Navigating the realities of CAR-T cell oncology trials

The notion that an individual’s own immune cells could be genetically reprogrammed to hunt down and destroy cancer cells in their body once sounded like the stuff of fantasy. Yet, like so many scientific breakthroughs, the seemingly impossible has become reality. Since first approval by the U.S. FDA less than a decade ago, seven chimeric antigen receptor (CAR) T-cell therapies have entered the market, giving 30,000 patients with formerly untreatable blood cancers a renewed sense of hope.

What makes CAR-T cell therapies truly unique is the method in which they operate. Instead of taking the broad, one-size-fits-all approach of most chemotherapies, CAR-T cells have a life of their own.

“When you give your body CAR-T, your body can actually make more and more of it,” says Kaitlin Morrison, Ph.D., assistant professor of medicine and executive director of clinical research at University of North Carolina’s Lineberger Cancer Center. “That’s the difference — it’s a living therapy, not a drug that gets cleared like a small molecule.”

When your teams are spread across disciplines and timing is critical, even small gaps become major issues.

— Dr. Brian Hess

Unlike traditional chemotherapy, which kills both healthy and cancerous cells indiscriminately, CAR-T therapies are designed to selectively attack cancer cells. They can even persist in the body, acting like memory cells that help prevent relapses.

Given the undeniably novel aspect of this new paradigm, however, conducting CAR-T clinical trials presents a unique set of obstacles for sponsors, sites and regulators to carefully navigate. Moreover, the complexity of manufacturing, delivering and managing genetically modified cells has made CAR-T trials both operationally intensive and logistically demanding.

While there is little question that CAR-T therapies are a successful scientific story, to move this important treatment into the mainstream, CAR-T must evolve further to tackle the persistent barriers it faces when it comes to scalability, cost, logistics and safety.

A delicate balance

To be successful, CAR-T trials require an unusually high level of preparation before moving forward.

You need a lot of organization and quality control,” says Brian Hess, MD, a lymphoma and cellular therapy specialist at the Medical University of South Carolina. “All of the different multidisciplinary services — apheresis, cryopreservation, and the clinical team including doctors, advanced practice providers, nurses, pharmacists, CAR-T and financial coordinators — need to be working in concert.”

Significant investment is required to get CAR-T trials off the ground.

Before you even treat a patient, you need a validated CAR-T construct with an IND approval and an IRB-approved protocol, in combination with the clinical coordination it requires to take care of these patients both leading up to and post CAR-T infusion,” Hess explains.

The need for cross-disciplinary coordination is amplified by the therapy’s individualized nature. Since each CAR-T product is made for a single patient, delays in manufacturing can significantly impact outcomes. And the therapies are also very intense. Patients must first receive high dose lymphodepleting chemotherapy. Then, once the CAR-T cells are administered, they may experience serious side effects such as cytokine release syndrome (CRS) and neurotoxicity.

“The healthier you are going in, the better you’ll do,” says Theodore Laetsch, MD, a pediatric oncologist at the Children’s Hospital of Philadelphia. “These are not benign therapies, but we’ve see over 80% of patients with acute lymphocytic leukemia achieve remission with the now FDA-approved CAR-T cell therapy tisagenlecleucel [Kymriah].”

Some patients may experience immune effector cell associated neurotoxicity syndrome (ICANS), which can include confusion, aphasia and seizures.

“It’s a balance between efficacy and toxicity,” Laetsch adds. “The same immune activation that fights the cancer can cause side effects like CRS and ICANS. That’s why multidisciplinary input is so critical — professionals with real CAR-T experience need to be at the table.”

These potentially severe and adverse responses underscore the necessity for strong organization and a highly precise protocol, including such practices as inpatient monitoring and rapid-response teams trained in managing CAR-T-related toxicities.

Tips from the field

Despite the challenges of managing such complex therapies, several essential priorities have emerged:

Engage operational leaders early and often: According to Morrison, a successful CAR-T protocol requires early input from site operations teams, not just investigators. “You need to understand what patients can withstand during the wait between collection and infusion,” she says. “What standard-of-care therapies can bridge that gap?”

Often, this is what makes a CAR-T trial far different than most typical trials. “You might have four weeks between collection and reinfusion,” Morrison continues. “If the patient’s too sick, they might not survive that wait so this must factor into the design.”

It’s a balance between efficacy and toxicity. The same immune activation that fights the cancer can cause side effects like CRS and ICANS. That’s why multidisciplinary input is so critical — professionals with real CAR-T experience need to be at the table.

— Dr. Theodore Laetsch

Build for toxicity management: “Toxicity management is a study design requirement — not an afterthought,” says Laetsch. “Patients can do remarkably well, but only if the right support systems are in place. These are small studies with high-risk patients. Sponsors and investigators need close collaboration to adjust quickly if unexpected side effects occur.”

Having standardized toxicity management algorithms, such as early administration of tocilizumab or corticosteroids, can make the difference between rapid recovery and life-threatening complications.

Communicate relentlessly: “Every team — from lab techs to ICU staff — must be aligned,” Hess notes. “There’s no room for gaps with a therapy this complex. CAR-T nursing coordinators and the physicians must consistently communicate across several specialties to ensure there are no gaps in care pre- or post-CAR-T infusion.”

