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For one in five children with T-cell acute lymphoblastic leukemia (T-ALL), the current chemotherapy treatment is not effective. For those relapsed/refractory patients, no other curative treatments now exist. My primary goal is to develop a new therapy for these high-risk T-ALL patients based on the recently successful Chimeric Antigen Receptor (CAR) T-cell technology. In addition, I aim to test if this potential therapy could be used to treat other T-cell malignancies, and I hope to learn more about the maturation of healthy T-cells in the process.
CAR T-cells against T-cell malignancies
CAR T-cells are a new form of immune therapy, produced from one type of the patient’s own white blood cells (T-cells). These cells are genetically modified in the lab so that they can recognize and kill other cells based on specific molecules on the target cell’s surface. This has been a very effective new treatment for other types of leukemia (B-cell ALL, or B-ALL), but unfortunately the road towards an effective CAR T-cell product against malignant T-cells is not straightforward:
1. CAR T-cells are T-cells, just like the malignant T-cells we are trying to target. Therefore, if CAR T-cells are made to recognize all T-cells, they will also recognize and kill each other in a process called “fratricide”.
2. The successful existing CAR T-cell therapies against CD19+ B-ALL is not specific for tumor cells only. It generally recognized all B-cells, including the tumor cells, and leaves the patient without B-cells altogether. Although this is survivable and can be overcome by periodical antibody transfusions, complete loss of T-cells is not survivable. Therefore, a successful CAR T-cell treatment against T-cell malignancies needs to be tumor-specific, or the patient will need a bone marrow transplant to replace the lost T-cells. A bone marrow transplant is not without risks either.
3. The molecular targets we find on malignant T-cells cannot be expressed anywhere else on healthy cells in the body. As CAR T-cells will kill anything they can recognize, they can potentially cause severe side-effects if they also recognize the patient’s healthy tissues.
To avoid these various pitfalls, we need to identify novel molecular targets expressed only on leukemic T-cells with no or limited expression in healthy tissues. However, searching through all the proteins expressed by T-ALL cells to find a tumor-specific molecule using traditional techniques is like looking for a needle in a haystack. Therefore, I am developing a method to use cell surface proteomics. This method compares to sifting through a haystack using a big magnet. We don’t need to look at all the hay, only at everything that is magnetic.
Based on the targets we find using surface proteomics, I aim to develop new T-ALL CAR T-cell therapies. The effectiveness of these new CAR T-cell therapies will need to be validated, and then we need to figure out if we can make these cells from the few healthy T-cells that T-ALL patients have left.
CAR T-cells are a new form of immune therapy, produced from one type of the patient’s own white blood cells (T-cells). These cells are genetically modified in the lab so that they can recognize and kill other cells based on specific molecules on the target cell’s surface. This has been a very effective new treatment for other types of leukemia (B-cell ALL, or B-ALL), but unfortunately the road towards an effective CAR T-cell product against malignant T-cells is not straightforward:
1. CAR T-cells are T-cells, just like the malignant T-cells we are trying to target. Therefore, if CAR T-cells are made to recognize all T-cells, they will also recognize and kill each other in a process called “fratricide”.
2. The successful existing CAR T-cell therapies against CD19+ B-ALL is not specific for tumor cells only. It generally recognized all B-cells, including the tumor cells, and leaves the patient without B-cells altogether. Although this is survivable and can be overcome by periodical antibody transfusions, complete loss of T-cells is not survivable. Therefore, a successful CAR T-cell treatment against T-cell malignancies needs to be tumor-specific, or the patient will need a bone marrow transplant to replace the lost T-cells. A bone marrow transplant is not without risks either.
3. The molecular targets we find on malignant T-cells cannot be expressed anywhere else on healthy cells in the body. As CAR T-cells will kill anything they can recognize, they can potentially cause severe side-effects if they also recognize the patient’s healthy tissues.
To avoid these various pitfalls, we need to identify novel molecular targets expressed only on leukemic T-cells with no or limited expression in healthy tissues. However, searching through all the proteins expressed by T-ALL cells to find a tumor-specific molecule using traditional techniques is like looking for a needle in a haystack. Therefore, I am developing a method to use cell surface proteomics. This method compares to sifting through a haystack using a big magnet. We don’t need to look at all the hay, only at everything that is magnetic.
Based on the targets we find using surface proteomics, I aim to develop new T-ALL CAR T-cell therapies. The effectiveness of these new CAR T-cell therapies will need to be validated, and then we need to figure out if we can make these cells from the few healthy T-cells that T-ALL patients have left.