Clinical relevance: Receptor engineering has significantly advanced NK cell-based cancer immunotherapies. As technical hurdles are overcome, these innovative treatments are poised to revolutionize cancer immunotherapy.
Studying the basics of natural killer (NK) cells, where they come from, and how they're used in therapy, including the pros and cons of engineered NK cells like CAR-NK cells, is an important area for future research in treating diseases. CAR-T therapies have emerged as a successful new approach for treating blood cancers. However, their use is hampered by notable drawbacks, such as neurotoxicity, graft-versus-host disease (GVHD), and cytokine release syndrome (CRS). These challenges have prompted researchers to explore safer alternatives, such as natural killer (NK) cells. CAR-NK therapy involves modifying NK cells using advanced chimeric antigen receptor (CAR) technology, leveraging their broad tumor-killing capabilities and unique mechanisms for recognizing target cells.
NKs in practice
A recent approval paving the way is nogapendekin alfa inbakicept, sold under the brand name Anktiva, which is used to treat bladder cancer.
Dr. Bobby Reddy , who is the Chief Medical Officer at ImmunityBio, the drug developer, spoke with SurvivorNet about why this new research, and Food and Drug Administration (FDA) approval is so exciting. "What we do with Anktiva is we combine it with the BCG [bacteria that can prevent the relapse of cancer], it's given directly into the bladder by the urologist in the urologist's office, and it stimulates an immune response. It stimulates and activates NK cells and T cells and memory T cells," Dr. Reddy explains. "So, what does that get you? The T cells are killer T cells, and they do what's advertised — they kill the cancer," he adds. "But importantly, you also activate memory T cells. With this, if you can activate the immune system, then, once you've stopped the medication, you still have a memory response. "So God forbid the cancer comes back, you have a defense system that's in the wings ready to go and can attack that cancer and help prevent a full relapse. Natural killer cells are really exciting." Compared to CAR-T therapy, CAR-NK therapy offers several advantages, including significantly reduced risks of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), as well as lower incidence of GVHD, enhancing overall treatment safety. Moreover, NK cells possess multiple tumor recognition sites, potentially minimizing the risk of cancer cells evading detection.
Natural killer cell and immunotherapy
Natural killer (NK) cell-based immunotherapies are gaining significant traction in cancer treatment. Early clinical trials have demonstrated promising results, showcasing both effective and safe products. Recent advancements have markedly increased the therapeutic potential of NK cells by enhancing their ability to recognize and destroy cancer cells. Most strategies involve the use of chimeric antigen receptors (CARs) to enable NK cells to target specific tumor antigens independently of human leukocyte antigen (HLA) restriction. This has improved the precision and efficacy of NK cell-mediated tumor recognition and destruction. Additionally, engineering NK cells with T-cell receptors has expanded the range of targetable peptides by allowing recognition of intracellular epitopes. The enhancement of NK cells’ indirect recognition of tumor peptides has been achieved by optimizing the expression and signaling of immunoglobulin constant fragment receptors. Consequently, engineered NK cells have shown an improved capacity to identify and eliminate antibody-coated target cells, thus enhancing their antibody-dependent cellular cytotoxicity. Research has also explored strategies to promote the expansion, persistence, and infiltration of transferred NK cells within the tumor microenvironment. Sustaining NK cell functionality in the face of tumor-induced immunosuppression has been a focal point, offering promising approaches to counteract these challenges.
Looking to the future
Looking ahead, NK cells represent a distinct group of cells crucial for fighting tumors, utilizing abilities such as MHC-independent cytotoxicity, cytokine production, and immune memory. These qualities make them pivotal in both innate and adaptive immune responses. CAR-NK cell therapy shows promise in clinical research, demonstrating notable safety and initial effectiveness in certain cancer patients. Unlike CAR-T cells, CAR-NK cells offer unique advantages but also face challenges. Improving cell proliferation, enhancing cytotoxic activation efficiency, and optimizing NK cell restoration are critical priorities. Advances in large-scale production methods, cryopreservation techniques, and effectiveness are essential. Addressing challenges like short in vivo persistence and exhaustion remains a frontier. Overall, CAR-NK cells are poised to become versatile cellular products, with potential advantages in single and combination therapies, monoclonal antibody applications, and other treatments. Building on NK cells' potent antitumor capabilities, overcoming these hurdles promises groundbreaking progress in cancer therapy. The rapid advancement of NK cell-based immunotherapy, as seen in expanding cancer therapy pipelines, underscores how CAR-NK enhancements will drive new breakthroughs. In the foreseeable future, the refinement of CAR-NK cell technology holds promise for a broader range of cancer patients, marking significant strides in tackling challenging cases of refractory and recurrent cancer treatments.
Remaining questions about NK cells
- What is known about how NK cells develop, function, and their use in treating diseases?
- How do NK cells fight cancer, and what are the ways they work against it?
- Why use CAR cell therapy, and how are CAR-T and CAR-NK cells different? What aspects and plans are important in designing CARs for engineered NK cells?
- What are the main challenges and future directions for CAR-NK cell technology? Also, where does CAR cell therapy stand in terms of moving from lab research to actual clinical use (from bench to bedside)?
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