Chimeric Antigen Receptor T-cell (CAR-T) therapies sold in the US marketplace include Kymriah (Novartis; Basel, Switzerland), Yescarta, and Tecartus — (Gilead; Foster City, CA), Abecma and Breyanzi (Bristol Myers Squibb; New York), and Carvykti (Janssen Biotech, Inc; Horsham, Pennsylvania). The FDA approved Kymriah and Yescarta in 2017, Tecartus in July 2020, Abecma and Breyanzi in 2021, and Carvykti in 2022. These cell therapies represent the hottest immunotherapies on the market today because they boost the body’s ability to recognize and attack cancer cells that our own immune system may miss.
According to Pharmaceutical Technology, by 2028, the market is expected to reach $25 billion, with a compound annual growth rate (CAGR) of 46.6%. This makes CAR-T one of the fastest-growing and potentially profitable therapeutic areas in oncology.
THE TRICKY TUMOR MICROENVIRONMENT
Theoretically, our immune system should recognize the unique proteins in diseased cells. However, there are two main reasons this doesn’t always happen:
- Early in tumor development, the cell composition is similar enough to healthy cells that the immune system can overlook the cancer.
- Later, as a tumor progresses, it releases chemical signals that suppress the immune response, helping it to evade detection. This trickery is known as the tumor microenvironment, which results in deadly cancer cells remaining in the body undetected.
So, what’s the biopharma industry to do? Figure out how to train T-cells ALWAYS to recognize and destroy cancer cells… enter the hero, CAR-T!
T-CELLS TO THE RESCUE
The CAR-T therapies currently on the market are all derived from CD8+ T-cells, also known as cytotoxic T-cells or killer T-cells. The job of these cells is precisely what the name implies—to kill infected or cancerous cells. CD8+ T-cells are equipped with cytotoxic molecules, such as perforin and granzymes, which allow them to induce apoptosis (cell death) in target cells.
Like the mythical chimera, this drug is composed of different parts. Genetic engineers remove the naturally occurring T-cell receptor (TCR) and replace it with a CAR or synthetic antibody. The manmade CAR is fused with a CD8+ T-cell to create a chimeric molecule. Each individual CAR-T cell possesses a distinctively shaped CAR receptor. The mission of CAR is to identify and bind a specific protein (antigen) on the tumor cells. This recognition occurs due to a complementary fit between the shape of the CAR and a unique antigen exclusively present on the surface of cancer cells. Once the CAR-T cell successfully attaches to its designated target, it releases cytotoxins that induce cell death. As a result of this process, the cancer cells are effectively eradicated.
HOW TO TRAIN AN IMMUNE SYSTEM
CAR-T therapies boost the body’s ability to recognize and attack cancer cells. These “super” cytotoxic T-cells have been physically enhanced to go after cancer. The synthetic CAR includes a targeting domain and an activation domain. The targeting domain is a manmade antibody that detects and locks onto a specific surface antigen on the patient’s cancer cells. Once the targeting domain binds to the cancer cell, the activation domain triggers to release cytotoxins.
The process begins with technicians removing cytotoxic T-cells from a patient’s body and isolating them in the lab. Next, scientists use a viral vector—a virus modified to contain a therapeutic gene—to deliver DNA that encodes the CARs to the CD8+ T-cells. The engineered CAR-T cells are then reinfused into the patient. Once back inside the patient, the CAR’s targeting domain finds the proper surface protein on the tumor cell and attaches to it. Then, the CAR’s activation domain signals the cytotoxic T-cell to replicate (make copies of itself) and release cytotoxins to kill the cancerous cells.
WHAT’S IN A NAME?
Chimeric antigen receptor therapy is broken down into:
- Chimeric: Composed of components from two distinct parts—a synthetic antibody or CAR and a CD8+ T-cell.
- Antigen: A protein that is recognized by an antibody, such as a protein on the surface of a tumor cell.
- Receptor: A protein embedded in a cell membrane that binds to a specific antigen and, upon binding, causes a reaction to occur in the cell.
- CD8+ T-Cell: A white blood cell that kills infected or cancerous cells
The medical community classifies CAR-Ts as a “cell-based gene therapy.” They’re immune cells that have been engineered using gene therapy techniques.
