For decades, cancer treatment has been anchored by surgery, chemotherapy, and radiation therapy. While these methods remain vital, new therapeutic categories have emerged, significantly reshaping the landscape of cancer care.
The dawn of the 21st century witnessed the rise of targeted therapies such as imatinib (Gleevec) and trastuzumab (Herceptin). These drugs selectively target and destroy cancer cells by focusing on specific molecular alterations unique to these cells. Today, numerous targeted therapies are standard treatments for a wide range of cancers.
Over the past decade, immunotherapy, treatments that harness and amplify the patient’s immune system to combat tumors, has rapidly ascended to what many consider the “fifth pillar” of cancer treatment. These immune-boosting agents have demonstrated remarkable capabilities in shrinking and even eradicating tumors in individuals with advanced cancer. In a subset of patients, these therapeutic responses can endure for many years.
Immune checkpoint inhibitors, for instance, are now widely used to treat various cancers, including melanoma, lung, kidney, bladder, and lymphoma.
Another exciting form of immunotherapy is CAR T-cell therapy. While not as broadly applied as immune checkpoint inhibitors, CAR T-cell therapies have shown a similar capacity to eliminate advanced leukemias and lymphomas and maintain long-term cancer remission. The concept of Programming Car-t Cells To Kill Cancer is central to this innovative approach.
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 enthusiasm, long-term survival is achieved in less than half of treated patients. The cost of these therapies, exceeding $450,000 for the most recently approved one, has also drawn criticism.
Nevertheless, CAR T-cell therapies, after years of dedicated research into programming car-t cells to kill cancer, have become a mainstream cancer treatment, according to Dr. Steven Rosenberg, a pioneer in immunotherapy and CAR T-cell therapy at NCI’s Center for Cancer Research (CCR).
“CAR T cells are now widely accessible in the US and other countries, becoming a standard treatment for aggressive lymphomas,” Dr. Rosenberg stated. “They are now integral to modern medicine.”
CAR T-cell therapy: A “living drug” Programmed to Fight Cancer
CAR T cells represent “giving patients a living drug,” explains Dr. Renier J. Brentjens, another pioneer in CAR T-cell therapy at Memorial Sloan Kettering Cancer Center. The essence of this therapy lies in programming car-t cells to target and destroy cancer.
T cells, critical for immune response and pathogen-infected cell destruction, form the foundation of CAR T-cell therapy.
Current CAR T-cell therapies are personalized. They are created by extracting T cells from the patient and reprogramming them in the lab to express chimeric antigen receptors (CARs) on their surface. These CARs are designed to recognize and bind to specific antigens on cancer cells, a key step in programming car-t cells to kill cancer.
“These receptors are synthetic, not naturally occurring,” explains Dr. Carl June, a leader in cellular therapy at the University of Pennsylvania Abramson Cancer Center. Programming car-t cells involves this crucial genetic modification.
After lab expansion into millions, these reprogrammed T cells are infused back into the patient. Ideally, these CAR T cells multiply, locate cancer cells via their engineered receptors, and eradicate them, demonstrating the power of programming car-t cells to kill cancer.
FDA-approved CAR T-cell therapies target CD19 or BCMA antigens on B cells, showcasing the specificity achieved through programming car-t cells to kill cancer.
New Hope Where Options Were Limited
Initial CAR T-cell therapy development focused on acute lymphoblastic leukemia (ALL), the most prevalent childhood cancer. Programming car-t cells to kill cancer was initially explored extensively in this area.
While intensive chemotherapy cures over 80% of children with B-cell ALL, effective treatments were scarce for relapsed cases.
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Second CAR T-Cell Therapy Approved for Lymphoma
Tisagenlecleucel offers a new option for certain lymphoma patients, marking progress in programming car-t cells to kill cancer in various blood malignancies.
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However, in 2017, a new avenue emerged with FDA approval of tisagenlecleucel (Kymriah), the first CAR T-cell therapy, based on trials showing its ability to eliminate cancer in children with relapsed ALL. This marked a significant milestone in programming car-t cells to kill cancer.
Long-term outcomes in children treated with CAR T-cell therapy for ALL are now emerging.
An NCI-led study reported long-term follow-up of relapsed ALL children treated with CAR T cells in a trial. Over half received a potentially curative stem-cell transplant, and approximately 60% of those children were alive and cancer-free 5 years later. These results underscore the durable impact of programming car-t cells to kill cancer.
