Interrogating T-cell apoptotic priming to improve CAR-T persistence in treatment of lymphoid malignancies
Anthony Letai
MD, PhDDana-Farber Cancer Institute
Project Term: October 1, 2024 - September 30, 2027
CAR-T cells are made from a patient’s own immune cells, altered so that they specifically recognize and kill the patient’s cancer cells. They are effective in many but not all cases of B-acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), among other blood cancers. In this proposal we seek to better understand ways to select T cells that will make better CAR-T cells as well as to treat CAR T cells them in ways to make them work better in the cancer patient.
There has long been an effort in cancer research to use the immune system to eliminate cancer cells. Recent efforts have created CAR-T cells. These are derived from a type of immune cell, the T-cell, taken from the patient. These T-cells are altered so that they recognize and attack features that are specific to the patient’s cancer cell upon infusion. There are many cases in the treatment of B-acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) where the treatment of CAR-T cells was life-saving, and likely even curative. However, in all too many cases, responses were incomplete or too short in duration. Moreover, in other blood cancers success of CAR-T cells has been more limited. One key determinant of the success of therapy with CAR-T cells is the survival of the CAR-T cells after they have been infused into the patient’s body. This survival in part depends on the ability of CAR-T cells to avoid apoptosis.
Apoptosis is a program of cell death that exists within every cell in our bodies. It is a way for our bodies to clear away cells that are useless or harmful. Increasing apoptosis signaling in cancer cells is probably the major way that successful drugs kill cancer cells. However, in the case of CAR-T cells, the goal is to decrease apoptosis signaling to let CAR-T cells survive longer. We have found that we can measure the overall level of apoptosis signaling in a cell, what we call “apoptotic priming”. We have also have preliminary evidence that reducing the apoptotic priming in CAR-T cells can prolong their survival and increase their effectiveness.
In this proposal, we will obtain samples of CAR-T cells from patients who have been treated. We will measure the amount of apoptotic priming and ask if patients infused with CAR-T cells with low apoptotic priming had a better clinical response. Moreover, we will investigate the mechanisms underlying apoptotic priming in CAR-T cells so that we can try to find ways to reduce apoptotic priming and aloe CAR-T cells to persist longer. In another aim, we make use of our recent finding that when a CAR-T cells binds the antigen it recognizes on a cancer cell, its apoptotic priming is reduced. We will investigate the mechanisms underlying this phenomenon. Our hypothesis is that if we understand these mechanisms, we can find ways to further reduce the priming of CAR-T cells, and therefore make them persist longer and cause greater tumor cell killing when a patient receives them. While these findings would be most immediately applied to our studies of CAR-T cells used in the treatment of B-ALL and DLBCL, the principles would be applicable to CAR-T cells used in any kind of blood cancer.