Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy that modifies a patient’s immune cells to fight cancer. The process involves collecting T-cells from a patient and genetically engineering them to produce chimeric antigen receptors (CARs). These receptors allow the T-cells to recognize and attach to specific proteins, or antigens, on cancer cells, targeting them for destruction.
After being multiplied into the millions, these CAR T-cells are infused back into the patient. A central aspect of this treatment is “persistence,” which is the duration the modified T-cells remain alive and active in the body. The longevity of these cells determines the treatment’s ability to produce a lasting response and provide a sustained defense against cancer.
The Role of Persistence in CAR T-Cell Therapy
When CAR T-cells persist, they can continue to identify and eliminate cancer cells, acting as a form of living surveillance within the body. This ongoing action helps prevent the cancer from returning, a phenomenon known as relapse. The ability of CAR T-cells to expand in number after infusion and then persist is a marker of a successful therapeutic outcome.
The required duration of persistence can differ depending on the type of cancer. For some blood cancers, CAR T-cells may not need to remain in the body for an extended period to be effective. In contrast, a longer persistence is thought to be necessary for solid tumors to overcome the challenges posed by the tumor’s environment.
This long-term activity distinguishes CAR T-cell therapy from treatments like chemotherapy. While chemicals from chemotherapy are cleared from the body, persistent CAR T-cells provide an enduring defense. This cellular memory and function are fundamental to achieving durable responses where the cancer remains in remission for years.
Factors Influencing CAR T-Cell Lifespan
Several elements determine how long CAR T-cells survive. The design of the CAR construct is a primary factor. These engineered receptors contain co-stimulatory domains, which send signals that encourage the T-cell to activate and survive, significantly impacting persistence.
The intrinsic qualities of the T-cells also play a part. CAR T-cells produced from less differentiated T-cell types, such as naive and central memory T-cells, tend to persist longer. The manufacturing process, including methods used to culture and expand the cells, can influence the final composition of these T-cell subtypes.
Patient-specific factors, like age and prior treatments, can affect T-cell health. The tumor microenvironment can also be hostile to CAR T-cells by releasing suppressive signals. Before infusion, patients undergo chemotherapy known as lymphodepletion, which reduces existing immune cells and creates a more favorable environment for the new CAR T-cells.
Outcomes of Suboptimal CAR T-Cell Persistence
When CAR T-cells fail to persist, the most significant consequence is treatment failure or cancer relapse. An initial positive response can be short-lived if the engineered cells die off too quickly, allowing remaining cancer cells to grow again. Researchers monitor CAR T-cell levels in a patient’s blood to measure persistence, as a rapid decline can indicate the treatment may not lead to durable remission.
In some cases, the cancer itself can evolve to evade the CAR T-cells. This happens if tumor cells stop expressing the specific antigen that the CAR T-cells are designed to target, a process called antigen escape. In this scenario, even if CAR T-cells are still present, they can no longer recognize and attack the cancer.
Advancements in Prolonging CAR T-Cell Activity
Scientists are exploring strategies to enhance CAR T-cell persistence, such as engineering more advanced CAR constructs. Newer generations of receptors are being designed with improved signaling domains that promote cell survival and prevent exhaustion—a state where T-cells lose effectiveness after prolonged activity. These modifications aim to create more resilient CAR T-cells.
Another approach involves selecting specific T-cell subsets known for longevity, such as T-stem cell memory (Tscm) or central memory (Tcm) cells, for manufacturing. Lab conditions are also being optimized with growth factors like IL-7 and IL-15 to favor the development of these memory-like cells.
Combination therapies are also showing promise. This involves using CAR T-cells alongside other drugs, like checkpoint inhibitors, to counteract suppressive signals within the tumor microenvironment. Scientists are also developing “armored CARs,” which are engineered to produce their own supportive molecules or to resist inhibitory factors.