The progress in CAR T-cell therapy for children with ALL has been “fantastic,” said Dr. Terry Fry, who led CAR T-cell therapy trials at NCI and Children’s Hospital Colorado. CAR T-cell therapy has become the standard care for relapsed ALL in children, highlighting the successful application of programming car-t cells to kill cancer.
CD19-targeted CAR T cells also offer hope for adults and children with advanced aggressive lymphomas. Before CAR T cells, many of these patients were “virtually untreatable,” said Dr. James Kochenderfer, who led CAR T-cell therapy trials for diffuse large B-cell lymphoma at NCI’s Center for Cancer Research. Programming car-t cells to kill cancer has revolutionized treatment for these lymphomas.
Lymphoma outcomes to date “have been incredibly successful,” Dr. Kochenderfer noted, with CAR T cells becoming a frequent therapy for several lymphoma types, demonstrating the broad applicability of programming car-t cells to kill cancer in blood malignancies.
Managing Side Effects of CAR T-cell Therapies
Like all cancer treatments, CAR T-cell therapies can cause severe side effects, including B-cell die-off and infections. Cytokine release syndrome (CRS) is a frequent and serious side effect. Understanding and managing these side effects is crucial as programming car-t cells to kill cancer becomes more widespread.
T cells release cytokines, immune response messengers. In CRS, infused T cells release excessive cytokines, causing severe side effects like high fevers and blood pressure drops. Severe CRS can be fatal.
Ironically, CRS is an “on-target” effect, indicating T-cell activity. Patients with extensive cancer are more prone to severe CRS, explained Dr. Kochenderfer. This reaction is a consequence of programming car-t cells to kill cancer effectively.
Mild CRS can be managed with supportive therapies, including steroids. Experience with CAR T-cell therapy has led to better management of severe CRS.
Tocilizumab (Actemra), initially for inflammatory conditions, is key in CRS management. It blocks IL-6, a cytokine often secreted in large amounts by T cells and macrophages. This drug helps mitigate the inflammatory storm caused by programming car-t cells to kill cancer.
Neurologic effects, including confusion, seizures, and speech impairment (ICANS), are another concern. The cause of ICANS remains unclear.
While effective for CRS, tocilizumab doesn’t help with ICANS. Steroids, particularly dexamethasone, are the best treatment for severe ICANS, as dexamethasone penetrates the central nervous system better than other steroids. Managing these neurotoxicities is a critical aspect of programming car-t cells to kill cancer safely.
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Remodeled CAR T-Cell Therapy Causes Fewer Side Effects
For lymphoma patients, a safer treatment, as effective as the original CAR T-cell design, demonstrates progress in refining programming car-t cells to kill cancer with enhanced safety profiles.
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Preventing CRS and ICANS is under intense study, said Dr. Brudno. Prophylactic tocilizumab and low-dose steroids are being explored with reassuring early data. Research is ongoing to improve the safety of programming car-t cells to kill cancer.
Anakinra (Kineret), for rheumatoid arthritis, may help prevent severe ICANS, smaller studies suggest.
Modifying CARs themselves is another approach to reduce CRS and ICANS.
A small trial of adults with lymphoma using a “remodeled” CD-19-targeted CAR T cell developed at NCI showed significantly fewer severe neurologic side effects compared to the original CAR, highlighting advancements in programming car-t cells to kill cancer with improved safety.
Expanding Targets to Solid Tumors
CAR T-cell research is rapidly progressing, with hundreds of ongoing clinical trials. Identifying new tumor cell antigens as CAR T-cell targets is a major focus. The future of programming car-t cells to kill cancer extends beyond blood malignancies.
While CD19 and BCMA are the only antigens with FDA-approved CAR T-cell therapies, therapies targeting other blood cancer antigens, including multiple antigens simultaneously, are in development.
However, applying CAR T cells to solid tumors like brain, breast, or kidney cancer is challenging. Identifying antigens on solid tumors but not healthy cells has been largely unsuccessful. Overcoming these hurdles is essential for expanding the application of programming car-t cells to kill cancer.
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Overcoming T Cell Exhaustion in Immunotherapy
Targeting proteins involved in T-cell exhaustion may boost immunotherapy, critical for improving the effectiveness of programming car-t cells to kill cancer in solid tumor environments.
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Solid tumor environments present further obstacles. Physical barriers can hinder CAR T-cell access to tumor cells. The tumor microenvironment, with immune-suppressing molecules, can cause CAR T-cell malfunction, impairing their cancer-killing ability. These factors complicate programming car-t cells to kill cancer in solid tumors.
