CAR-T cell therapies offer many cancer patients a shot at a cure, but the technology comes with some critical drawbacks. Treatments are complex, costly, time-intensive and often inaccessible. They require invasive procedures and present serious risks.
In vivo CAR T-cell therapy could be a game-changer in a global market projected to reach $88.5 billion by 2032. The investigational technology sidesteps external manufacturing, instead using a gene vector to modify immune cells inside the body. This could eliminate many drawbacks of both autologous CAR-T and experimental off-the-shelf allogeneic treatments, enabling cell therapy to reach more patients and new indications including autoimmune diseases, where it has shown significant promise.
“If in vivo CAR-T pans out and we're able to retain all the all the positives, particularly the powerful efficacy of a living drug . . . but do away with all the limitations, autologous and even allogeneic CAR-T could become obsolete, and should become obsolete,” said Dr. Ramin Farzaneh-Far, chief medical officer of Capstan Therapeutics. “That’s really the vision, to retain all the pros and do away with all the cons.”
“The field will change dramatically if one of us shows that this can work."
David Fontana
Chief operating officer, Umoja Biopharma
The field is moving ahead quickly, with as many as four companies rumored to publicly disclose an IND this year or next, according to David Fontana, chief operating officer at Umoja Biopharma, an early-stage CAR-T cell therapy company.
“I'd like to believe we’ll be first,” Fontana said. “We are confident we're going to be in the clinic this year.”
Rethinking the approach
Since 2017, the FDA has approved six autologous CAR-T cell therapies for blood cancers. Treatments require a multi-step process of harvesting T cells from the patient, reprogramming them to find and destroy cancer cells, and then multiplying and reinfusing them.
Due to the slow manufacturing process and capacity bottlenecks, some patients die before the treatment can reach them, and quality varies, depending on the health of extracted cells. Patients undergo chemotherapy to eliminate existing T-cells before infusion, which provides a fresh canvas for the new cells but raises the potential for complications, including life-threatening infections.
Avoiding chemo could help in vivo CAR-T improve outcomes, Fontana said. Eliminating the need for chemotherapy could also expand CAR-T’s applications.
There’s rising interest in using the technology to treat autoimmune diseases, such as lupus, triggered by a malfunctioning immune system that mistakenly attacks healthy tissues. CAR-T has shown dramatic results in calling off this immune system attack in some patients, putting the disease into a drug-free remission.
However, due to its risks, traditional CAR-T will likely only be an option for people with severe illness. Capstan aims to change this and treat more patients with its lead in vivo CAR-T therapy, CPTX2309, an autoimmune candidate, which recently secured $175 million in a series B financing.
In vivo CAR-T could also democratize treatment access and allow developers to tap into a large underserved patient population, said Fontana. Only 20% of U.S. hospitals offer autologous CAR-T, which means the vast majority of cancer patients, even those who could benefit, go without. In vivo treatments could be manufactured and stored in hospitals or distribution centers and may be easier to administer, allowing more sites to offer treatment within and outside the U.S.
At least one autologous company has made moves to overcome some of these logistical challenges. Gilead’s Kite Pharma, which manufactures Yescarta and Tecartus, is working to speed up manufacturing times and bring CAR-T into more community oncology practices. Others, such as TG Therapeutics, which recently acquired an allogeneic CAR-T candidate from Precision Biosciences, are pursuing off-the-shelf therapies, using donor cells to hasten treatment and improve quality. Still, allogeneic treatments face unique challenges, such as keeping the patient’s immune system from attacking foreign cells.
Facing challenges
In vivo CAR-T also faces challenges that include scaling the production of treatment components such as engineered viruses and synthetic genetic material. The field also needs to sort out the best technological approach.
A handful of startups including Ensoma and Exuma Biotech are testing in vivo CAR- technology using gene vectors such as lentiviral or adeno-associated viruses, and non-viral platforms such as lipid nanoparticles or nanocarriers, according to Fran Gregory, vice president of emerging therapies at Cardinal Health.
Farzaneh-Far believes Capstan’s delivery method, using a lipid nanoparticle similar to those used in COVID-19 vaccines, may have an advantage over companies using adeno-associated viral vectors, which he said carry potential safety concerns. Using AAVs in vivo could be toxic to the liver or brain and could potentially cause thrombotic microangiopathy, a condition marked by blood clots in small arteries and capillaries, Gregory said.
“Non-viral vectors like lipid nanoparticles or nanocarriers may help but this is still being studied,” she said.
The success of in vivo technologies will also hinge on whether developers can find ways to mitigate adverse events, including those common to CAR-T, such as neurotoxicity and cytokine release syndrome, Gregory said.
“Developers also need to prevent off-target transduction and ensure only target cells are affected,” she said.
Umoja decided to focus on the CD-22 molecule to test its technology and avoid the additional risk related to an unfamiliar target. This molecule has shown efficacy in people who have failed to respond to CD-19 targeting CAR-T treatments, such as Kymriah, Fontana said.
“There’s clearly an unmet medical need because there is nothing available for those patients,” he said. Once the technology is proven, the doors can swing open to new in vivo CAR-T indications, Fontana said, including solid tumors.
For now, the most formidable barrier for in vivo CAR-T is the unknown. While companies have seen promising early results in non-human primates, monkeys aren’t people.
“The field will change dramatically if one of us shows that this can work,” Fontana said. “This field has progressed probably quicker in the last two years than anything I've seen.”
Next year may be pivotal, showing whether in vivo CAR-T cell therapy holds transformational potential or needs more tweaking, Fontana said.
“I feel pretty confident by this time next year, there's going to be at least a couple of us out there with data,” he said.
