A Promising Immunotherapy for Cancer: Natural Killer Cells
Natural killer cells (NK) are emerging as a promising cellular immunotherapy platform due to their innate immune regulatory role.
They efficiently kill cancer cells without relying on specific markers, offering potential advantages over traditional therapies. Despite tumors’ resistance mechanisms, NK cells can be activated, expanded, and genetically modified in vitro, enhancing their anti-tumor activity.
Clinical trials involving NK cell infusion in patients with various cancers have shown promising results. Compared to CAR-T cell therapy, which has shown success but comes with high costs and toxicities, CAR-NK cells, generated through genetic engineering, offer a safer and potentially more cost-effective alternative.
Cancer poses a significant threat to global health. Traditional treatments like surgery, chemotherapy, and radiotherapy have long been mainstays in cancer therapy. However, the emergence of resistance to these treatments often leads to cancer recurrence. Additionally, these treatments can weaken the body’s immune response, allowing the remaining tumor cells to spread and metastasize. Therefore, researchers are urgently seeking new strategies to combat resistant cancer cells.
Immune cells play a crucial role in defending against cancer. They can be broadly categorized into innate and adaptive immune cells. Innate immune cells, including natural killer (NK) cells, dendritic cells (DCs), monocytes, and macrophages, provide immediate responses against cancer through cytokine release and direct killing of cancer cells. Adaptive immune cells, such as T cells and B cells, mount long-lasting responses tailored to specific antigens, establishing immune memory.
Despite the body’s immune defenses, cancer cells employ various mechanisms to evade detection and destruction. They produce immunosuppressive cytokines and manipulate immune cell function to promote tumor growth and metastasis. Some cancers also evade immune surveillance by altering their surface molecules to avoid recognition by immune cells.
Understanding these immune evasion strategies is crucial for developing effective cancer therapies. Researchers are exploring innovative approaches, including immunotherapy, to harness the power of the immune system in targeting and eliminating cancer cells. By unraveling the complex interplay between cancer and the immune system, novel treatments can be developed to overcome resistance and improve patient outcomes.
Immunotherapies aim to activate the body’s immune system to fight cancer actively. Various types of immunotherapies have been developed and used in clinical practice, including cytokines, monoclonal antibodies, vaccines, adoptive cell transfer (such as T cells, dendritic cells, natural killer cells, and NK-T cells), and toll-like receptor agonists. Among these, NK cell immunotherapy has shown great promise for over three decades. Recent advancements in understanding NK cell biology have led to significant progress in utilizing NK cells as effective tools in cancer treatment. Clinical trials investigating NK cell therapy have reached phases I and II.
NK cells play a crucial role in the body’s defense against cancer by directly killing tumor cells through various mechanisms. Unlike other immune cells, NK cells don’t rely on specific markers to identify cancer cells. Instead, they recognize “stress” or “danger” signals often exhibited by tumor cells. This makes tumor cells prime targets for NK cell attacks.
One key mechanism of NK cell-mediated killing involves the release of perforin and granzyme, which induce apoptosis (cell death) in cancer cells upon direct contact. Another method is through the binding of membrane TNF family molecules to tumor cell membrane ligands, triggering apoptosis without direct contact. Additionally, NK cells can facilitate antibody-dependent cell-mediated cytotoxicity (ADCC) by acting as a bridge between tumor-targeting antibodies and cancer cells.
Furthermore, NK cells produce cytokines like IFN-γ, which have anti-tumor effects by inhibiting tumor blood vessel formation and activating other immune responses.
Understanding these NK cell-mediated anti-tumor mechanisms is crucial for developing effective cancer therapies. By harnessing the power of NK cells, researchers aim to improve treatments and outcomes for cancer patients.
Allogeneic and autologous NK cell treatment
Allogeneic or autologous NK cells can be derived from peripheral blood, umbilical cord blood, bone marrow, or stem cells. They are often infused alone or with other cells as part of treatments like hematopoietic stem cell transplantation (HSCT).
Allogeneic NK cells, from a different donor, can recognize and attack cancer cells that lack suitable MHC class I ligands. They have shown promise in treating hematological malignancies like AML and multiple myeloma, potentially inducing remission or suppressing relapse. However, challenges exist, such as the risk of graft-versus-host disease (GVHD), which may be exacerbated by certain treatments.
On the other hand, autologous NK cells, derived from the patients themselves, have shown early recovery after transplantation in hematological cancer patients. While they have demonstrated anti-cancer abilities, their efficacy in treating solid tumors like metastatic melanoma or gastrointestinal cancer has been limited. Autologous NK cells may require additional stimulation to effectively kill tumor cells.
Both allogeneic and autologous NK cell therapies have shown clinical efficacy, either alone or in combination with other treatments. Ongoing research is exploring their potential, with numerous clinical trials underway.
In summary, NK cell therapy offers promise in cancer treatment, but further studies are needed to optimize its effectiveness and understand its full potential.
CAR-NK cells
CAR-NK Cells offer several advantages for cancer therapy. Firstly, they are readily available and can be derived from allogeneic cells, eliminating the need for the patient’s immune cells.
Secondly, NK cells do not rely on MHC molecules for antigen recognition, allowing them to target a wide range of antigens with greater potency. Thirdly, NK cells produce fewer cytokines that trigger adverse reactions like cytokine release syndrome (CRS), reducing the risk of side effects. Lastly, allogeneic NK cells do not cause graft-versus-host reactions, making them safer for transplantation.
However, CAR-NK cell therapy faces challenges. Firstly, expanding NK cells in the lab takes time, and obtaining enough cells for therapy remains a hurdle. Secondly, selecting the right method for introducing CARs into NK cells is crucial. Viral vectors have high efficiency but pose risks like insertional mutations, while nonviral methods like mRNA transfection offer safety but transient effectiveness.
Thirdly, the tumor microenvironment (TME) can influence CAR-NK cell therapy effectiveness. Lastly, preclinical evaluation is limited by the lack of animal models accurately representing the complex interactions in the TME.
Addressing these challenges is essential for advancing CAR-NK cell therapy and realizing its potential in cancer treatment.
Future Perspectives:
Several approaches have been developed to harness the cancer-fighting abilities of NK cells. Scientists are investigating cytokines like IL-2 and IL-15, which boost NK cell activity, but there are concerns about overstimulating the immune system.
One method involves stimulating NK cells from healthy donors in the lab with IL-2 and IL-15, and then infusing them into cancer patients. This exploits differences between donor and patient cells to enhance NK cell function against tumors.
The emergence of CAR engineering has changed the landscape of cell therapy. CAR-T cells, the first engineered immune cells showing promise in clinics, have set a precedent for future CAR-based treatments. NK cells, known for their rapid response and strong anti-tumor abilities, have gained attention as alternative candidates for CAR engineering. Research into peripatetic NK cell immunotherapy, particularly in hematological cancers, has shown promising results in terms of safety and efficacy, both alone and combination with standard treatments.
Additionally, CAR-NK cell therapy, which involves modifying NK cells to express tumor-targeting receptors, has shown increased effectiveness in fighting cancer. Antibodies targeting inhibitory receptors on NK cells, like KIRs, NKG2A, and TIGIT, are also being studied in clinical trials to enhance NK cell responses against tumors.
Considering NK cells’ ability to recognize a broad range of targets, combining NK cell therapy with other immune-based treatments could further improve anti-tumor effects. This multi-pronged approach holds promise for enhancing cancer treatment outcomes and warrants further exploration.
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References:
- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
- Canfell K, Kim JJ, Brisson M, et al. Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet. 2020;395(10224):591–603.