CAR-T has been hailed as a cure for cancer, but what really is this miraculous technology and what can we actually expect from it?
The field of immuno-oncology is booming with billions of euros in investment. The ability to rewire our own immune system to fight cancer has certainly created huge expectations. After the success of the first checkpoint inhibitors on the market, many are turning their attention to CAR-T therapy, the next big cancer therapy to hit the market.
The first CAR-T has recently been approved, and the field is booming, with over 300 CAR-T clinical trials running. But is this therapy really a cure for cancer, as many seem to believe? Can the technology meet such high expectations? Are the deaths in clinical trials a sign that CAR-T is not yet ready? What will the future bring?
To answer some of the most burning questions, I talked with some of the leaders in this field to draw an overview of the current state of the CAR-T technology.
How does this “Miracle Cure” work?
“CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy. It represents a radical departure from all forms of medicine in existence until now,” Michel Sadelain, co-founder of Juno Therapeutics, told The Scientist.
A CAR-T therapy consists in the infusion of engineered T-cells that express a Chimeric Antigen Receptor (CAR) on their cell membrane. This receptor counts with an external target-binding domain designed to recognize a specific tumor antigen and an internal activation domain responsible for activating the T-cell when the CAR-T binds its target. Second and third generation CAR-Ts have additional costimulatory domains that further enhance the immune response.
The most common procedure for CAR-T therapy consists in the extraction of T-cells from the own patient, which are then genetically modified and expanded in vitro. Finally, they are reinfused into the patient, ready to fight the tumor.
How has CAR-T Changed the Scene?
Checkpoint inhibitors have already been incredibly successful. The drugs inhibit the mechanism that tumor cells use to inhibit T-cell activity and overcome the immune system. CAR-T goes one step further and engineers the T-cell itself to enhance the immune response against a specific tumor antigen.
CAR-T clinical trials have shown huge remission rates, of up to 94% in severe forms of cancer, which is particularly impressive considering most of the trials recruit patients that have not responded to all other available treatments for their form of cancer. These preliminary results have fed the expectations of patients and investors alike, but it’s important to remember that the therapy also has flaws.
André Choulika, CEO of Cellectis, said it bluntly during an interview. “I’m just trying to be realistic, CAR-T is not the miracle cure for cancer.” Indeed, CAR-T cells have in fact been linked to severe side-effects, such as neurotoxicity and cytokine release syndrome. The recent report of several deaths in CAR-T trials made many realize that the technology might not be as perfect as they had originally expected.
These results mostly come from the most studied application of CAR-T, which targets the CD19 antigen found in B-cells. All the leading CAR-T companies target the CD19 antigen to treat B-cell malignancies, which include several forms of lymphoma and leukemia.
“The initial furor and excitement of CAR-T has led to extensive and rapid clinical development in the CD19 target space,” says David Gilham, R&D VP at Celyad. “Research is busy catching up at the moment, in particular concerning toxicity. The lack of good preclinical models hampers this work, but with clinical samples available, ongoing investigations are now closer to identifying the underlying mechanisms and further refining the approach.”
Who’s Leading the Race?
Novartis has been the first to launch a CAR-T therapy, called Kymriah, and formerly known as CTL019. It is a one-time treatment for B-cell acute lymphoblastic leukemia (ALL) that has shown an 83% remission rate after three months in clinical trials with patients that do not respond to standard treatments. However, the same trial revealed that 49% of the patients suffered strong cytokine release syndrome (CRS), a side effect that has been responsible for several deaths in trials run by Novartis’ closest competitors.
Indeed, Juno Therapeutics, which used to lead the race, announced the termination of its lead CAR-T program after a total of 5 patients died of cerebral edema caused by the therapy. The company had created huge expectations, and its market cap reached over €2.5Bn only 3 years after its inception. Now, however, it’s back to Phase I.
Kite Pharma will likely be the next to make it to the market, with a decision from the FDA expected by November. Its therapy axicabtagene ciloleucel (previously KTE-C19), managed to keep 36% of patients with lymphoma clear of the disease after 6 months in clinical trials. However, the trial reported three deaths, two of them linked to the administration of the CAR-T therapy.
Let’s Make CAR-T Better
Despite severe side effects and several deaths in clinical trials, some argue that CAR-T therapy is worth the risk when a patient has not responded to any other available treatments. But others are already developing improved versions of CAR-T that are safer for the patients.
Cellectis originally developed UCART19, now licensed to Servier and Pfizer. It’s a CAR-T therapy with a switch control system that only activates the engineered cells when rapamycin is present. The therapy is in Phase I and has already saved two babies with aggressive forms of leukemia. Bellicum Pharmaceuticals, in the US, is developing a similar technology called GoCAR-T that requires rimiducid for CAR-T cell activation.
For its part, Celyad is developing a version of CAR-T that makes T-cells express natural killer receptors (NKRs). “It’s disruptive because NKR-2 binds to 8 different ligands that are expressed on above 80% of solid and hematological malignancies,” said Christian Homsy, CEO and co-founder of Celyad. “We’ve started one of the largest and broadest trials in the sector, targeting 7 indications.”
Targeting solid tumors is a big challenge in the field of immuno-oncology. Low T-cell infiltration and an immunosuppressive environment prevent the immune system from effectively attacking solid tumors. Bluebird bio and Celgene are developing their own CAR-T technology for solid tumors from the US.
Others think that the way to go for CAR-T is combination therapies. “We are excited about combining checkpoint inhibitors such as PD-1 inhibitors and anti-CTLA4 drugs with CAR-T cells,” Zelig Eshhar, pioneer of the CAR-T technology at the NIH, told The Scientist.
Off-the-Shelf CAR-T Therapy
Most approaches to CAR-T engineer the patient’s own cells, but this process requires several weeks and is expensive; Novartis priced the first therapy at $475,000 (€400,000). A possible solution is allogeneic CAR-T therapy, i.e. sourced from a healthy donor and ready to go when the patient needs it.
Cellectis and Celyad are developing their own allogeneic CAR-T each, and there’s friction between them both. Celyad, still in the preclinical stage, has licensed the technology to Novartis, while Cellectis recently started a Phase I trial with UCART123, making it the first study for allogeneic CAR-T in humans.
The technology promises a faster and cheaper approach to CAR-T, but developing an off-the-shelf therapy is a “scientifically challenging avenue” according to Celyad’s CEO Christian Homsy.
“I doubt that allogeneic CAR-T can be a real off-the-shelf therapy,” he commented. “There are still some significant scientific challenges with regards to immunology, as well as manufacturing, transportation, traceability and banking solutions necessary to reach the scale needed for widespread patient treatment.”
As you can appreciate, there’s plenty going on in the CAR-T space. The technology is not perfect yet, but it offers hope for patients that had none before. With the first therapy already in the market, the way is open for more and better alternatives to arrive in the next few years.
Images from CI Photos /Shutterstock; Kite Pharma; Klebanoff et al. (2014) Nature Reviews Clinical Oncology 11, 685–686; Bellicum Pharmaceuticals