IN THE PIPELINE
CAR-T is an effective treatment for liquid tumors, also known as blood cancers, but the treatment of solid tumors lacks effectiveness. Scientists are slapping synthetic CARs on different immune cell types, such as macrophages. In the tumor microenvironment, macrophages are the innate immune cells with the highest infiltration rate. Because macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment (including tumor cells and other immune cells), researchers are experimenting with macrophages modified with CAR against solid tumors. These are known as CAR-M or CAR-MA. Natural Killer Cells are being used to create CAR-NK. NK cells’ innate cytotoxic properties can target a variety of cells, including cancer cells. Other CAR therapies being explored include gamma-delta T-cells as a basis for CAR engineering, but these approaches are still in the experimental stages.
The overall goal of CAR-T cell therapy is to enhance the patient’s immune response against specific target cells, often blood cancer cells, by redirecting T-cells to recognize and eliminate those cells more effectively. The specific T-cell type used and the design of the CAR can vary depending on the therapeutic strategy and the type of cancer being addressed. The CARs are synthetic receptors designed to recognize specific antigens on the surface of diseased target cells.
FREQUENTLY ASKED QUESTIONS
1. WHAT EXACTLY ARE CAR-T THERAPIES?
CAR-T therapies are a type of immunotherapy where a patient’s T-cells are genetically engineered to recognize and attack cancer cells. The “CAR” stands for Chimeric Antigen Receptor, which is an artificial receptor added to the T-cells to help them target specific cancer antigens.
2. WHY IS THERE A NEED FOR CAR-T WHEN OUR BODY HAS ITS IMMUNE SYSTEM?
While our immune system can naturally detect and combat diseased cells, tumors can evade them. In the early stages, tumor cells can appear similar to healthy cells, and as the tumor grows, it can release chemicals that suppress the immune response. CAR-T therapies help bridge this gap by training our T-cells always to recognize and destroy cancer cells.
3. HOW ARE T-CELLS MODIFIED FOR CAR-T THERAPY?
T-cells are extracted from a patient, and in a lab setting, they are exposed to a viral vector carrying a therapeutic gene. This gene introduces the chimeric receptor (CAR) to the T-cells, which is an amalgamation of an antibody and a T-cell receptor. Once modified, these T-cells are reinfused into the patient.
4. WHAT HAPPENS ONCE THE ENGINEERED T-CELLS ARE REINTRODUCED INTO THE PATIENT?
The modified T-cells target and bind to specific cancer antigens. Once connected, the CAR signals the T-cell to replicate and release cytotoxins to kill the blood cancer.
5. ARE THERE ANY RISKS ASSOCIATED WITH CAR-T THERAPIES?
CAR-T cell therapy is a groundbreaking and powerful treatment but comes with certain risks and potential side effects. It’s important to note that the severity and likelihood of these risks can vary depending on factors such as the specific CAR-T therapy, the patient’s health status, and the type of cancer being treated. Here are some of the potential risks and side effects associated with CAR-T therapy:
Cytokine Release Syndrome (CRS): CRS is a systemic inflammatory response that can occur due to CAR-T cells’ rapid activation and proliferation. It can lead to fever, low blood pressure, flu-like symptoms, and in severe cases, organ dysfunction. Treatment with immunosuppressive medications may be necessary to manage CRS.
Neurological Toxicities: Some patients may experience neurological side effects, including confusion, delirium, seizures, and difficulty speaking or understanding speech. These symptoms are collectively called CAR-T cell-related encephalopathy syndrome (CRES) or immune effector cell-associated neurotoxicity syndrome (ICANS).
Cytopenias: CAR-T therapy can cause a drop in blood cell counts, including red blood cells, white blood cells, and platelets. This can lead to anemia, infections, and bleeding issues.
Tumor Lysis Syndrome (TLS): Rapid destruction of cancer cells can release a large amount of cellular material into the bloodstream, potentially leading to metabolic imbalances and organ damage.
Hypotension: Low blood pressure can occur due to the release of cytokines and the overall immune response.
Organ Toxicities: CAR-T therapy can affect various organs, including the liver and kidneys, potentially leading to dysfunction and requiring medical intervention.
Long-Term Effects: Long-term effects of CAR-T therapy are still being studied, and some patients may experience ongoing immune system changes, including B cell aplasia (loss of normal B cells) and potential susceptibility to certain infections.