Content provided by Nature (https://www.nature.com) Note: Content, including the headline, may have been edited for style and length.
Engineered immune cells, called CAR T cells, are among the most powerful therapies oncologists have to treat many types of blood cancer. And studies suggest that they might hold promise for brain cancer and other solid tumours , as well as autoimmune and other diseases . One research firm estimates that the value of the CAR-T-therapy market, expected to hit US$11 billion this year, will grow to nearly $190 billion by 2034.
But CAR-T therapies come with a serious downside — they are laborious to make and difficult to administer. After removing the immune cells, called T cells, from a person’s blood, physicians ship them off to a manufacturer, where technicians genetically engineer the cells to carry a specialized protein called a chimeric antigen receptor (hence ‘CAR T’) on their surface. The cells are grown and amplified into hundreds of millions more cells, frozen and returned to the hospital for re-infusion. Because of the complexity, only about 200 centres in the United States offer the therapy.
“This whole process, it’s just inefficient,” says Saar Gill, a haematologist and oncologist also at the Perelman School of Medicine. “If I’ve got a patient with cancer, I can prescribe chemotherapy and they’ll get it tomorrow.” With commercial CAR T, however, people have to wait weeks for treatment. That delay, along with the high cost of the therapy, plus the need for chemotherapy before people receive the CAR T cells, means many people who could benefit from CAR T never receive it. “We all want to get to a situation where CAR T cells are more like a drug,” says Gill.
Some biotechnology companies have an answer: alter T cells inside the body instead . Treatments that deliver a gene for the CAR protein to cells in the blood could be mass produced and available on demand — theoretically, at a much lower price than current CAR-T therapies. A single dose of commercial CAR-T therapy costs around $500,000. A vial of in vivo treatment might cost an order of magnitude less.
The idea has some high-profile proponents. The founders of Capstan Therapeutics, a company in San Diego, California, that is focused exclusively on in vivo cell therapies, include CAR-T pioneers Levine and Carl June, as well as Drew Weissman, who won a Nobel prize for his work on messenger RNA vaccines. CRISPR–Cas9 pioneer and Nobel prizewinner Jennifer Doudna has co-founded a separate company, Azalea Therapeutics in Berkeley, California, that is developing in vivo CAR T. And big pharma is taking notice. In March, the biopharmaceutical firm AstraZeneca agreed to pay up to $1 billion for the Belgium-based in vivo CAR-T company EsoBiotec, which launched its first human trial of an in vivo CAR-T therapy in January.
Although human trials have just begun, many researchers are excited about the potential of a simpler iteration of CAR T. “If it’s efficacious and safe, it could really challenge the current paradigm,” says Joseph McGuirk, a haematologist and oncologist who studies cellular therapies at the University of Kansas Medical Center in Kansas City. And “we need to challenge the current paradigm”.
Many of the in vivo CAR-T therapies under development have taken pages from the ex vivo playbook. Similar to the approved therapies, in vivo approaches aim to destroy white blood cells called B cells, and so treat cancers that form in these cells. (CAR-T therapies destroy healthy B cells, too, but people can live without these cells.)
As with ex vivo , many in vivo therapies rely on an engineered version of a lentivirus to grab onto T cells and deliver the gene for the CAR protein into the cell’s genome (see ‘Made within’). But engineering cells inside the body is a tricky business. With ex vivo , the T cells have been removed from the body, so researchers don’t have to worry about introducing the gene into other cell types. But in the body, many cells share common receptors, so researchers have to find ways to specifically target T cells — or other immune cells that could join the fight.
“The stumbling block is, how do you get it to the right cell, the right place, right time?” says Michel Sadelain, a genetic engineer and director of the Columbia Initiative in Cell Engineering and Therapy at Columbia University in New York City and another CAR-T pioneer.
Each company has developed its own approach to solving this problem, and each has tweaked its vector in different ways. For example, Interius BioTherapeutics in Philadelphia, co-founded by Gill, is testing a vector that latches onto CD7, a protein found only on T cells and natural killer cells.
Umoja Biopharma in Seattle, Washington, is testing a lentiviral vector decorated with a protein that targets three receptors on T cells at once. The company has evidence from animal models that this strategy is more effective than targeting just one receptor, and hopes that it will more closely mimic what happens when a T cell becomes activated naturally, after an infection, for example.
If effective, such approaches could simplify manufacturing and get CAR-T therapy to more people more quickly. McGuirk notes that when the ex vivo CAR-T therapy Carvykti (ciltacabtagene autoleucel) was approved in 2022 for people with multiple myeloma, the manufacturer had limited production capacity, leading to long waiting times.
Content provided by Nature (https://www.nature.com) Note: Content, including the headline, may have been edited for style and length.
