For decades, cancer treatment has been anchored by surgery, chemotherapy, and radiation therapy. While these remain crucial, the landscape of cancer care has been dramatically reshaped by innovative treatment categories. The early 2000s witnessed the rise of targeted therapies, exemplified by drugs like imatinib (Gleevec) and trastuzumab (Herceptin). These medications selectively target and destroy cancer cells by focusing on specific molecular changes unique to them. Today, numerous targeted therapies are standard treatments for a wide range of cancers. Over the past decade, immunotherapy has emerged as the “fifth pillar” of cancer treatment. Immunotherapies harness and amplify the patient’s immune system to combat tumors. These immune-boosting agents have demonstrated remarkable abilities to shrink or even eradicate tumors in individuals with advanced cancer, with some experiencing long-lasting responses. Immune checkpoint inhibitors are now widely used to treat various cancers, including melanoma, lung, kidney, bladder, and lymphoma. Another immunotherapy, CAR T-cell therapy, has sparked significant excitement among researchers and oncologists. While not as broadly applied as checkpoint inhibitors, CAR T-cell therapies have shown a similar capacity to eliminate advanced leukemias and lymphomas, offering long-term remission in many cases. Since 2017, the Food and Drug Administration (FDA) has approved six CAR T-cell therapies, all for blood cancers, including lymphomas, certain leukemias, and multiple myeloma. Despite the optimism, these therapies result in long-term survival in fewer than half of treated patients and face criticism for their high costs, exceeding $450,000 for the most recently approved treatment. Nevertheless, CAR T-cell therapy, after years of dedicated research, has become a significant part of mainstream cancer treatment. Dr. Steven Rosenberg, a pioneer in immunotherapy and CAR T-cell therapy at NCI’s Center for Cancer Research (CCR), emphasizes their widespread availability and status as a standard treatment for aggressive lymphomas, firmly establishing them in modern medicine.
Understanding CAR T-Cell Therapy: A “Living Drug” Approach
CAR T-cell therapy is often described as “giving patients a living drug,” as explained by Dr. Renier J. Brentjens, a leading figure in the field from Memorial Sloan Kettering Cancer Center. At its core, this innovative therapy utilizes T cells, critical components of the immune system responsible for coordinating immune responses and directly eliminating infected cells. Current Car-t Therapy approaches are personalized for each patient. The process begins with collecting T cells from the patient’s blood. These cells are then sent to a specialized laboratory where they are genetically modified to produce chimeric antigen receptors (CARs) on their surface. CARs are engineered proteins designed to recognize and bind to specific antigens, or proteins, found on the surface of cancer cells. Dr. Carl June, another pioneer in cellular therapy from the University of Pennsylvania Abramson Cancer Center, clarifies that these receptors are “synthetic molecules, they don’t exist naturally.”
After the T cells are re-engineered, they are multiplied in the lab to reach millions in number. These enhanced CAR T-cells are then infused back into the patient’s bloodstream. Ideally, these cells will continue to proliferate within the patient’s body. Guided by their engineered CARs, they will identify and destroy cancer cells displaying the targeted antigen on their surfaces. The FDA-approved car-t therapies currently target either CD19 or BCMA antigens, both found on B cells.
CAR T-Cell Therapy: Providing Hope Where Options Were Limited
The initial focus of CAR T-cell therapy development was largely on acute lymphoblastic leukemia (ALL), the most common childhood cancer. While intensive chemotherapy cures over 80% of children with B-cell ALL, effective treatments were scarce for patients whose cancer relapsed after chemotherapy or stem-cell transplant. However, in 2017, a significant breakthrough occurred with the FDA approval of tisagenlecleucel (Kymriah), the first CAR T-cell therapy to receive agency approval. This approval was based on clinical trials demonstrating its effectiveness in eradicating cancer in children with relapsed ALL. Long-term outcomes for children treated with car-t therapy are increasingly available. A recent NCI-led study reported long-term follow-up data on children with relapsed ALL treated with CAR T cells in a clinical trial. Over half of these children received a potentially curative stem-cell transplant, and approximately 60% of those children were alive and cancer-free five years later, without disease-related complications. Dr. Terry Fry, who has spearheaded numerous car-t therapy clinical trials at NCI and Children’s Hospital Colorado, describes the progress in pediatric ALL as “fantastic.” He notes that car-t therapy has rapidly become the standard of care for relapsed ALL in children as its availability has expanded.
CD19-targeted CAR T cells are also offering new hope to adults and children with advanced aggressive lymphomas. Before car-t therapy, many of these lymphoma patients were considered “virtually untreatable,” according to Dr. James Kochenderfer of NCI’s Center for Cancer Research, who has led trials of car-t therapies in diffuse large B-cell lymphoma. The outcomes in lymphoma have been “incredibly successful,” Dr. Kochenderfer states, and CAR T cells have become a frequently used treatment for several lymphoma types.
