A pioneering study conducted by a team of researchers at UCLA has unveiled a groundbreaking advancement in the field of cancer immunotherapy that holds immense promise for treating a wide range of solid tumors. This novel therapy hinges on the use of engineered invariant natural killer T cells (NKT cells), which possess a remarkable ability to infiltrate and destroy solid tumor masses — a feat that has eluded many existing immunotherapeutic approaches, particularly those based on CAR-T cells. This research offers an unprecedented systematic comparison of different chimeric antigen receptor (CAR) designs tailored for NKT cells, resolving a pivotal question regarding which CAR construct provides the optimal balance of potency and persistence necessary for an effective anti-tumor response.
Immunotherapy, especially CAR-T cell therapy, has revolutionized treatments for blood cancers like leukemia and lymphoma by genetically modifying patients’ T cells to recognize and attack cancer cells. However, extending these successes to solid tumors has been challenging due to the complex microenvironment and heterogeneity of these cancers. Solid tumors develop dense stromal barriers that immune cells struggle to penetrate, and they frequently display diverse antigenic profiles that allow malignant cells to evade immune detection. The structural sophistication of these tumors, coupled with their immune evasion strategies, has posed formidable obstacles for conventional CAR-T therapies.
Unlike CAR-T cells, engineered CAR-NKT cells leverage the innate tumor-homing properties of NKT cells, enabling them to traverse the physical and immunosuppressive barriers that characterize solid tumors. NKT cells uniquely combine features of both innate and adaptive immunity, allowing them to rapidly respond to tumor antigens and secrete a variety of cytokines that modulate the tumor microenvironment. This dual functionality encourages the destruction of cancer cells while simultaneously dismantling the immunosuppressive shield typically maintained by regulatory cells within the tumor milieu, thereby amplifying the overall immune assault on cancer.
The UCLA study undertook a rigorous comparison of four distinct CAR designs engineered into human NKT cells. Each CAR carries a targeting domain specific to mesothelin, a surface protein highly expressed in several solid tumors, including ovarian, pancreatic, lung, and breast cancers. The four CAR constructs varied primarily in their intracellular signaling and co-stimulatory domains: one featured CD28, another 4-1BB, the third incorporated both CD28 and 4-1BB, and the fourth employed NKG2D and 2B4 costimulatory motifs. These variations influence T cell activation, expansion, cytokine production, and longevity — all critical factors in the therapeutic efficacy of CAR-based immunotherapies.
The team first validated the cytotoxic capabilities of each CAR-NKT variant in vitro by exposing these engineered cells to tumor cells derived from multiple solid cancer types. They meticulously quantified tumor cell lysis, cytokine profiles, and the ability of the engineered NKT cells to persist over time. This extensive laboratory characterization revealed distinct performance profiles aligned with the signaling domains present in each CAR construct, underscoring how molecular engineering of CARs dictates both the intensity and durability of anti-tumor responses.
Following promising in vitro results, the researchers advanced to in vivo models, employing ovarian cancer mouse models to assess therapeutic outcomes. Here, they tracked tumor regression, survival outcomes, and biodistribution of the infused CAR-NKT cells within the animals. Notably, the 4-1BB-containing CAR design emerged as the leading candidate, demonstrating sustained anti-tumor activity coupled with prolonged cellular persistence. This construct outperformed its counterparts by maintaining a functional presence within tumors and secondary lymphoid tissues, translating into significantly improved survival metrics in treated mice.
The superior performance of the 4-1BB costimulatory domain aligns with previous findings in T cell-based therapies where 4-1BB signaling enhances cell survival and promotes a memory-like phenotype. This attribute is especially critical for solid tumor immunotherapy, where continuous immune surveillance and prolonged effector function are required to prevent tumor relapse and overcome immune evasion tactics. The study’s findings strongly suggest that optimizing intracellular signaling domains within CAR-NKT cells can tailor their function for maximal therapeutic benefit.