“Tumor heterogeneity” is another major barrier, said Dr. Crystal Mackall. Solid tumors of the same type can vary molecularly between and within patients. Some tumor cells may lack targetable antigens, or have insufficient antigens for CAR T cells to function effectively. Addressing tumor heterogeneity is crucial for effective programming car-t cells to kill cancer in solid tumors.
Despite these challenges, researchers are persistently seeking ways to use CAR T cells for solid tumors.
One approach involves “armored” CAR T cells designed to overcome the immune-suppressing solid tumor environment by secreting specific cytokines and molecules. This advanced programming of car-t cells to kill cancer aims to enhance their efficacy in challenging tumor settings.
Other researchers are pursuing conventional CAR engineering, targeting single surface antigens on cancer cells.
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CAR T-Cell Study Suggests Promise for Childhood Cancers
In mouse models of pediatric cancers, treatment shrank or eradicated tumors, indicating potential for programming car-t cells to kill cancer in childhood solid tumors.
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Following promising lab and animal studies, Dr. Mackall’s group launched an NCI-supported trial of CAR T-cell therapies targeting B7-H3 protein on solid tumors. Another trial investigates CAR T-cell therapy targeting GD2 molecule in children and young adults with DIPG, a fatal brain cancer. These trials explore novel applications of programming car-t cells to kill cancer in solid tumors.
The GD2 CAR T-cell trial evolved from initial intravenous infusion to include direct brain infusions for responders, improving tumor responses and cancer-related symptoms. This adaptive approach highlights the dynamic nature of programming car-t cells to kill cancer research.
Rapid modifications to GD2 CAR T cells and their manufacturing improved efficacy and safety, emphasizing continued innovation in cellular therapies.
“We’re just scratching the tip of the iceberg about what we can do with regard to engineering these CAR T cells,” Dr. Mackall said. “There are many, many next-generation approaches to the problems that are limiting their effectiveness in solid tumors.” The future of programming car-t cells to kill cancer is ripe with possibilities.
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NCI Aims to Boost CAR T-Cell Therapy Clinical Trials
Initiative will manufacture therapies to be tested at multiple trial sites, expanding access to and research on programming car-t cells to kill cancer.
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Off-the-Shelf CAR T-cell Therapies: CRISPR and Beyond
Researchers are rethinking the immune cell source for CAR T-cell therapies, exploring healthy donor T cells for “off-the-shelf” therapies. This aims for immediate availability, eliminating patient-specific manufacturing delays in programming car-t cells to kill cancer.
While FDA-approved CAR T-cell therapies use viruses for gene delivery, off-the-shelf CAR T cells in trials utilize gene-editing technologies like CRISPR to induce CAR production in donated T cells. These advancements streamline programming car-t cells to kill cancer.
Other off-the-shelf CARs use natural killer (NK) cells. CAR NK cell therapies are being tested in trials, broadening the cell types used in programming car-t cells to kill cancer.
Therapy manufacturing location is also evolving, with nanotechnology and mRNA-based approaches enabling in-body CAR T-cell creation, representing cutting-edge advancements in programming car-t cells to kill cancer.
Beyond Last-Ditch Treatment
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CAR T Cells: Second-Line Treatment Option for NHL?
Clinical trials indicate CAR T cells may be more effective than standard treatment, suggesting a move towards earlier intervention with programming car-t cells to kill cancer.
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CAR T-cell therapy is typically considered after cancer progression following multiple treatments. However, this is changing.
Recent trials showed CAR T-cell therapy to be more effective than standard treatment for non-Hodgkin lymphoma patients whose cancer relapsed after first-line chemotherapy. This suggests a paradigm shift in when programming car-t cells to kill cancer is considered.
Experts suggest CAR T-cell therapy could replace chemotherapy as standard second-line treatment for these patients, marking a significant step in the earlier application of programming car-t cells to kill cancer.
Dr. Fry noted CAR T cells as a particularly attractive option for high-risk ALL children, potentially sparing them from prolonged chemotherapy. Trials are underway for CAR T cells in children with ALL not optimally responding to initial chemotherapy. This proactive approach showcases the evolving role of programming car-t cells to kill cancer.
For responders, “they could be spared 2 more years of chemotherapy,” Dr. Fry concluded. “That’s amazing to think about,” highlighting the transformative potential of programming car-t cells to kill cancer.
