“Using Donor Natural Killer Cells for Cancer Treatment”
Natural killer (NK) cells are a type of white blood cell that can kill cancerous cells without needing prior exposure to them.
Using NK cells from donors for cancer treatment is appealing because they work differently from standard treatments and have fewer overlapping side effects. However, there are challenges to overcome, such as not having enough NK cells, difficulty getting them to the tumor, and problems with their effectiveness due to various factors like exhaustion and tumor evasion.
Recent advances in understanding NK cells and biotechnology have led to progress in making treatments more effective and safer. This involves selecting the right donors based on genetics, improving how NK cells are prepared, and finding new ways to boost their effectiveness while reducing resistance from tumors.
Although most research has focused on blood cancers, efforts are underway to explore their use in other types of cancer. NK cells offer a promising avenue for treating cancers that don’t respond well to current therapies.
Cancer cure rates are still low, but advances in genetics and immunology have led to new therapies that work differently and have fewer overlapping side effects.
Immunotherapy, which uses the body’s immune system to fight cancer, has become possible with various approaches involving different parts of the immune system, like natural killer (NK) cells.
NK cell therapy is a newer addition to the field of cellular immunotherapy, compared to other types of immune cells used in treatment. NK cells were first recognized for their ability to kill cancer cells without needing help from T cells back in the 1970s, but it wasn’t until the 1990s and early 2000s that researchers discovered their potential for treating cancer in humans. This review looks at how NK cells work against cancer and discusses the ongoing research in clinical trials.
NK Cell Biology
NK cells were first identified by Kiessling in Sweden and Herberman in the US. They earned the name “natural killer” because they naturally occur in animals and can kill certain cancer cells without needing prior exposure. Some called them “N-cells” or “K cells.” These cells are unique because they don’t have markers found on other immune cells like B and T lymphocytes, and they don’t engulf other cells. They mainly attack cells coated with antibodies.
NK cells form in the bone marrow and develop in mice without a thymus and in humans with DiGeorge syndrome. They can start killing target cells within minutes, much faster than T cells.
In human blood, about 5% to 15% of lymphocytes are NK cells, with most being CD56dim and responsible for early immunity and antibody-dependent cell killing. About 10% are CD56bright, which helps in later inflammatory responses by releasing certain substances. NK cells also play a role in priming adaptive immunity and can interact with other immune cells like T and B cells.
Regulatory receptors
Human NK cells are controlled by a complex system of surface receptors, which help them quickly identify healthy cells from abnormal ones. When the activating signal outweighs the inhibitory one, NK cells destroy their target cells. Early studies noticed similarities between mouse NK cells and cells that reject foreign tissue grafts. It was proposed that this rejection was due to receptors recognizing the absence of certain proteins on the cell surface. This led to the “missing self” idea in the 1980s. In the early 1990s, researchers discovered the KIR gene family, which recognizes specific proteins in healthy cells. Other receptors like NCRs, NKG2D, DNAM, 2B4, and CD94/NKG2A have since been identified, revealing a complex network that regulates human NK cell activity.
Surface receptors on human NK cells can be categorized based on their primary function and are color-coded accordingly: inhibitory receptors are shown in red, activating receptors in green, inhibitory coreceptors in red-black stripes, and activating coreceptors in green-black stripes. Their ligands are indicated within parentheses. Other receptors like chemotactic receptors (CCR-2, -5, -7; CXCR-1, -3, -4, -6; CX3CR1; and Chem23R), adhesion receptors (CD2 and β1 and β2 integrins), and activating coreceptors (CD96, CS1, and TLR) are not displayed in this illustration.
NK Cell Processing and Quality Assurance
NK Cell Purification:
The next step in therapy involves purifying NK cells and checking their quality before infusion. This includes assessing cell count, viability, sterility, type, function, and purity. Earlier studies mainly used mixed T cells with low NK cell levels.
The most effective method for isolating highly pure NK cells is through immunomagnetic separation.
This process results in a product containing over 90% NK cells with minimal T cells, B cells, and monocytes, reducing the risk of various complications. Purified NK cells maintain their original characteristics and have strong abilities to multiply and fight tumors in the body. Importantly, they can be given in small doses and be safe without causing certain complications. They stay in the recipient’s bloodstream for about 2 to 4 weeks after infusion, with certain types showing better growth than others.
To enhance the effectiveness of donor NK cells, they can be modified outside the body using various methods. One challenge is preventing NK cell exhaustion, where cells lose their ability to produce certain substances over time.
Additionally, the acidic environment of tumors can make NK cells less effective. One common approach is to activate and prepare the cells using substances like IL2, IL12, IL15, IL18, IL21, or type I IFN.
Studies have shown that combining IFNα and IL2 can boost NK cells against solid tumors, while IL12 with IL2 or IL18 can help overcome resistance. By using these substances in cell cultures, it’s possible to greatly increase the number of mature NK cells. In one study involving patients with multiple myeloma, NK cell numbers expanded significantly after 20 days of culture, leading to an improved ability to kill cancer cells.
Another approach to activate NK cells is by using artificial presenting cells with molecules like IL15, IL21, and 41BB ligand. Studies in animals have shown that these cells are effective against certain types of cancer and can prolong survival without causing graft-versus-host disease (GVHD).
Another method to enhance NK cell effectiveness is through chimeric antigen receptor (CAR) therapy. This involves inserting receptors into NK cells using different techniques like retroviral or lentiviral methods. Research has demonstrated that NK cells with anti-CD19 CAR or NKG2D are powerful against certain cancers both in the lab and in animal studies. Clinical trials are ongoing for hematologic malignancies.
For centers without gene modification capabilities, NK cells can be activated by culturing them with unmodified cells and stimulating cytokines. Recent studies have shown that this method can produce highly effective NK cells against neuroblastoma without causing GVHD.
One challenge in NK therapy is getting the cells to the tumor site. Researchers have used CCR7+ cells to improve NK cell homing to tumors in animal models. Immunocytokines, like an antibody against GD2 linked to IL2, can also help NK cells stick to tumor cells.
To enhance NK therapy, researchers are finding ways to increase the activity of certain receptors on NK cells. One method is using drugs that increase the expression of these receptors or prevent them from being removed from the cell surface. These drugs include HDAC inhibitors, proteasome inhibitors, and demethylating agents. High-throughput screening identified spironolactone as a new drug that activates a pathway to increase the expression of certain proteins on cancer cells, making them more vulnerable to NK cell attack. Another study found that silencing certain genes in cancer cells makes them more susceptible to being killed by NK cells.
Summary:
NK cells offer promising potential for cancer therapy due to their quick response, strong ability to kill cancer cells, and suitability for various cancer types. They come with few side effects, are easy to prepare and administer, and are readily available. Selecting donors for NK cells is also feasible, and they work well alongside other treatments. Their distinct characteristics pave the way for innovative cell-based immunotherapy against cancers resistant to current therapies.
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