Hi Zadie, no, it is a checkpoint inhibitor. Car-T is a reprogrammed T-cell, a cellular therapy, but often the T cell is highly modified using cellular reprogramming.
Car-T stands for Chimeric Antigen Receptor (CAR) T-cell therapy. It is a type of immunotherapy that involves genetically engineering a patient's T cells (a type of immune system cell) to recognize and attack cancer cells. The process of creating CAR T-cell therapies involves several steps:
1. **Collection of T Cells**: Blood is drawn from the patient, and T cells are isolated from the blood sample using a process called leukapheresis. Basically the same process or very similar to what NWBO does to get the relevant cells for DCVax-L and DCVax-Direct. Some Car-T treatments start with fully reprogrammed universal immune cells, reprogramming original blood cells from one donor or a few donors for a baseline set of cells. The idea is to create an off-the shelf treatment. You have companies like Fate Therapeutics using these cells. And there are others. NWBO might someday go that route, but the challenge is, the more you manipulate baseline cells and program them, the more you have a potential for mutation. One of the recent risks revealed with Car-T therapies. So those companies modify a baseline cell into a universal T Cell that they then program to attack the cancer. But the approved therapies, like DCVax-L are not using original reprogrammed cells but are using the patients own cells generally, and that should reduce the genetic manipulation. But not entirely, because if the next step.
2. **Genetic Modification of T Cells**: The isolated T cells are then genetically modified in a laboratory to express chimeric antigen receptors (CARs) on their surface. These CARs are synthetic receptors that can specifically recognize antigens (proteins) present on the surface of cancer cells. The genetic modification is usually achieved by using a viral vector, which is a virus that has been engineered to be harmless and carry the gene encoding the CAR into the T cells.
3. **Expansion of CAR T Cells**: After the T cells have been genetically modified to express the CAR, they are cultured in the lab to increase their numbers. This process can take a few days to several weeks, during which the T cells multiply and become more specialized in recognizing the cancer cells.
4. **Patient Preparation**: Before the CAR T cells are infused back into the patient, the patient might undergo a process called lymphodepletion. This typically involves treatment with chemotherapy and sometimes radiation to reduce the number of existing immune cells in the patient's body. This step helps create space for the infused CAR T cells to expand and function more effectively.
5. **Infusion of CAR T Cells**: The expanded CAR T cells are then infused back into the patient’s bloodstream through an intravenous (IV) line. Once inside the patient's body, the CAR T cells further multiply and start to recognize and attack the cancer cells that have the specific antigen they were engineered to target.
6. **Monitoring and Support**: After the CAR T-cell infusion, patients are closely monitored for any signs of side effects, which can range from mild to severe. The most notable side effect is cytokine release syndrome (CRS), which can occur when the engineered T cells rapidly release cytokines (chemical messengers) into the blood, leading to fever, fatigue, and in severe cases, organ dysfunction. Other potential side effects include neurologic complications and an increased risk of infections due to the lymphodepletion process.
Recently, the FDA has required manufacturers of CAR-T therapy drugs to add a "boxed warning" - the strongest safety notice - to their labels due to a potential risk of developing secondary blood cancers from this kind of therapy.
The specific concern is the development of T-cell malignancies, including a type called CAR-positive lymphoma, which can be serious and even life-threatening.
CAR T-cell therapy has shown promising results, particularly in certain types of blood cancers such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. It’s really done best in blood cancers so far, not so much in solid cancers.
Keytruda is a checkpoint inhibitor.
Checkpoint inhibitors are a class of drugs used in cancer immunotherapy that work by blocking proteins that inhibit the immune system's ability to destroy cancer cells. Really, the immune system uses these checkpoint proteins to hide cancers, mistaking the immune response to cancer as an auto-immune response. The checkpoint inhibitors inhibit the checkpoint proteins and can also induce severe autoimmune reactions as well, in normal cells.
These checkpoint inhibitor proteins, known as checkpoints, are used by the body to prevent the immune system from attacking normal cells. However, cancer cells seem to exploit these checkpoints to avoid being targeted by the immune system. By inhibiting these checkpoints, checkpoint inhibitors help restore the immune system's ability to recognize and destroy cancer cells.
