Identifying and Understanding Differentiators in CAR T-Cell Therapy

Some 65 years on from the first successful bone marrow transplant, the bioengineering of human cells continues to evolve into further discoveries in hematological oncology and other therapeutic areas. Cell therapy, the transplantation of viable human cells to treat and repair damaged cells, remains a hot topic – one that has yielded astounding clinical results and a viable, competitive market.1

Chimeric antigen receptor (CAR) T-cell therapy has further refined that success into FDA-approved treatment for B-cell non-Hodgkin’s lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. While not theoretically limited to hematology, CAR T-cell therapy has created a very novel treatment for blood cancers that requires deep biological understanding and logistical oversight.

“For a long time, CAR T-cell therapy was more akin to science fiction,” noted hematologist Robert S. Negrin, MD, Professor of Medicine and former Chief of the Division of Blood and Marrow Transplantation at Stanford University, and Biorasi Scientific Advisory Board member. “Today, treatment is quite real and effective. However, as with all cancer therapy clinical trials, it is not without its challenges.”

Manufacturing Differentiators

CAR T-cell therapy begins with apheresis. First blood cells are taken from an individual patient. Then the patient’s T-cells are collected and sent to a manufacturing facility to conduct the modifications needed to transform these normal cells into immune cells that will locate and attack cancer cells. The cells are then frozen and shipped back to the center administering the therapy. However, this process is significantly different than other drug development.

“For a more common drug, the specifications are sent to a research pharmacy to be produced and distributed to patients participating in that clinical trial,” said Dr. Negrin. “CAR T-cell therapy is more unique; each cell product is individualized to the patient and the logistics are quite different.”

Once the cells are collected, they are sent to a manufacturing facility that manages:

• The logistical transfer of the cells to their facility
• The identification and tracking of cells, ensuring the right cells to the right patient
• Gene transfer techniques that modify the cell with a new receptor to target cancer cells
• The delivery of the cells back to the clinical site to be stored, thawed, and infused back into the patient

“Cell therapy not only requires that trial sponsors have the logistical wherewithal to handle all of these different components – all of these moving parts – but also have the laboratory capability to track, thaw, and infuse the cells” said Dr. Negrin. “So while the cell therapy market is competitive, it is also cumbersome and very expensive. This clinical research requires capital and logistical support from the very beginning.”

Clinical Trial Differentiators

As mentioned above, cell therapy trials are complex and burdensome. So how are logistical issues addressed?

“The organization of cell therapy trials is the biggest challenge to its successful execution,” stated Dr. Negrin, “collecting the cells from the patient and providing them to the facility that can manufacture cells effectively, on time, and in specification over the course of three to four weeks.”

“CAR T-cell therapy clinical trials require collaborations with companies experienced in the processing, analysis, and transit of these patient samples – ensuring that the cells survive both the initial transit and modification as well as the return trip. As with all clinical trials, unforeseen challenges can delay or halt research. It is crucial to develop strong lines of communication between all parties involved in the study as well as implement systems designed to review study activities and identify potential obstacles.”

“With multiple stakeholders involved and systems in place to make sure that the trial is on track, these barriers act as checks and balances throughout the study to prevent errors. As with all clinical trials, there is zero tolerance for avoidable errors.”

Unique Toxicities

Another differentiator involves addressing unique toxicities attributed to CAR T-cell therapy, a critical factor in patient treatment and survival. For example, chemotherapy and immunosuppressants elicit common acute toxicities, such as hair loss and nausea, with the potential of more severe toxicities affecting the heart or lungs. 2

“Cell therapy toxicity is different than other cancer treatments in terms of type and severity,” said Dr. Negrin. “As these new immune cells are infused, they recognize their target in the cancer cells and become activated. When normal cells become activated, they produce byproducts known as cytokines – small, secreted proteins released by each cell individually.”

“The abundance of cytokines creates toxicity in the patient. While this signals the efficacy of the treatment itself, it can cause biological side effects similar to infection or shock. Neurological effects are also possible, such as seizures or coma. While these side effects were challenging to understand at the beginning of cell therapy treatment, clinicians now know what to look for and can address toxicity directly.”

Cell Therapy Evolution

Just as bone marrow transplants paved the way for successful CAR T-cell therapy, pioneering research in cell therapy continues to move forward into different therapeutic indications and treatment types. Currently, CAR T-cell therapy is approved as third-line therapy for patients that do not respond to initial and subsequent treatment for B-cell non-Hodgkin’s lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. Randomized studies are ongoing for second-line treatment for these diseases as well, but there are greater applications ahead.

“While cell therapy has been well developed and tolerated in hematological cancers, the next step is its application to solid tumors,” noted Dr. Negrin. “The top concern is how the solid tumor microenvironment differs from the mostly liquid hematological environment. Current studies are searching for answers – finding the right targets and the right cells, discovering why tumors are resistant to cell therapy, and understanding which components in the microenvironment need to be dismantled or disrupted for treatment to be tolerated and successful.”

“A further goal is to develop off the shelf cell products that don’t require the individualization of the current cell products, so called allogeneic CAR T cells. The biggest barrier to allogeneic cell therapy is the human body’s immunological response. People have a great capacity to reject foreign tissues and cells, which has so far kept cell therapy autologous (i.e., from the patient themselves) – useful only on a single individual. Moving beyond the confines of this therapy, to the infusion of third-party cells, is a significant biological challenge. While suppressing the immune system of the recipient of the cells is an option, in most cases these patients are already immune challenged and risk severe illness or infection.”

“The key to successful innovation in the mass production of cell therapy applications is to focus on further engineering sample cells to prevent them from being rejected by a different patient from the donor. Of course, these ideas need to be tested in well-constructed clinical trials. These clinical studies are very important, not only for research and patient treatment, but also for the further development of this therapy. We need to learn absolutely everything from our patients in order to move to the next stage in cell therapy.”

Resources:

1 “Facts About Cellular Therapies.” aabb.org accessed August 12, 2021.

2 Plenderleith, Ian H. “Treating the Treatment: Toxicity of Cancer Chemotherapy.” October 1990, NCBI.