CAR-T Cell Therapy: Hope and Challenges in Conquering Acute Myeloid Leukemia
- Fay
- 2 hours ago
- 9 min read
Introduction
Acute myeloid leukemia (AML) is the most common type of adult leukemia and one of the most aggressive blood cancers. It mainly affects older adults and is marked by the rapid buildup of abnormal white blood cells that crowd out healthy ones. Standard treatments like chemotherapy and stem cell transplantation can help some patients, but many—especially older individuals—either cannot tolerate these treatments or eventually relapse.
In recent years, scientists have made progress with targeted drugs such as venetoclax and FLT3 inhibitors, yet relapsed or treatment-resistant AML remains one of the toughest cancers to cure. This has led researchers to explore immunotherapy—treatments that harness the body’s own immune system to fight cancer.
Among these new approaches, CAR-T cell therapy has shown remarkable success in other blood cancers, such as leukemia and multiple myeloma, by engineering a patient’s immune cells to attack tumor cells. However, applying CAR-T therapy to AML presents unique challenges. This article explores how CAR-T therapy works, why AML has been difficult to target, and what new advances are bringing this promising treatment closer to reality.
What Is CAR-T Therapy and How Does It Work?
CAR-T cell therapy is a groundbreaking form of personalized cancer treatment that uses a patient’s own immune cells—specifically, T cells—to find and destroy cancer. Scientists take T cells from a patient’s blood and reprogram them in the lab to better recognize cancer cells. Once these modified cells are multiplied and infused back into the patient, they act like a “living drug,” actively seeking out and killing cancer cells.
The “CAR” in CAR-T stands for Chimeric Antigen Receptor—a special structure added to the surface of T cells. You can think of it as a custom-made sensor that helps T cells spot cancer cells more accurately. This receptor has several parts that work together like a high-tech machine:
The outer part acts like an antenna, recognizing specific markers on cancer cells.
The middle part connects the antenna to the inside of the cell.
The inner part sends activation signals, telling the T cell to attack once a cancer cell is detected.
Over time, researchers have developed five generations of CAR-T designs, each one improving on the last. The earliest versions could recognize cancer cells but didn’t stay active long enough to fight them effectively. Newer generations include built-in “booster systems” that help the cells live longer, multiply, and remain powerful inside the body. Some of the latest experimental versions can even release immune-stimulating molecules, making the surrounding tumor environment more hostile to cancer.
All of the CAR-T therapies currently approved by the U.S. FDA—such as Yescarta®, Tecartus®, and Carvykti®—belong to the second generation. These treatments have achieved remarkable success in certain blood cancers like leukemia and lymphoma. Scientists are now building on these breakthroughs to design more advanced CAR-T therapies that are safer, last longer, and may one day be effective for tough-to-treat cancers such as AML.
From Discovery to Breakthrough: The Rise of CAR-T Cell Therapy
The story of CAR-T therapy began more than 30 years ago, when scientists first realized that the immune system could be trained to recognize and destroy cancer. Early cancer immunology research revealed that T cells—white blood cells that normally fight infections—could also detect and attack tumor cells. However, this natural process was often too weak or inconsistent to cure cancer on its own.
In the 1980s, a few visionary scientists proposed a bold idea: what if we could reprogram T cells to recognize cancer more precisely? Two teams independently built the first “chimeric antigen receptors,” or CARs—synthetic molecules that allow T cells to detect cancer cells directly, bypassing some of the natural immune system’s limitations. These early versions, while simple, laid the foundation for the CAR-T revolution.
The first CAR-T cells could identify cancer but weren’t strong or long-lasting enough to eliminate it. Over time, scientists learned how to make these engineered cells more powerful. They added “booster” signals that help T cells survive longer and multiply after entering the body.
These refinements led to what we now call second-generation CAR-T cells—the version used in all currently approved treatments. By combining specific targeting with improved activation, researchers finally had a therapy that could persist in patients and deliver meaningful, sometimes curative, responses.
In the early 2000s, research teams at top cancer centers in the United States—like the National Cancer Institute and the Children’s Hospital of Philadelphia—began testing CAR-T cells that target a protein called CD19, found on the surface of most B-cell cancers. This target proved ideal: it is highly specific to malignant cells but largely absent from healthy tissues.