So for instance, in some cancers, when DCVax Direct turned a “cold” cancer with no immune response, into a hot cancer with an induced immune response, one way they could also tell it was working was that often the immune response then induced a checkpoint response. The expectation is that by adding checkpoint inhibitors, you could keep the immune response going. The immune system is complicated. It does not just consist of a-b, simple stimulus and response. You have what are called secondary and other tertiary immune responses that can be ways that a normal immune system protects a person, but in the context of cancer, it can be counterproductive. Dr. Liau and her team are working on addressing these secondary and then tertiary immune responses to keep the effects of treatments like DCVax-L going, so that more patients can be helped and the immune response can last long enough to eliminate the cancer, keep the cancer from recurring and to keep as many patients as possible, and all, alive, as long as possible, and hopefully cancer won’t be the cause of death but simple old age.
Checkpoint inhibitors work by targeting and blocking the activity of specific immune checkpoint proteins. For example:
- **CTLA-4 Inhibitors**: CTLA-4 is a protein that regulates T-cell activity early in the immune response. Inhibiting CTLA-4 can enhance T-cell activation and proliferation, leading to a stronger immune response against cancer cells.
- **PD-1/PD-L1 Inhibitors**: PD-1 is a protein on the surface of T-cells that, when engaged by PD-L1 on cancer cells, inhibits T-cell activity. Blocking either PD-1 or PD-L1 can prevent this inhibition, allowing T-cells to attack cancer cells more effectively.
By blocking these checkpoints, inhibitors enable the immune system to better recognize and attack cancer cells, leading to reduced tumor growth or even tumor regression in some cases. Checkpoint inhibitors have shown significant success in treating a variety of cancers, including melanoma, lung cancer, kidney cancer, bladder cancer, and Hodgkin lymphoma, among others. However, not all patients respond to these therapies, and research is ongoing to understand why and to develop strategies to overcome resistance.
The challenge with checkpoint inhibitors is they turn off the mechanism by which the immune system allows cancers to hide, but they do not turn on an immune response. So if the cancer is “cold”, the body may not reject the cancer cells.
More in Keytruda:
Keytruda (pembrolizumab) is a checkpoint inhibitor that targets the PD-1 (Programmed Death-1) pathway. It works by inhibiting the interaction between PD-1, a protein on the surface of T-cells (a type of white blood cell involved in the immune response), and PD-L1 (Programmed Death-Ligand 1), a protein expressed on the surface of many cancer cells and some normal cells.
The PD-1/PD-L1 interaction normally serves as a "checkpoint" that helps regulate the immune system's response, preventing T-cells from attacking normal cells in the body. This mechanism is crucial for maintaining self-tolerance and preventing autoimmune reactions. However, many cancer cells express high levels of PD-L1, which binds to PD-1 on T-cells and inhibits their ability to attack and kill the cancer cells.
By binding to PD-1, Keytruda blocks this inhibitory signal, enabling the T-cells to recognize and destroy cancer cells more effectively. Essentially, where there is an actual immune response, Keytruda would work by reactivating the immune system's ability to detect and fight those recognized cancer cells, leading to reduced tumor growth or even regression in some patients. But that assumes the immune system actually sees the tumor and wants to eliminate it or some other tertiary immune response does not interfere and inhibit any immune response to kill the cancer.
Keytruda has been approved for the treatment of various types of cancers, including melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, and others, demonstrating significant efficacy in improving patient outcomes in these settings. Merck also has a general approval for Keytruda where certain biomarkers are detected. Getting a generalized approval that allows a treatment to be given to patients not having a specific location based approval is really where we want to go with immunotherapies, so that we can get approvals that enable a platform to be utilized against many types of cancer, whether they are in the neck, mouth, breast, lung, brain, toe or tongue. That old form of classification was really about the fact that pharmaceuticals were better for a particular application, but the immune system operates entirely differently and is a systemic process for the human body. So programming an immune response is really the holy grail of oncology, in my opinion. Clearly controlling and getting dendritic cells, the generals of the immune system, to mobilize the entire immune system us and will be a major coup against cancer.
