Cancer immunotherapy relies on modified immune cells to detect and destroy cancer cells. Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary immunotherapy approach in which T cells are genetically modified to express a receptor that recognizes specific markers on cancer cells, enabling targeted destruction of malignant cells.
This approach has shown substantial success in treating cancers that do not respond to conventional therapies.
In a recent review published in JAMA, researchers examined the mechanisms, applications, and clinical outcomes of CAR T-cell therapy, as well as the challenges and ongoing advancements to improve its safety and broaden its scope.
Study: CAR T Cells and T-Cell Therapies for Cancer. Image Credit: ArtemisDiana/Shutterstock.com
CAR T-Cell Therapy — Mechanisms and Applications
One of the most promising forms of immunotherapy developed in recent times is CAR T-cell therapy, in which the receptors in T cells are genetically engineered to recognize and attack specific proteins in cancer cells. The CARs allow the T cells to bind directly to cancer cells and initiate an immune response to destroy them.
The CAR structure has two main parts — an extracellular segment that recognizes cancer-specific proteins and an intracellular region that activates the T cell response. CAR T cells are created by extracting T cells from the patient through apheresis and using a viral vector to modify the T cells to express the CAR receptor genetically.
Furthermore, chemotherapy is often administered before the infusion to suppress immune cells that could hinder CAR T cells and to create a favorable environment for CAR T-cell activity by increasing the levels of interleukin (IL)-15, IL-7, and other cytokines.
Six CAR T therapies are currently approved bythe United States (U.S.) Food and Drug Administration (FDA), and these focus mainly on hematological cancers such as non-Hodgkin lymphomas and acute lymphoblastic leukemia.
Tisagenlecleucel and axicabtagene ciloleucel are two of four CAR T-cell therapies used for B-cell blood cancers and are engineered to target the transmembrane antigen CD19 on B cells.
Studies and clinical trials have reported that axicabtagene ciloleucel showed a five-year survival rate of 43% for large B-cell lymphoma patients, which was significantly higher than the 20% two-year survival rate observed with conventional treatments.
Furthermore, CAR T-cell therapies, such as idecabtagene vicleucel that target the B-cell maturation antigen, have also shown promising results for multiple myelomas, with a 73% response rate and progression-free survival of more than 27 months in certain patients.
Challenges Associated with Cellular Therapies
However, significant challenges hinder the broader use of CAR T-cell therapy, including adverse reactions such as cytokine release syndrome and ICANS or immune effector cell-associated neurotoxicity syndrome.
While cytokine release syndrome can cause symptoms such as fever and low blood pressure that can sometimes escalate to life-threatening conditions, ICANS, which affects the nervous system and may lead to symptoms such as confusion, tremors, or seizures, is often reversible.
Some patients also experience a limited duration of remission post-treatment, especially in cases where the cancers have pre-treated aggressively. Long-term issues also include persistent low blood cell counts, immunosuppression, and heightened infection risk, which can complicate recovery.
Another major limitation of CAR T-cell therapy is antigen escape, where cancer cells adapt by altering or losing the proteins targeted by CAR T-cells, leading to possible relapse. For example, while CAR T-cell therapy targeting the CD19 antigen has proven effective in certain leukemias, some patients have relapsed after treatment due to loss of CD19 expression in cancer cells.
Creating CAR T-cell therapies also involves a complex and extensive manufacturing process, which contributes to long wait times. For patients with aggressive cancers, these delays are a major hindrance and could potentially lead to disease progression.
Furthermore, CAR T-cell therapy is also expensive, costing hundreds of thousands of dollars per treatment, which further restricts access to these therapies and could potentially introduce disparities based on socioeconomic and insurance status.
Improvements and Future Applications
To improve the efficacy of CAR T-cell therapy in treating hematological, ongoing research is focused on decreasing toxicity, boosting remission rates, and improving access to the therapy.
Moreover, new CAR T-cell structures and combination treatments are being explored to prevent antigen escape and enhance the functionality of T cells. The researchers believe that experimental administration of CAR T-cell therapy earlier in the course of the treatment, before heavy chemotherapy, may also improve response rates.
Furthermore, applying CAR T-cell therapy to solid tumors has also presented unique challenges due to factors such as the location of the tumor, the tumor microenvironment, and antigen specificity. Since CAR T-cells mainly target surface proteins, finding suitable markers in solid tumors without affecting healthy cells remains a challenge.
T-cell receptor (TCR) therapies and tumor-infiltrating lymphocyte (TIL) therapies are promising alternatives, with TIL therapy now being approved by the FDA for treating advanced melanoma. These therapies often use T cells that can identify internal tumor markers and withstand harsh tumor environments.
Ongoing research aims to address these challenges by designing CAR T-cells for multiple cancer-specific markers and expanding their applications beyond hematological cancers.
Promising approaches, such as off-the-shelf CAR T-cells made from healthy donor cells, could potentially improve access by reducing the time needed to manufacture patient-specific CAR T-cells. These approaches may also enable faster treatment, broaden patient eligibility criteria, and lower production costs.
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