The results were astonishing. Patients with advanced leukemia or lymphoma who had run out of options suddenly began to show deep, lasting remissions. One of the most famous cases was a young girl treated in 2012—her cancer disappeared, and she has remained cancer-free for more than a decade.
After years of refinement, these breakthroughs led to the first FDA approvals of CAR-T therapies in 2017. Two pioneering treatments, Kymriah® and Yescarta®, became the first living drugs capable of re-educating a patient’s immune system to find and destroy cancer.
Since then, CAR-T therapy has transformed the treatment landscape for several blood cancers and inspired global collaboration between scientists, clinicians, and biotechnology companies. Thousands of patients have now received these therapies, and new generations of CAR-T cells are in development—aiming to be safer, more effective, and applicable to solid tumors as well.
Although challenges remain—such as managing side effects and extending the success of CAR-T beyond blood cancers—this therapy marks a new era in personalized medicine. It demonstrates what is possible when biology and engineering come together: the ability to design immune cells that can cure cancers once considered untreatable.
CAR-T Therapies for Blood and Solid Cancers
CAR-T cell therapy has brought a true revolution to the treatment of blood cancers. In just a few years, six CAR-T therapies have been approved by the U.S. Food and Drug Administration (FDA), offering new hope to patients who previously had very few options.
The first approval came in 2017 with Kymriah®, designed for children and young adults with acute lymphoblastic leukemia (ALL). Soon after, more CAR-T therapies—Yescarta®, Tecartus®, and Breyanzi®—were approved to treat different types of lymphoma and leukemia. These treatments all target a molecule called CD19, found on the surface of many B-cell cancers.
More recently, two CAR-T products—Abecma® and Carvykti®—were developed to attack another protein called BCMA, which appears on multiple myeloma cells. For patients with relapsed or resistant blood cancers, these therapies have sometimes achieved long-lasting remission, showing what can happen when science and the immune system work together.
Despite these remarkable successes, extending CAR-T therapy to solid tumors—such as lung, breast, or colon cancers—has proven much more difficult. Unlike blood cancers, solid tumors form dense clusters surrounded by a harsh environment that protects them from attack. This tumor microenvironment can block CAR-T cells from reaching cancer cells and weaken them once they arrive.
Another challenge is that solid tumors often display a mix of different targets, meaning one CAR-T design rarely fits all. As a result, even though researchers have tested many CAR-T candidates in clinical trials, none have yet been approved by regulators for solid tumors.
That said, progress is being made. In one small study, a patient with aggressive brain cancer (glioblastoma) responded well to CAR-T cells targeting a protein called IL-13Ra, with benefits lasting several months. Other studies testing GD2-targeted CAR-T cells in children with certain brain tumors and neuroblastoma have shown encouraging results, with many patients experiencing tumor shrinkage and some achieving complete remission.
In addition, a new CAR-T therapy that targets claudin 18.2, a protein found in some stomach and pancreatic cancers, has shown promise in early clinical trials, where about half of patients saw their disease controlled or improved.
Even though CAR-T therapies are not yet approved for solid tumors, other immune-based treatments are showing promise. One example is tebentafusp, a drug that helps T cells recognize and kill melanoma cells in the eye; it became the first T-cell–engaging therapy approved for a solid cancer in 2022. Another experimental treatment, called afami-cel, reprograms a patient’s own T cells to target a specific tumor protein and has shown meaningful responses in early studies of rare sarcomas.
CAR-T Cell Challenges in Acute Myeloid Leukemia (AML)
While CAR-T therapy has transformed the treatment of some blood cancers, applying it to acute myeloid leukemia (AML) remains a major challenge. AML is a particularly complex disease that behaves very differently from B-cell malignancies. Three key issues make it difficult to design effective CAR-T treatments: the genetic diversity of the disease, the suppressive environment of the bone marrow, and the lack of a truly specific target antigen on leukemia cells.
AML is not a single disease—it is a group of related cancers that vary greatly from patient to patient. Each case can involve a different combination of gene mutations and chromosomal changes, which affect how the leukemia grows and how it responds to treatment. These genetic variations create many subtypes of AML, each with its own behavior and prognosis.
