Source The Scientist

The company Cell Vault offers to hold consumers’ T cells for later use, but scientists suggest the service would benefit very few users.

new cryopreservation bank offers customers the chance to stash away their T cells for use in future cancer treatments. Using a similar model to cord blood banks, the startup Cell Vault announced that it has already raised $1 million from Silicon Valley investors in an initial round of funding. The field of T cell–based cancer therapies has rapidly blossomed in recent years, but at this point, scientists doubt the utility of stowing healthy T cells in a freezer, just in case.    

Cell Vault proposes that, once frozen, customers’ T cells can be readily available for adoptive cell transfer, an emerging form of cancer treatment. One treatment of this kind equips T cells with chimeric antigen receptors (CAR), which enable the cells to seek out and destroy specific tumor types bearing complementary antigens. 

The International Society for Cell and Gene Therapy (ISCT) has taken a hard stance. On August 7, the organization issued a statement objecting to the marketing of “unproven T-cell preservation services.” The release presented a list of technical, regulatory, and ethical concerns surrounding third-party T cell banks, including several voiced by ISCT President-Elect Bruce Levine, who helped develop the first FDA-approved CAR T treatment. 

I don’t think there has been any experimental or clinical demonstration that archived cells . . . are superior to T cells you have later, once you have the disease.—Michel Sadelain, Memorial Sloan Kettering Cancer Center

“I’m personally concerned about patients, and even healthy donors,” Levine tells The Scientist. “This company, other companies, they cannot point to an example of a company with a commercial product that accepts what they collect.”

Normally, CAR T cells are collected from patients themselves, genetically modified to target particular antigens on the cancer cell surface, and then reintroduced into the body where they beeline toward tumors. Cell Vault posits that all healthy individuals should bank their T cells, and soon, according to their website: “The sooner, the better because an individual’s t-cells decrease in number and functionality as they age.” 

“It’s kind of life insurance, really,” says Parameswaran Hari, chief of hematology and oncology at the University of Wisconsin and Cell Vault’s scientific advisor. “You’re taking insurance against a lack of healthy T cells being a problem with getting effective immunotherapy in the future.” 

Healthy cells for a rainy day 

The Cell Vault business model is straightforward; customers register and receive a blood collection kit in the mail, and the company schedules a five-minute blood draw with an ExamOne phlebotomist to take place at home or in the office. The sample is then shipped overnight to the Cell Vault partner lab, Brooks Life Sciences in New York, where the peripheral blood mononuclear cells in the sample are frozen according to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), according to Hari.    

Cell Vault offers three payment plans, which vary depending on how long a customer wishes their cells to be stored. Users pay $300 a year to renew the service, with a one-time $700 collection fee. For the 20-year plan, the collection fee is waived and customers pay an annual fee of $200, or $4,000 total. To store cells for a lifetime, they pay $100 a year, up to $8,000 total. 

The FDA has approved CAR T cell treatments for diffuse large B-cell lymphoma (DLBCL) and a certain form of acute lymphoblastic leukemia (ALL), seen in pediatric and young adult patients. Both interventions are approved as a second line of therapy, to be administered after a patient has not responded to or has relapsed after at least two different treatments. Undergoing cancer therapy can leave patients with a severely compromised immune system and too few T cells to collect for therapy. Patients must also wait two to four weeks while CAR T cells are being manufactured. 

Cell Vault proposes that, if you have cells stored away, you can sidestep both these problems. T cells collected before cancer takes hold are “probably much better at making more potent T cell based treatments,” Hari explains. The company’s website proclaims that, assuming you’re healthy, “your t-cells will never be as strong, viable, and plentiful as they are right now.” 

But it’s unknown whether cells collected before disease sets in are actually better suited for CAR T therapy.

“Biologically, I don’t think there has been any experimental or clinical demonstration that archived cells, archived before the disease is diagnosed, are superior to T cells you have later, once you have the disease,” says Michel Sadelain, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center. “It’s not an unreasonable hypothesis, but it is just a hypothesis.”  

