Cancer Immunotherapy Using Unconventional Effector Cells

The last decade has brought a series of breakthroughs in cancer immunotherapy, including the development of novel cell-based therapeutics. While cell therapy products manufactured from a patient’s own T cells have been proven safe and effective for B-cell leukemias and lymphomas, patients with solid tumors, representing over 90% of cancer patients, remain largely resistant to chimeric antigen receptor (CAR)-T cell treatment. This disparity is where the Center for Advanced Innate Cell Therapy (AICT) at Texas Children's Cancer and Hematology Center is focusing its efforts: developing new therapies for childhood cancers using natural and engineered properties of the immune system. 

Just one year since its inception, the AICT is already making significant progress toward future therapies, specifically in studying natural killer T cells (NKTs) and developing NKT-based cancer immunotherapies. In fact, the team was the first to demonstrate that NKT cells localize to primary tumors in human patients and that presence of these cells at the tumor site is associated with favorable outcomes. 

Image

“CAR-T cells do not traffic effectively to solid tumors. Further, it is difficult for them to infiltrate the tumor site, and the cells are easily exhausted and suppressed in this environment,” said Leonid Metelitsa, MD, PhD, director of the center. “Our goal is to enhance the therapeutic potential of T cells via genetic engineering and also to go beyond conventional T cells, exploring other types of immune cells with natural anti-tumor properties.” 

Breakthrough cell therapies 

Within the center, a multidisciplinary team of basic, translational and clinical investigators works collaboratively toward this goal. Currently, the center has five phase I clinical trials underway evaluating novel cell therapy products developed in AICT laboratories.  

Several features make NKT cells an attractive option for use in adoptive cell therapy, including their ability to localize to different tumor types and their potential as an off-the-shelf allogeneic (donor-derived) product. Off-the-shelf therapeutics using NKT cells pose a low risk for inducing graft versus host disease (GvHD), unlike similar T cell-based products that recognize the patient’s body as foreign. 

“NKT cells also have the ability to activate other cells, such as T and NK cells, to amplify the body’s immune response,” Dr. Metelitsa said. “In addition to these natural anti-tumor properties, we can engineer synthetic receptors to increase therapeutic effectiveness.” 

In addition to demonstrating the association of NKT cells with favorable clinical outcomes, the team also showed that human NKTs can be engineered to express CARs and expanded to clinical scale. These findings led to the initiation of first-in-human clinical trials evaluating CAR-NKTs in children with neuroblastoma and adults with leukemia and lymphoma. Results from the former trial have shown a 25% overall response rate and a 58% disease control rate, indicating that CAR-NKTs are safe and mediate clinical responses in relapsed neuroblastoma that is resistant to standard therapies.  

Image

The AICT is also working on a growing pipeline of innovative CAR-T and CAR-NKT therapeutic products for patients with liver tumors, including hepatoblastoma in children and hepatocellular carcinoma in adults. One such ongoing trial is led by Andras Heczey, MD, director of the Liver Tumor Program at Texas Children’s. In this study, T cells expressing a CAR specific for liver tumor antigen GPC3 are further armored with cytokine interleukin-15, which enhances T cell survival and function. So far, several patients have shown robust expansion of therapeutic cells in the blood and, even at the lowest dose level, resolution of large metastatic masses has been detected. This trial is now supported by the National Institutes of Health, and eligibility has been extended to a larger group of children with GPC3-positive solid tumors, including liver, rhabdoid, yolk sac, Wilm’s tumors and rhabdomyosarcomas. 

What’s next in research and development 

“To enable rapid availability of these potentially lifesaving therapeutic cells for this large patient population, we’re working to change the current standard of therapy, which uses patient-specific products that are expensive and require 6 weeks or more for manufacturing and testing. Instead, we're generating a bank of GPC3-CAR NKT cells that is readily available and can be infused into any patient,” Dr. Metelitsa said. 

Based on the results to date, the AICT has received approval from Baylor College of Medicine and the U.S. Food and Drug Administration to test the next generation of GPC3-CAR T cells armored with interleukin (IL)-15 (which helps protect GPC3-CAR T cells) in children and adults. The first patient treated with this new product showed robust expansion of GPC3-CAR-IL15 T cells in the blood and complete resolution of large metastatic lung masses.  

Laboratory research has also led to important discoveries for future therapies. For instance, the team discovered that a protein known as LEF1 plays a central role in driving the central memory-like program in NKTs, helping the cells to maintain their ability to proliferate and function after multiple encounters with tumor cells. Other work helped to identify how  tumor-supportive inflammation is initiated and sustained, leading to new investigation of the tumor necrosis factor inhibition properties of etanercept. 

“NKT cells are the template to explore the therapeutic potential of other immune effectors. Other examples we are working to explore include gamma/delta T cells and mucosal invariant T (MAIT) cells,” Dr. Metelitsa said. “Our center’s structure allows very close collaboration between researcher and clinical investigators, which means we’re able to quickly begin patient testing and bring products to development.” 

The AICT is actively recruiting additional researchers to explore the therapeutic potential of immune effectors such as NK cells, gamma/delta T cells or MAIT cells as well as develop the next generation of artificial immune receptors for the successful treatment of solid tumors using cellular immunotherapies. Learn more.