Managing the Side Effects of CAR T-Cell Therapies
Like all cancer treatments, CAR T-cell therapies can induce severe side effects, including a significant decrease in antibody-producing B cells and increased susceptibility to infections. Cytokine release syndrome (CRS) is a common and serious side effect. T cells release cytokines, which are chemical messengers that stimulate and direct immune responses. In CRS, the infused CAR T cells release a surge of cytokines into the bloodstream, leading to dangerously high fevers and a sharp drop in blood pressure. Severe CRS can be fatal in some instances. Ironically, CRS is considered an “on-target” effect, indicating that the car-t therapy is working. Patients with a higher cancer burden are more prone to experiencing severe CRS, Dr. Kochenderfer explains. Mild CRS can often be managed with supportive care, including steroids. Experience with car-t therapy has led to improved management strategies for severe CRS. Tocilizumab (Actemra), initially used for inflammatory conditions like juvenile arthritis, is a key drug in managing CRS. It blocks IL-6, a cytokine often released in large quantities by T cells and macrophages. Another significant side effect is neurologic effects, termed immune effector cell–associated neurotoxicity syndrome (ICANS). ICANS can manifest as severe confusion, seizure-like activity, and speech impairment. The exact cause of ICANS remains unclear. Tocilizumab is effective for CRS but not ICANS. Steroids, particularly dexamethasone, are the primary treatment for severe ICANS due to their ability to penetrate the central nervous system better than other steroids, explains Dr. Jennifer Brudno, involved in car-t therapy trials at NCI’s Center for Cancer Research.
Research is actively exploring ways to prevent CRS and ICANS. Prophylactic use of tocilizumab and low-dose steroids is one approach showing promising early data. Other treatments for ICANS are under investigation. For example, anakinra (Kineret), used for rheumatoid arthritis, has shown potential in preventing severe ICANS in car-t therapy patients in smaller studies. Modifying the CARs themselves is another strategy to reduce severe CRS and ICANS. A clinical trial of a “remodeled” CD-19-targeted CAR T cell developed at NCI demonstrated significantly fewer severe neurologic side effects in lymphoma patients compared to the original CAR design.
Expanding Targets: CAR T-Cells for Solid Tumors and Novel Antigens
CAR T-cell therapy research is rapidly advancing with numerous ongoing clinical trials. This expansion is fueled by the identification of new tumor antigens that could be targeted by CAR T cells. While CD19 and BCMA are currently the only FDA-approved targets, car-t therapies targeting other antigens prevalent in blood cancers are in development, including therapies targeting multiple antigens simultaneously. However, applying car t therapy to solid tumors like brain, breast, or kidney cancer has been challenging. Identifying antigens unique to solid tumors and absent in healthy cells has proven difficult.
Solid tumors also present a complex microenvironment that hinders car-t therapy effectiveness. Physical barriers can prevent CAR T cells from reaching tumor cells. Furthermore, immunosuppressive molecules within the tumor microenvironment can impair CAR T cell function, rendering them unable to kill cancer cells. Tumor heterogeneity is another significant obstacle. Solid tumors of the same type can vary greatly in molecular characteristics between patients and even within the same patient. Some tumor cells may lack targetable antigens or have insufficient levels for effective CAR T cell function. Despite these challenges, researchers are actively seeking strategies to utilize car-t cells for solid tumors. One approach involves “armored” CAR T cells engineered to overcome the immunosuppressive tumor microenvironment by secreting specific cytokines and other molecules. Other researchers are pursuing conventional CAR engineering to target single surface antigens on solid tumor cells.
Promising preclinical results have led Dr. Mackall’s group at Stanford to launch an NCI-supported clinical trial of car-t therapies targeting B7-H3, a protein found on solid tumors. Another trial is investigating a car-t therapy targeting GD2, a molecule on cancer cells, in children and young adults with DIPG, a fatal brain cancer. The GD2 CAR T-cell trial has evolved based on animal model data. Initially planned as a single intravenous infusion, the protocol was modified to include additional direct-to-brain infusions for responding patients. Multiple doses have led to improved tumor responses and symptom relief. Rapid modifications to CAR T cells and their manufacturing processes are also underway to enhance efficacy and safety. Dr. Mackall emphasizes that ongoing innovation in cellular therapies is crucial, stating that “we’re just scratching the tip of the iceberg about what we can do with regard to engineering these CAR T cells.”
The Future Landscape: “Off-the-Shelf” CAR T-Cells and Beyond
Researchers are also exploring alternative sources for immune cells in car-t therapy, moving towards “off-the-shelf” therapies using T cells from healthy donors. This aims to provide immediately accessible treatments, eliminating the patient-specific manufacturing time. Current FDA-approved car-t therapies use viruses to deliver genetic material into T cells. However, off-the-shelf approaches utilize gene-editing technologies like TALON and CRISPR to induce donor T cells to produce CARs. Another off-the-shelf strategy involves using natural killer (NK) cells instead of T cells. CAR NK cell therapies are currently in early clinical trials. Beyond cell source, the location of therapy production is also being re-evaluated. Nanotechnology and mRNA-based approaches are being explored to enable car-t cell creation directly within the patient’s body.
CAR T-Cell Therapy: Moving Beyond Last-Resort Treatment?
Traditionally, car t-cell therapy has been considered after cancer progression following multiple treatments. This paradigm is shifting. Recent large clinical trials demonstrated car-t therapy to be more effective than standard treatment for non-Hodgkin lymphoma patients whose cancer relapsed after first-line chemotherapy. This has led experts to suggest car-t therapy could replace chemotherapy as the standard second-line treatment for these patients. Dr. Fry suggests car-t cells could be particularly beneficial earlier in treatment for high-risk ALL children, potentially sparing them from prolonged chemotherapy. Clinical trials are underway to evaluate car-t therapy in children with ALL who show suboptimal response to initial chemotherapy. For these responders, “they could be spared 2 more years of chemotherapy,” Dr. Fry concludes, highlighting the transformative potential of car t-cell therapy.
