We recently had the opportunity to interview Saad Kenderian (Mayo Clinic, MN, USA) in which we discussed the current challenges with CAR-T therapy resistance. In addition, Kenderian provides his opinions on how we can expand the application of CAR-T therapy, as well as predictions for the future of the field.
Could you briefly introduce yourself?
My name is Saad Kenderian and my current role is a physician scientist at the Mayo Clinic in Rochester (MN, USA). I am a hematologist and treat patients with leukemia and patients receiving CAR-T therapy. At the Mayo Clinic, I direct a laboratory program focused on the development, optimization and translation of novel CAR-T therapies to the clinic.
Could you outline mechanisms of action that are driving resistance to CAR-T therapy?
There are two mechanisms that have been identified. The first mechanism includes antigen negative relapse. Here, tumor cells splice the B cell antigen CD19 and the tumor relapses as a CD19 negative disease. This means that although CAR-T cells are still present they are unable to recognize tumor cells. The second mechanism is loss of CAR-T cells, resulting in relapse of the original tumor. In this case, CAR-T cells develop a state of dysfunction and exhaustion after their infusion.
What progress has been made in overcoming CAR-T therapy resistance?
To overcome antigen negative relapse, CAR-T cells that target two antigens at the same time are being developed. For example, in the case of CAR-T19, to avoid antigen negative relapse, CAR-T cells targeting multiple antigens are entering the clinic, such as CAR-T19 and CAR-T22 or CART19 and CAR-T20. To overcome the issue of CAR-T cell exhaustion, strategies are being developed to either combine CAR-T therapy with other immune modulatory strategies, or to develop CAR-T cells that are resistant to exhaustion. For example, PD-1 knockout CAR-T cells are currently in early phase clinical trials for sarcoma and multiple myeloma.
In your opinion, how can we expand the application of CAR-T therapy across more hematologic malignancies and into solid tumors?
I think that there are two main hurdles before we can expand the application of CAR-T therapy. The first one is identification of unique targets that are expressed on the tumor cells. The second is engineering CAR-T cells in a way to make them resistant to inhibition caused by the tumor microenvironment. We are seeing a wave of CAR-T cells entering clinical trials that have been modified to enhance their trafficking and efficacy.
What are your predictions for the future of CAR-T therapy and how would you like to see the field progress over the next 5–10 years?
The field is moving very quickly as new constructs are developed and new clinical trials are launched every day. I hope to see more potent and less toxic CAR-T cells entering the clinic and becoming mainstream over the next 3–5 years. I think in the next decade we will see more effort towards the development of currently available CAR-T therapy in clinical trials.