It’s also unknown how T cells fare after being frozen for one, 20, or 50-odd years. Frozen T cells are sometimes used to produce existing CAR T treatments, according to Levine, but under carefully controlled protocols and quality assurance measures to which Cell Vault may or may not adhere. Studies of cryopreserved bone marrow and umbilical cord blood, both used for stem cell transplantations, suggest that the cells lose little viability for grafting over the course of 10 years, with time frames up to 20 years proving successful in animal models. Hari suggests that T cells would likely react the same way over extended periods of time and remain useful for CAR T cell therapy. 

“Viability declines are easy to overcome because you just give more of the product,” says Hari. He has advised Cell Vault to undertake feasibility studies by using thawed out T cells to generate a CAR T product, and see if the result holds up to scrutiny. 

But there’s a question about how much product Cell Vault will get. Sadelain says a five-minute blood draw is a red flag. Existing CAR T cell therapies require that patients’ blood be collected through apheresis, a process that separates specific components of the blood over the course of several hours. Billions of white blood cells can be collected at an apheresis appointment. 

A quick blood draw would supply “several hundred to a thousand less [T cells] than is necessary to generate FDA-approved T cell products,” adds Levine. Expanding an inadequate quantity of cells to achieve the correct volume would result in cells of “poor quality,” he says.

Chain of custody

Provided the frozen cells are plentiful and number in the required billions, would clinicians be able to accept T cells from a third-party banking service?

“On research protocols developed with INDs [Investigational New Drug applications vetted by the FDA], the answer is no,” says physician-scientist David Miklos, the clinical director of the Cancer Cell Therapy program at Stanford University Medical Center. “The chain of custody for the cells is critical,” as is standardized quality control, he says. INDs outline a rigid protocol as to how T cells can be collected, stored, and modified for use in an FDA drug candidate or fully approved treatment. As third-party T cell banking is a new phenomenon, it’s unlikely that the infrastructure exists for clinical institutions or commercial enterprises to accept their preserved products. 

Levine affirms this statement in the ISCT release, stating that commercial manufacturers of CAR T products are unlikely to use cells collected by a third-party bank “in the near future.” The FDA strictly regulates how companies track where their cells came from, monitor the cells during storage, and test their viability once thawed. “It’s absolutely outlined in the Biologics License Application” submitted during the approval process, he says, and there’s no wiggle room.

Miklos says he could envision a scenario in which T cells could be collected and stored for patients with aggressive high-risk cancer early in their therapy if they have reached remission, so that the cells would be readily available in case of relapse. The strategy would be analogous to the “harvest-and-hold” protocol for stem cells used in autologous transplantation for managing multiple myeloma, wherein enough cells are collected after the first phase of treatment to be sufficient for at least two transplants, he says. But this isn’t the model Cell Vault has proposed.

“Highly aspirational”

The market for CAR T cell therapies is still quite small, given that only two such treatments have been approved to date. One recent report found that 900 patients at 58 hospitals across the US have received either an approved or experimental CAR T therapy since May 2017. Clinical trials are underway for additional cancer types, and it’s likely the number of eligible patients will grow.   

“At this time, many academic centers and also companies are launching programs to tackle solid tumors,” such as breast and colorectal cancers, says Sadelain. Inherent challenges lie in identifying unique markers on different cancer types that CAR T cells could target, he says, as well as overcoming obstacles in the tumor microenvironment.  

“The type of treatment you will get is probably not, you know, out in the market yet,” Hari says. “That’s the thing, if you’re keeping these cells for 10 years, there’s going to be several other targets discovered in other cancers at that time. . . . This is highly aspirational, right?”

Beyond tackling new cancer types, researchers aim to learn how T cells drawn from donors could be adapted for use in CAR T therapies. Once allogeneic, or off-the-shelf, transplants from donors prove viable, freezing T cells from patients themselves could become obsolete?—and this breakthrough is on the near-horizon. In April, the FDA approved the IND for the first allogeneic CAR T product to make it to clinical development, created by the pharmaceutical company Cellectis to treat patients with multiple myeloma. 

Still more researchers are working to grow T cells from pluripotent stem cells, while others have used nanoparticles to deliver DNA straight to T cells in mouse models, thus eliminating the need to remove cells from the body. As the burgeoning field of CAR T therapies continues to swell, it’s unclear whether cryopreservation banks will prove their worth in time.