Biopharmaceutical manufacturers, healthcare providers, and patients alike are optimistic about the future of adoptive cell therapies. Chimeric antigen receptor (CAR) T-cells are the only adoptive cell therapy that has been approved for use as of 2021, but at least three other types under development could make cell therapy cheaper to design, faster to manufacture, and even more effective at treating cancer.
 
Adoptive cell therapies use the power of a patient’s own immune cells to attack cancer. Scientists have discovered that T cell receptors (TCRs), tumor-infiltrating lymphocytes (TILs), and natural killer (NK) cells, offer both manufacturing and clinical benefits that CAR-T cells do not provide. Here, we explore the potential and the limitations of these different cell therapies for everyone involved, from the scientists who develop them to the patients who receive them.
 
CAR-T Cells
 
T cells naturally seek out foreign invaders in our bodies. Modified to express the CAR gene, CAR-T cells specifically target tumor cells and destroy them. The FDA has approved five CAR-T cell therapies and they have all shown success in the clinic.
 
All the CAR-T cells used today are autologous, meaning they are derived from a patient’s blood. This makes current CAR-T cell therapies highly personalized but also slows down their development and their delivery to each patient.
 
CAR-T cell development faces several manufacturing challenges. For example, an antigen needs to be identified in advance, CAR needs to be expressed at the proper copy number in T cells, and biomanufacturers must remove replication-competent viruses from their batches. Tools that measure nucleic acid concentration directly, such as Droplet Digital PCR, can be used to characterize the success of genetic engineering and the presence of biological contaminants in CAR-T cells.
 
T Cell Receptors (TCRs)
 
Like CAR-T cells, TCR therapy involves modifying T cells, but these cells operate via different mechanisms that may make TCRs more personalized and flexible. For example, unlike CAR proteins, which can only recognize cell surface proteins, T cells that express TCRs can target any antigen expressed on the cell surface or within the cell.
 
TCR therapy involves modifying T cells to express a receptor that binds to the histocompatibility complex on tumor cells, the immune system’s protein structure that identifies foreign antigens and target cells for destruction. Because TCR therapies simply amplify the body’s natural immune response, they might be effective at treating solid tumors—an area where CAR-T cells have shown limited success in the clinic so far.
 
TCR development faces similar challenges to CAR-T cell development related to genetic modification and turnaround time. Fortunately, their similarity implies that working out the kinks associated with CAR-T cell therapy development will pave the way for easier TCR development.
 
Tumor-Infiltrating Lymphocytes (TILs)
 
If a lymphocyte has infiltrated a tumor, it is called a TIL. These immune cells’ ability to penetrate cancer cells gives them the potential to treat many forms of cancer that CAR-T cells cannot.
 
TILs are inherently less complex than CAR-T cells. In particular, TILs are agnostic to specific tumor antigens. As a result, biomanufacturers do not need to identify antigens in advance or genetically engineer the cells.
 
No TILs have reached the clinic yet, primarily because they are difficult to manufacture at scale. It takes roughly six to eight weeks to develop TILs. The process is laborious and complicated, creating a barrier to large-scale manufacturing. However, researchers are hard at work developing methods to reduce the production time for TILs.
 
Natural Killer (NK) Cells
 
NK cells also contribute to the body’s immune response, but they may be safer, more effective, and cheaper to manufacture than CAR-T cells.
 
NK cells naturally surveil the body for tumor cells. Like TILs, they do not require the identification of specific antigens to target them towards tumor cells, and therefore do not need to be genetically modified. When they detect tumor cells, they release lethal enzymes along with chemokines and cytokines that modulate the adaptive immune system.
 
Allogeneic NK cells have been proven safe, making them an appealing, cheaper alternative to T cell therapies. In addition, NK cells can also be modified to express CAR proteins, creating a potential avenue for the development of allogenic CAR-mediated immune cell therapy.
 
NK cells pose several challenges. Like T cells, they are difficult to expand ex vivo and they struggle to infiltrate solid tumors. They also do not persist in patients’ blood for as long as T cells. Scientists are currently developing protocols to improve NK cells for use in cancer therapy.
 
The Future of Adoptive Cell Therapy
 
There is no perfect adoptive cell therapy. Each of these four approaches has significant clinical potential for treating certain types of tumors, and they all pose specific limitations. Researchers are recruiting for or running more than 1,600 adoptive cell therapy trials, and the market is expected to reach roughly $25 billion in the next five to seven years. Having a menu of options available in the future will enable physicians to treat a wider variety of cancers and save more lives.