CAR NKT cells offer a promising approach to combating difficult-to-treat solid...

Natural killer T cells (NKT), a type of immune cell known for their potent anti-cancer properties in murine tumor models, have been developed into a novel form of immunotherapy for treating cancer patients.

Researchers at Baylor College of Medicine and the University of North Carolina at Chapel Hill have genetically engineered human NKT cells with a chimeric antigen receptor (CAR) that allows them to specifically recognize neuroblastoma, a form of childhood cancer, and to attack. Interleukin-15 (IL-15), a natural protein that supports the survival of NKT cells, is expressed with the CAR.

The study appears in Natural medicineThe researchers present interim results from an ongoing clinical study showing that the modified cells are safe, resident in tumors, and induced an objective response with regression of bone metastases in one in three patients.

Enhancing NKT cells’ anti-tumor abilities

The earliest CAR-modified cells were immune T cells. CAR-T cells have been shown to be effective in treating certain types of leukemia and lymphoma. However, a number of challenges have been encountered in attempts to treat solid tumors with CAR T cells. Preclinical studies have shown that NKT cells offer a novel approach that can improve CAR-guided cancer immunotherapy.

The presence of NKT cells in solid tumors is not only capable of effectively fighting tumors in mouse models, but has also been linked to beneficial results in cancer patients. ”

Dr. Leonid Metelitsa, Co-Corresponding Author, Professor of Pediatric Oncology at Baylor and Texas Children’s Hospital and Member of the Dan L Duncan Comprehensive Cancer Center in Baylor

Previous work has shown that NKT cells display a spectrum of anti-tumor activities. For example, these cells migrate to tumor sites where they kill tumor-associated macrophages, a type of immune cell that can promote tumor growth and metastasis. In addition, NKT cell activation indirectly promotes an anti-tumor response mediated by two other types of immune cells, NK and T cells.

“We believe that NKT cells have significant potential to make valuable contributions to the fight against cancer,” said co-corresponding and first author Dr. Andras Heczey, Assistant Professor of Pediatric Oncology at Baylor and Texas Children’s and a member of the Dan L Duncan Comprehensive Cancer Center. “For the past 10 years we have focused on improving the tumor-fighting abilities of these cells, ultimately bringing them to the clinic.”

Preparation of the NKT for clinical studies

The path to developing NKT cells into a form of immunotherapy involved finding solutions to a number of challenges. For example, NKT cells represent a small percentage of the cells in the blood, so Metelitsa, Heczey, and colleagues developed methods to grow NKT cell populations with high purity on a clinical scale.

Although NKT cells can fight tumors in a number of different ways, they all appear to be indirect. “In cooperation with Dr. Gianpietro Dotti from the UNC we gave NKT cells a tool – the CAR – with which they can attack tumors directly, ”said Metelitsa. “We also equipped them with IL-15, an additional tool that helps them survive in the patient while they fight the tumor.”

“The area of ​​cellular CAR cancer immunotherapy has so far mainly focused on manipulating T-lymphocytes,” said Dotti, professor and director of cellular cancer immunotherapy at UNC Lindberger Comprehensive Cancer Center. “Based on previous clinical evidence that NKT infiltration within the tumor correlates with favorable clinical outcomes, we decided to take advantage of this intrinsic property of NKTs and arm them with an additional bullet – called a CAR – to increase their ability to Destroying the tumor further potentiating the tumor. ”

With all of these innovations, the researchers tested CAR NKT cells in a clinical study in patients with neuroblastoma.

Clinical results

The clinical study is still ongoing. The results of the first three patients with heavily pretreated, relapsed / refractory metastatic neuroblastoma are presented in this study. Patients were treated with CAR NKT cells made from the patient’s own white blood cells at the Cell and Gene Therapy Center in Baylor and Texas Children’s. The researchers constructed 95 percent pure NKT cells, some of which were armed with CAR-IL15.

“Our initial results show that high-purity NKT cells can be expanded on a clinical scale, genetically engineered to express CAR and IL15, and used to safely treat patients with advanced neuroblastoma,” said Metelitsa.

“We also found that CAR-IL15-NKT cells can be detected in the peripheral blood, where they expand post-infusion, traffic to bone metastases and bone marrow, and have anti-tumor activity,” said Heczey. “We observed an objective reaction in one of the patients, the elimination of at least 50 percent of the metastases.”

Dr. Antonio Montalbano and other co-authors from Immunai, a company specializing in single cell technologies and AI approaches to immunology, used its cutting edge technology platform to analyze all genes in the single cell level in the CAR-NKT patient products. These analyzes provided new information about the heterogeneity of human NKT cells and the molecular details of their therapeutic modifications. The researchers discovered nine subsets of NKT cells and that the CAR receptor appeared to preferentially go to a group identified as cluster 3. Further study will help understand the implications of these results.

“Our study shows that it is possible to use immune cells with natural anti-tumor capabilities and improve their tumor-fighting power with synthetic designer receptors, which opens up the possibility of using this strategy to combat difficult-to-treat solid tumors,” said Metelitsa.

“Using Immunai’s end-to-end platform for artificial intelligence and computational analysis, we were able to identify CAR-engineered NKT cells from patients at the single cell level. The results of this study are critical to the development of more precise, more precisely effective therapies for cancer patients, “said Montalbano, Genomics Technologies leader at Immunai. “We look forward to continuing our research with Baylor to advance therapeutic discoveries, accelerate drug development and improve patient outcomes.”

The NKT platform developed in this study in Baylor was licensed to Kuur Therapeutics to advance clinical development.

“Baylor’s relationship with Kuur Therapeutics is producing exactly the results we envisioned at the beginning,” said Shawn Davis, vice president and chief ventures officer, Baylor. “The modified NKT platform developed in the Metelitsa laboratory differs from other cell therapy platforms and offers new avenues for the treatment of cancers that have posed challenges to immunotherapeutic approaches. The encouraging results announced today support the NKT platform’s potential to provide promising alternatives. especially for the treatment of solid tumors. ”