match for blood or marrow transplants.) Yet some patients with chronic progressive illnesses can’t tolerate immunosuppressant drugs. And the “off-the-shelf” approach is not as effective for people of diverse backgrounds because cell banks tend not to have wide representation of the entire population. For example, a 100-line HLA-matched bank would cover 78% of European-Americans. However, it would only cover 52% of Hispanics and less than 50% of African-Americans.
The main advantage of the autologous approach is a cell therapy that doesn’t risk immune rejection, since it’s made of the patient’s own cells. To date, four single-patient in-human transplants of autologous iPSC-derived cells have taken place worldwide. None of the patients suffered serious adverse events, despite not undergoing immunosuppression, with the most extended follow-up reported in the literature being 4 years post-transplant. Such therapies are currently in development to treat heart failure, age-related macular degeneration, rare inherited skin disorders, and more.
The issue is the cost and time of making the bespoke treatments. Building a manufacturing facility costs at least $50 million, and the process is incredibly laborious. Cells must be cultured by hand, which is hard to reproduce even for experienced scientists, given the variabilities between cell colonies. Not to mention the time to get such a therapy to patients, which could take as long as six months, although new processes in development are working to greatly shorten this.
So how should we move forward to reach the White House’s ambitious goal, given both the pressing urgency and the enormous challenges?
We believe it’s essential not to stifle ourselves by creating a false dichotomy between autologous and allogeneic approaches, but rather to hit the gas on both fronts. A holistic view is necessary to solve the field’s most pressing challenges now and deliver treatments to all patients who stand to benefit.
In autologous transplants, one solution is to develop scalable manufacturing. Right now, we’re at an analogous point in time to genome sequencing 20 years ago, when the cost was $3 billion; last year for the first time, the cost came down to $100 per genome. Today, we’re at the starting line in cell therapy, but we can already glimpse the futuristic innovations that will be possible with enough resources and dedication. One exciting platform is a “process-in-a-box,” which will allow thousands of patients’ own cells to be processed in parallel into ready-to-use therapies using machine learning, laser editing, and automated cell reprogramming.
But experts must urgently come together with regulators to determine good manufacturing standards now to move away from the current paradigm of manual, custom labor toward automated, reproducible outcomes. This is a huge bottleneck and solving this would greatly accelerate the time to patients as well as reduce costs.
On the allogeneic side, scientists are working to create a gene-edited universal master cell that could be injected into anyone no matter their HLA. This would also dramatically bring down costs if shown to be safe and effective. But even if costs come down, there’s still the access problem. Right now, there are only a limited number of national centers where patients must go to receive cell therapy, and only for a limited number of blood malignancies. One solution to reach many more patients is an on-site bioreactor the size of a cabinet, placed at big hospitals in every city, which would produce cells on demand for infusion into each patient.
Another parallel solution is to develop in vivo CAR T-cell therapy for patients with solid tumors – meaning that technologies like gene editing can be deployed to modify immune cells directly inside the patient’s body, thus avoiding the complications of manufacturing the treatment in a facility. This approach could bring the best of both worlds, with traditional drug-like medicines turning a patient’s own cells into highly personalized therapies. Last week at the annual meeting of the American Society of Cell and Gene Therapy (ASCGT), at least six companies presented promising preclinical data on their platforms working to advance in vivo CAR T-cell therapy, including safety data in non-human primates and efficacy data in mice.
Scientifically, we’re at a watershed moment. Many varied and important technological solutions are within reach for the first time. That said, the most brilliant innovations won’t help most patients if they are too inaccessible, expensive, and difficult to manufacture. Let us seize the moment now through investment and collaboration at every level to avert the cost, equity and access issues that will otherwise be our fate. Together with developers and regulators, we must work in lockstep to advance effective, affordable, and accessible cell therapies for every patient, everywhere.
Thank you to Kira Peikoff for additional research and reporting on this article. I’m the head of Leaps by Bayer, the impact investment arm of Bayer AG. We invest in potentially breakthrough technologies to overcome ten of humanity’s greatest challenges, which we call “Leaps,” including to prevent and cure cancer. Some of our 55+ portfolio companies are working to develop the next generation of cell therapies.