Adding to this complexity, AML often evolves over time. Within one patient, multiple subclones of leukemia cells may coexist, each with slightly different mutations. When treatment kills one group of cells, another subclone may survive and cause relapse. This dynamic nature makes it very difficult for a single CAR-T cell design to recognize and destroy every malignant cell, opening the door for antigen escape, where cancer cells lose or change the surface markers targeted by CAR-T therapy.
Another important feature of AML is the presence of leukemia stem cells—rare but resilient cells that can lie dormant for long periods and later regenerate the disease. These cells often share characteristics with normal blood stem cells, making it hard to target them without harming healthy tissue.
AML develops and thrives in the bone marrow, which is also where normal blood cells are produced. Unfortunately, this environment becomes highly immunosuppressive in leukemia, protecting cancer cells and weakening immune attacks.
AML cells actively reshape their surroundings, producing molecules like lactate, adenosine, and kynurenine that create a hostile environment for immune cells. These substances lower the local pH and send inhibitory signals that make CAR-T cells less active, shorten their survival, and push them into a state of exhaustion.
The bone marrow also contains many immune cells—T cells, macrophages, and myeloid-derived suppressor cells—that become “reprogrammed” by AML to tolerate the disease instead of fighting it. Exhausted T cells lose their ability to multiply and attack, while macrophages and suppressor cells release factors that further block immune activity. On top of that, changes in bone marrow structure, such as abnormal blood vessels and low oxygen levels, make it physically harder for CAR-T cells to move and reach their targets.
For CAR-T therapy to work, it needs a precise target—a molecule that appears on leukemia cells but not on healthy ones. In B-cell cancers, this is relatively straightforward: the CD19 molecule is abundant on tumor cells but not on essential tissues. In AML, however, the situation is far more complicated.
Many of the proteins expressed on AML cells, such as CD33 or CD123, are also found on healthy blood-forming stem cells. This overlap creates a serious safety concern: CAR-T cells designed to attack AML could also destroy the bone marrow’s ability to produce normal blood, leading to life-threatening toxicity.
Researchers have tested a range of possible targets, including Lewis Y, CD33, and CD123, but none has proven both safe and effective. Ideally, the perfect target would be present on leukemia stem cells and absent on normal tissues—a combination that has yet to be discovered.
Together, AML’s genetic diversity, its protective bone marrow environment, and the lack of safe target antigens form a “triple barrier” that has so far limited the success of CAR-T cell therapy. Scientists around the world are now exploring creative solutions, including combining CAR-T cells with other immunotherapies, reprogramming them to resist exhaustion, and developing new molecular targets unique to leukemia stem cells.
The journey toward effective CAR-T therapy for AML is far from over, but the lessons learned from blood cancers—and the rapid pace of innovation—offer hope that these obstacles may eventually be overcome.
Conclusion
The emergence of CAR-T cell therapy represents the culmination of decades of breakthroughs in immunology and genetic engineering. From early scientists discovering the anti-cancer potential of T cells to the launch of the first FDA-approved CAR-T products—Kymriah® and Yescarta® for treating B-cell tumors—this technology has brought unprecedented hope for cure to patients with hematologic malignancies.
However, applying this revolutionary therapy to acute myeloid leukemia (AML) remains fraught with challenges. Compared to B-cell tumors, AML exhibits greater complexity. It is not a single disease but a heterogeneous group of leukemias characterized by distinct genetic mutations, chromosomal abnormalities, and molecular features. This very “heterogeneity” leads to inconsistent treatment responses and a high susceptibility to relapse. Additionally, AML cells often reside within the immunosuppressive microenvironment of the bone marrow. This environment not only aids cancer cells in evading immune attacks but also impairs CAR-T cell function, hindering their sustained efficacy.
A greater challenge lies in target selection. An ideal CAR-T therapy target should be present exclusively on leukemia cells while absent in normal hematopoietic cells to avoid collateral damage. However, no perfect target has been identified to date. Researchers are actively exploring multiple candidate molecules, including CD33, CD123, CLL-1, and FLT3, while attempting innovative designs such as “dual-target CAR-T” or “safety switches” to enhance efficacy and reduce side effects.
Future success of CAR-T therapy in AML may hinge on multi-target combination strategies, more precise cell engineering techniques, and deeper understanding of the bone marrow microenvironment. While the path ahead remains long, ongoing research advances hold promise for CAR-T therapy to become a new hope for AML patients.
Source
Assessed and Endorsed by the MedReport Medical Review Board