Importantly, the investigation also addressed safety concerns that often shadow novel cellular therapies. The engineered CAR-NKT cells did not induce off-target toxicity, displayed no signs of graft-versus-host disease (a dangerous immunological reaction common in allogeneic cell therapies), and showed no aberrant clonal expansion, alleviating fears of potential malignancies resulting from uncontrolled proliferation. These safety profiles bolster the clinical feasibility of using CAR-NKT cells as an off-the-shelf, allogeneic immunotherapy product.
This off-the-shelf capability distinguishes CAR-NKT therapy from conventional autologous CAR-T cell treatments, which require harvesting, engineering, and expanding each patient’s own T cells— a process that is time-consuming, expensive, and logistically complex. In contrast, CAR-NKT cells can be mass-produced from donated blood stem cells, cryopreserved, and distributed for immediate use. This paradigm shift could democratize access to advanced immunotherapies, dramatically reducing treatment delays and improving patient outcomes, especially for aggressive solid tumors needing urgent intervention.
The researchers have already published compelling preclinical evidence demonstrating the efficacy of CAR-NKT cells against multiple solid tumors beyond ovarian cancer, including pancreatic and triple-negative breast cancers, two notoriously challenging malignancies to treat. These findings collectively highlight the broad applicability and versatility of CAR-NKT cells across diverse tumor types, expanding the horizon of immunotherapy beyond hematologic cancers.
Dr. Lili Yang, the study’s senior author and a prominent figure in immunology and regenerative medicine at UCLA, emphasized the importance of this work. By systematically dissecting the functional differences among CAR designs in NKT cells, the study provides a critical roadmap for future clinical translation. It empowers scientists and clinicians with concrete data to select CAR configurations that balance immediate cytotoxicity and long-term immune memory, essential for sustained therapeutic success in solid tumor oncology.
As the field moves towards clinical trials, these insights lay the groundwork for a new generation of cellular immunotherapies that combine biological precision with manufacturing scalability. With continued validation, CAR-NKT cells stand poised to become a transformative weapon in the fight against cancer, potentially surmounting challenges that have long confined CAR-based therapies to blood cancers and revolutionizing the treatment landscape for solid tumors worldwide.
This research exemplifies the power of engineering biology at the molecular level to fine-tune immune interventions, combining the inherent tumor-penetrating capacity of NKT cells with tailored CAR signaling domains to create smart, potent cellular therapies. Such innovations reflect a broader trend in cancer immunotherapy towards harnessing the nuances of immune cell biology for optimized design and delivery — paving the way for more effective, safer, and widely accessible cancer treatments.
Subject of Research:
CAR-NKT Cell Therapy Design for Solid Tumor Immunotherapy
Article Title:
Engineering Optimal Chimeric Antigen Receptor Constructs for Allogeneic NKT Cell-Based Solid Tumor Immunotherapy
News Publication Date:
Not specified in the source content
Web References:
https://stemcell.ucla.edu/member-directory/lili-yang-phd
https://stemcell.ucla.edu/
https://www.uclahealth.org/cancer
https://newsroom.ucla.edu/releases/immunotherapy-car-nkt-pancreatic-cancer-ucla
https://newsroom.ucla.edu/releases/ucla-scientists-develop-one-product-fits-all-immunotherapy-breast-cancer
https://newsroom.ucla.edu/stories/immunotherapy-ovarian-cancer-ucla-scientists-develop
https://ashpublications.org/bloodict/article/2/1/100025/557344/Engineering-optimal-CAR-constructs-for-allogeneic
References:
Yanruide Li, Yichen Zhu, Tyler Halladay, Xinyuan Shen, Youcheng Yang, Zhe Li, Enbo Zhu, Yuning Chen, Jie Huang, and Lili Yang. “Engineering optimal CAR constructs for allogeneic invariant natural killer T cell therapy.” Blood Immunology & Cellular Therapy.
Image Credits:
UCLA Broad Stem Cell Research Center
Keywords:
Immunotherapy, Cancer Immunotherapy, Cancer, Cancer Cells, CAR-NKT Cells, Solid Tumors, Chimeric Antigen Receptors, 4-1BB Costimulatory Domain, Mesothelin Targeting, Cellular Therapy, Off-the-Shelf Immunotherapy, Tumor Microenvironment
