Cancer treatment has come a long way over the past century. From surgery and chemotherapy to radiation therapy, targeted therapies, and immune checkpoint inhibitors, each breakthrough has improved outcomes for patients and reshaped the way we treat cancer. Today, a new era has emerged, one in which the immune system itself becomes the treatment. Rather than delivering a conventional drug, cellular immunotherapy harnesses and engineers a patient’s own immune cells, transforming them into living medicines capable of recognizing and destroying cancer.
Among these innovations, Chimeric Antigen Receptor T-cell (CAR-T) therapy has become one of the greatest breakthroughs in modern oncology. Since the first CAR-T products were approved, patients with relapsed or refractory blood cancers who previously had very limited treatment options have achieved durable remissions that were once considered impossible.
Unlike chemotherapy, which directly kills rapidly dividing cells, or immune checkpoint inhibitors, which release the brakes on existing immune responses, CAR-T therapy takes a completely different approach. Scientists collect a patient’s own T cells, genetically reprogram them to recognize cancer, multiply them in the laboratory, and return them to the patient, where they actively seek out and destroy tumor cells.
Today, CAR-T therapy is changing the standard of care for several hematologic malignancies and is one of the fastest-growing areas of cancer research. At the same time, researchers are working to overcome the biological barriers that have limited its success in solid tumors and are developing next-generation cellular therapies that may further expand its potential.
Tumor Irradiation May Improve CAR T Cell Therapy in Solid Tumors
What is CAR-T Therapy?
CAR-T stands for Chimeric Antigen Receptor T-cell therapy.
To understand CAR-T therapy, it is important to first understand the role of T cells.
T lymphocytes are one of the body’s most powerful immune defenses. Every day, they patrol the bloodstream and tissues searching for infected, damaged, or abnormal cells. Under normal circumstances, T cells recognize their targets through specialized proteins called T-cell receptors (TCRs). These receptors detect small peptide fragments that are presented on the surface of cells by molecules known as the major histocompatibility complex (MHC).
Cancer, however, has evolved numerous strategies to escape immune surveillance. Many tumors reduce MHC expression, alter antigen presentation, or create an immunosuppressive environment that prevents T cells from recognizing and attacking malignant cells.
CAR-T therapy was developed to overcome many of these escape mechanisms.
Instead of relying on the natural T-cell receptor, scientists genetically engineer T cells to express a synthetic receptor known as a chimeric antigen receptor (CAR). Unlike the natural TCR, a CAR recognizes proteins directly on the surface of tumor cells without requiring antigen presentation through MHC molecules.
In simple terms, CAR-T therapy gives the immune system a completely new way to recognize cancer.
How Does CAR-T Therapy Work?
Although patients usually receive CAR-T therapy as a single infusion, producing this treatment is a highly sophisticated, personalized manufacturing process.
Step 1. Collecting the Patient’s T Cells
Treatment begins with leukapheresis, a procedure that separates T lymphocytes from the patient’s blood while returning the remaining blood components to the circulation.
These collected T cells become the starting material for the therapy.
Step 2. Genetic Engineering
The T cells are transported to a specialized manufacturing laboratory, where they are genetically modified.
Using viral vectors—or increasingly, non-viral gene-editing technologies—the DNA encoding the chimeric antigen receptor is inserted into the patient’s T cells.
The CAR itself consists of several functional components:
- An extracellular antigen-binding domain, usually derived from an antibody, that recognizes a specific protein on cancer cells.
- A hinge region that provides flexibility.
- A transmembrane domain that anchors the receptor within the cell membrane.
- Intracellular signaling domains, including CD3ζ and co-stimulatory molecules such as CD28 or 4-1BB, which activate the T cell after it encounters its target.
Once this receptor is expressed, the T cell gains the ability to recognize cancer cells independently of MHC presentation.
Step 3. Cell Expansion
After genetic modification, the engineered T cells are stimulated to grow.
Over several days, millions of modified cells expand into hundreds of millions of CAR-T cells capable of recognizing the target antigen.
Each manufactured product undergoes extensive quality-control testing before being released for patient treatment.
Step 4. Preparing the Patient
Before CAR-T cells are infused, patients receive lymphodepleting chemotherapy, most commonly fludarabine and cyclophosphamide.
This step reduces competing immune cells and creates a more favorable environment for CAR-T-cell expansion by increasing the availability of homeostatic cytokines such as IL-7 and IL-15.
Step 5. CAR-T Cell Infusion
The engineered cells are then infused intravenously.
Unlike conventional drugs, CAR-T cells remain alive after administration. They circulate throughout the body searching for cells that express their target antigen.
How Do CAR-T Cells Kill Cancer?
When a CAR-T cell encounters a cancer cell expressing its target antigen, the chimeric antigen receptor binds directly to the tumor cell. This interaction immediately activates the engineered T cell. Activated CAR-T cells eliminate cancer through several complementary mechanisms.
They release perforin, which creates pores in the tumor-cell membrane, allowing granzymes to enter the cell and trigger programmed cell death (apoptosis). They also activate additional apoptotic pathways through Fas/FasL signaling and produce inflammatory cytokines such as interferon-γ and tumor necrosis factor that recruit other immune cells into the antitumor response.