Dedicated CAR-T coordination teams and weekly multidisciplinary rounds have been shown to significantly reduce errors and improve patient throughput. So be sure to tighten communication from the start.

“When your teams are spread across disciplines and timing is critical, even small gaps become major issues,” says Hess.

The devil is in the details

The logistics for CAR-T studies are not for the faint of heart. Sites must be equipped not only for leukapheresis but for cryopreserving cells, delivering chemotherapy, and safely handling the genetically modified products. Facilities require Class II biosafety cabinets, negative pressure rooms, and trained staff to manage both the therapy and the risks to caregivers and the environment. Seemingly mundane details such as an upholstered chair in an infusion room, could pose an unacceptable contamination risk.

Even the shipping process is a delicate matter. Delays in transport can derail treatment timelines, resulting in poor patient outcomes. And once the product arrives, coordination must be nothing short of flawless.

Moreover, sites must ensure ultra-low temperature storage is available, often requiring ultra-low freezers or liquid nitrogen dewars. Investigational pharmacies may need to dispense CAR-T products in controlled environments such as biological safety cabinets.

Like the trial protocols themselves, managing a CAR-T study requires a delicate and complex balance.

Regulatory realities

Every CAR-T trial must undergo Institutional Review Board (IRB) review, which evaluates patient risks and ethical considerations. But they also often require Institutional Biosafety Committee (IBC) review, particularly when NIH support is involved, and the therapy involves genetically engineered materials. While the IRB focuses on patient safety, the IBC ensures environmental and occupational safety during the handling and disposal of the therapeutic product.

Sites that pre-register with the NIH and maintain an active IBC can significantly reduce startup timelines. Sponsors also must plan to support less experienced sites with training and resources.

In addition, the IBC review process addresses post-treatment exposure precautions, such as how to manage bodily fluids or contaminated waste or how to ensure the genetically modified material doesn’t pose a risk to a caregiver or the environment.

Access and equity

Even as CAR-T enters the mainstream for cancers like lymphoma and multiple myeloma, its availability is far from universal. Today, only about two out of 10 eligible patients in the United States and in Europe receive access to CAR-T cell therapy, a stark gap that underscores significant barriers within our health care systems.

“The treatment isn’t offered everywhere,” says Morrison. “Patients travel across borders to access it, but not everyone can afford to do that. Unfortunately, it is still a predominantly first-world treatment even as other countries are evolving.”

Moreover, many protocols require patients to stay near the treatment center for up to a month after infusion to monitor for acute toxicities. For many, the cost of travel, lodging, and missed work is prohibitive.

The FDA’s requirement for life-long, long-term follow-up can pose another barrier. While some sites have successfully partnered with local providers to conduct remote follow-ups, this decentralized approach is not yet a standard part of the protocol.

Partnerships with community oncology networks and digital platforms that can extend CAR-T monitoring beyond the walls of major academic centers are key to providing greater access to CAR-T, but this is still in early stages.

“The extended monitoring period is essential for tracking delayed adverse events, understanding the durability of the therapy, and ensuring the long-term impact on patients. But when implemented in a brick-and-mortar fashion, it can make these CAR-T and other cell and gene therapies logistically impossible for patients,” explained Pamela Tenaerts, MD, chief medical officer at Medable, in a recent interview.

Tenaerts continued, “Not only is this burdensome and costly for patients but it is also incredibly expensive for drug sponsors who cannot reap financial gain over decades, if ever. As a result, these potentially curative treatments are either not being studied or are not getting to some patients because they live too far from a major health care center.”

The promise of allogeneic CAR therapies

As researchers continue to refine CAR-T technologies, one promising direction is the development of allogeneic CAR-T (alloCAR-T) therapies. Unlike autologous products, which are derived from the patient’s own cells, alloCAR-T therapies are manufactured in advance from healthy donors and can be stored off-the-shelf. This breakthrough eliminates the weeks-long wait for production and could stand to dramatically expand access.

“AlloCAR-T could offer a major advantage for a subset of patients who cannot afford to wait for CAR-T collection and subsequent manufacturing,” says Hess.

Since AlloCAR-T will still require the same coordinated care to manage toxicity and long-term follow-up, it won’t reduce all the barriers patients face. Yet additional research is making progress on safety and scalability, including the gene editing techniques that might reduce the risk of graft-versus-host disease in alloCAR-T therapies.

A call for coordination

CAR-T therapies offer real hope where little existed before. But their ultimate success hinges on more than just scientific ingenuity. CAR-T demands an ecosystem of coordination between sponsors, sites, regulators, providers, patients, and payers unlike anything we’ve seen before. And, as these therapies continue to progress, stakeholders must prioritize operational practicality, equitable access, and patient-centered design.

While CAR-T represents a major scientific leap forward, extending its impact to more patients requires more innovation. Achieving this goal will require unparalleled precision, collaboration and dedication from every corner of the care ecosystem. 

References

Perales. M. (2025). A vision to double the number of patients treated with CAR T-cell therapy by 2030. PharmaLive.

FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous CAR-T cell Immunotherapies. (2024, April). FDA. [Biologics Safety and Availability Communications]

Peter, R. M. (2025, June). ASCO 2025: key highlights in cancer therapeutics. Labiotech