Generation of Patient-Specific Humanized Mouse Models to Recapitulate Human Tumor Microenvironments for Optimal CAR-T Cell Therapy in Kidney Cancer
Abstract
The survival rate of people with advanced kidney cancer remains dismal, with the majority surviving around 13 months despite multiple treatment options. There is an urgent need to develop new and effective treatments. A state-of-the-art therapy called CAR-T cells has shown outstanding success in certain blood cancers leading to cures in patients. CAR-T cells are a new class of living drugs that are made from a patient s own immune cells. The immune cells are taken out of the patient s blood and are modified to express a receptor (analogous to a missile) that is specific for a target expressed on the surface of cancer cells. We call these modified patient immune cells CAR-T cells, and we put them back into the patient. Like a missile that seeks out its target, the CAR-T cells seek out and destroy the cancer, sparing normal healthy tissue. Our goal is to make a CAR-T cell that destroys kidney cancer and cures patients. Unfortunately, to date, the results of using CAR-T cells for non-blood cancers like kidney cancers have not been successful. The treatment has either made the patient sick or not worked at all. The good results obtained when CAR-T cells are tested in the laboratory do not seem to translate into the good results we hope for when used in patients. Since it would be dangerous to try to fine-tune these living drugs in humans, we use a special breed of mice instead. These special mice are useful because they were created to have no immune system, which allows us to grow a human cancer inside the animal without the cancer being attacked by the immune system. However, because these mice lack an immune system, the human cancers grown inside of them are not fully representative of a patient s cancer, which by contrast is full of many different types of immune cells supporting the spread of cancer and preventing CAR-T cells from working effectively. Therefore, testing CAR-T cells in these special mice without an immune system is like scoring a touchdown without the defense present to block you. The overarching aim of this proposal is to make a mouse model that resembles the patient scenario as closely as possible so that we can figure out ways to make our treatments better and safer before they are used in patients. To make our human-mouse model, we will replace a mouse immune system with a human immune system specifically from a kidney cancer patient. We get the patient s immune cells by taking a small sample of blood from the hip bone at the time of kidney cancer surgery. We use this blood to make a patient-specific human-mouse: All the organs and tissues are still mouse but the blood, and all the cells inside it, are human. We then implant tumor donated by the same patient into this human-mouse. We now have a human-mouse with tumor and an immune system from the same patient, in which we can test our CAR-T cells made from that patient--this time we can try to score a touchdown but the defense is there to run interference. By developing this human-mouse model, we can test the safety and effectiveness of our CAR-T cell therapy in a more real-world scenario for the benefit of kidney cancer patients, and other patients with aggressive cancers, who might one day receive CAR-T treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310335
Entities
People
- Sophie Hanina
Organizations
- Sloan-Kettering Institute
- United States Army