One of the most remarkable features of CAR-T therapy is that these engineered cells do not simply kill cancer cells—they also multiply after recognizing their target. A relatively small number of infused CAR-T cells can expand dramatically inside the patient, creating a large population of highly specialized immune cells capable of sustained antitumor activity.
For this reason, CAR-T therapy is often described as a living drug rather than a conventional medicine.
Why Has CAR-T Therapy Been So Successful?
The greatest success of CAR-T therapy has been observed in hematologic malignancies.
Blood cancers such as B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma often express highly consistent target antigens.
CD19 became the first major CAR-T target because it is present on most malignant B cells while its loss can be managed clinically. More recently, BCMA has become a highly successful target for multiple myeloma.
Because these antigens are relatively uniform, CAR-T cells can efficiently recognize and eliminate malignant cells, leading to remarkable response rates in patients whose disease had progressed after multiple previous treatments.
Why Are Solid Tumors More Difficult?
Despite these extraordinary successes, translating CAR-T therapy to solid tumors has proven much more challenging.
Unlike blood cancers, solid tumors are biologically complex ecosystems. Many potential target antigens are also expressed on healthy tissues, increasing the risk of on-target, off-tumor toxicity.
Tumors are also highly heterogeneous. Different cancer cells within the same tumor may express different antigens, allowing antigen-negative clones to survive even after CAR-T treatment.
In addition, the tumor microenvironment actively suppresses immune function through regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, inhibitory cytokines, hypoxia, abnormal metabolism, and dense stromal tissue that physically limits immune-cell infiltration. Finally, CAR-T cells often struggle to persist long enough within this hostile environment to generate durable responses.
Overcoming these challenges has become one of the highest priorities in cellular immunotherapy research.
Expert Insights: The Future of CAR-T and Cell Therapy
Brendan Zangari
Immune-Oncology and Gene-Therapy Scientist | United States
What is the greatest barrier to successful CAR-T therapy in solid tumors, and which emerging innovation gives you the most hope?
“This is a hard one, I am split between the target and cell persistence.
There is a line of thinking that the success of TIL therapy is due to the therapy’s ability to target multiple tumor antigens. While this is possible with CAR-T cells, and underlined by efforts to make products capable of recognizing two targets, TIL target dozens if not hundreds.
An innovation that gives me hope is the development of methods to:
(i) efficiently identify targets
(ii) develop receptors that can bind targets with a high-degree of sensitivity.
These methods are particularly advanced for TCR-based modalities. Papers are being produced which describe the ability to:
(i) identify neoantigens
(ii) identify neoantigen-reactive TCRs
(iii) determine which TCRs are optimal for therapy.
Further, companies are developing technologies that can be applied to doing this in an efficient manner, for example T-Scan. One could speculate that these approaches could be pursued with CARs through methods which have yet to be established.
It is tempting to choose persistence but there are just so many ways to enhance persistence. Of course, exogenous cytokines represent the most practical solution. However, there is a tradeoff with toxicity.
I think the most interesting innovation to address this is orthogonal cytokines; cytokines that target the product alone. Alternatively, there are efforts to use genetic techniques to enhance persistence. In the paper shared we saw transcription factor knockouts achieve nice results in mouse models, for some donors.”
How do you envision the relationship between CAR-T, TCR-T, TIL therapy, and in vivo CAR-T evolving over the next decade? Will these approaches compete, converge, or complement one another?
“I think that in vivo therapies will be pursued and represent an attractive approach to some cancers but standard cell therapies will dominate the treatment of most.
I think that effective CAR-T cells will be developed for solid tumors but TCR-T cells will present the best approach to personalization.
I think these therapeutic modalities will complement one another.
For example, one can imagine a scenario where TIL products are made to include PBMC-derived T cells transduced with TCRs or CARs specific to commonly expressed tumor targets. Such products could not only provide the wide targeting of TIL but also the deep targeting mediated by the engineered T cells.”
What scientific question in cell therapy do you believe the field should be prioritizing today, but isn’t receiving enough attention?
“I think there should be a prioritization of the question of how allogeneic cell lines could be made for the treatment of a wide range of patients.
Autologous products are ideal but limited by the need for patient cells which don’t always expand as well as desired.
In a futuristic scenario we could imagine the invention of a bank of designer allogeneic cell lines which are impervious to recognition by host immune cells, incapable of graft versus host disease, and which can be outfitted with receptors uniquely suited to a given patient’s cancer.
The logistics of this is challenging but could be achieved through multiple organizations pursuing each effort independently.
For example one company could make a bank of the described cell lines. Another company could specialize in developing receptors for the product.”
If you could make one bold prediction about the future of cell therapy, what breakthrough do you think will surprise the oncology community most over the next decade?
“I would like to see innovation in the application of cell therapies.
Many cancer patients undergo resection yet still experience relapse. This is common in pancreatic cancer.
I think it would be a major breakthrough if these patients could be treated with cell therapies after resection; to serve as an adjuvant.
The pitfall here is that cell therapies are expensive and have side effects. However, targeting approaches for these therapies could be devised from tumor resections.
The cell products could eliminate residual tumor cells responsible for relapse.”
How Legend Biotech Plans to Expand the Reach of CAR-T Therapy | Dr. Ying Huang