Cell & Gene Therapy
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Alex Sargent, PhD
Cancer’s Natural Predator
How the evolution of natural killer cell therapies can turn the tide against cancer
Today, Dr. Steven Rosenberg is chief of surgery at the National Cancer Institute, the US government’s principal agency in our fight against cancer. Forty years ago, he was an up-and-coming cancer researcher with the groundbreaking idea to use a newly discovered type of immune cell to fight cancer.1 Natural killer cells (NK cells) earned their wonderful designation in 1975, because from a biological perspective, they do one thing superbly well: kill.2 They are sentinels of the immune system, surveying and destroying cells they do not recognize, cells infected with viruses or pathogens, and cells that become or already are cancer. Given their natural inclination to target and destroy cancer, the idea of collecting, growing, and transplanting these cells into cancer patients took off with a fury.1,2
Basic biology of cancer killers
Yet isolating and expanding NK cells in the laboratory can be challenging, especially when you consider how little we know about what makes a “good” NK cell. Like other immune cell therapies, NK cells are commonly isolated from the blood, where they make up a small but mighty proportion of specialized white blood cells, called lymphocytes, that comprise the immune system. NK cells are one of the rarest types of immune cells in circulation, typically comprising only 5%-10% lymphocytes.3 In contrast, their closely related cousins, T cells, usually make up 60%-80% of the lymphocytes in the blood.4 Beyond frequency, these two types of white blood cells also differ in their purpose and function.
T cells are a major component of the adaptive immune system; they are activated to respond to external threats or changes in the body, like germs or infections. NK cells, on the other hand, are a key component of the innate immune system; they constantly scan and survey as a first line of defense, dealing with anything that seems out of place and killing any cell that does not belong.
The problems of producing NK cells
Due to their low frequency, isolating NK cells in sufficient numbers from the blood can be difficult. Expanding these NK cells to larger numbers in the laboratory can also prove tricky for different reasons. One, to grow large numbers of NK cells usually requires other cells, called feeder cells, to be cultured with them. These feeder cells are often cancer cell lines that have been treated with radiation or chemicals to halt or suppress their ability to outgrow the NK cells.5 Two, NK cell biology and function can vary remarkably between different donors, so finding the best blood and the best people to grow NK cells from is very important. NK cell activity seems to change with a person’s age, diet, gender, stress level, and even movie preferences.6 One infamous study reported that people who viewed funny or humorous videos had better NK cell activity compared to those who watched boring tourism videos.7 Whoever said laughter is the best medicine may be right when talking about NK cells.
To be effective therapies for patients, NK cells need to be expanded to very large numbers and in large volumes. However, the more proliferative NK cells are and the more they grow, the more likely they may be to lose their innate ability to kill and function.8 Balancing NK cell growth with killing capacity is a challenge, especially because NK cells can also lose their killing capacity when frozen for storage and shipment to hospitals and clinical centers.9 Until scientists better understand the biology of NK cells, how to screen and select the best ones, and optimal methods to expand and preserve them, manufacturing these unique cells at a clinical and commercial scale can prove daunting.
The evolution of NK cells to CAR NK cells
Early clinical trials using NK cell-based therapies to treat cancer, including pioneering trials from Dr. Rosenberg, showed surprisingly little efficacy against the likes of melanoma, renal cell carcinoma, and leukemia.10 This was in stark contrast to early results using a type of T cell-based therapy for cancer. As NK cell therapies stalled, chimeric antigen receptor (CAR) T cell therapies grew as a powerful treatment and even cure for certain types of cancer, with six FDA-approved CAR T cell therapies on the market today./ No NK cell-based therapies have crossed this threshold thus far, and researchers are now turning to CAR T cells as a model for how to arm and evolve our body’s natural killers.
If the “CAR” in CAR T cells makes this therapy so deadly, then equipping NK cells with this powerful receptor could allow them to better target and kill cancer. A CAR is designed to bind and recognize a specific protein or antigen on the surface of cancer cells, with different CARs engineered for different proteins and types of cancer.12 As part of the innate immune system, NK cells already have receptors that help them identify cells to kill. In keeping with the fierce nomenclature of NK cells, these are called killer Ig-like receptors, or KIRs.13 These are not specific to any one protein or antigen, though, and for NK cells, it can take binding and recognition of a complex pattern of different KIRs before an NK cell decides to kill. Engineering cells with a CAR can streamline and simplify this process, where binding of the target antigen to the CAR alone signals the NK cell to ready, aim, and fire.
Clinical trials with newly evolved CAR NK cells are just beginning, and early results from these trials are promising, with CAR NKs being able to effectively eliminate different types of blood cancer.14 If successful, CAR NK cell therapies could rival CAR T cell therapies as the best cell therapy to treat cancer. CAR NK cells may even be superior to CAR T cells from a safety, efficacy, and cost standpoint.15 First, CAR NK cells may be able to kill cancer without triggering a massive and potentially dangerous immune response. For CAR T cell therapies, this dangerous side-effect is called Cytokine Release Syndrome (CRS), and CAR NK cell therapies appear to have a much lower risk of triggering this phenomenon.15 Second, CAR NK cells are innately designed to detect and kill cancer cells, so they may be more effective at killing different types of cancer, like solid tumors that CAR T cells currently struggle with.15,16 Finally, CAR NK cell therapies are a type of allogeneic cell therapy, and as discussed elsewhere, this can make them much less costly to produce compared to autologous CAR T cell therapies.15,16
Only time will tell if CAR NK cells are as formidable as CAR T cells, or if they surpass CAR T as the ultimate cellular assassin for cancer. If CAR NK cells do emerge victorious, it will represent the culmination of 50 years of research and hard work on understanding this rare but remarkable piece of our immune system. The evolution of CAR NK cells may bring the rise of a new type of ultimate predator for cancer, one poised to strike and ready to finish the job nature intended for it.
References:
1. Steven Rosenberg, Lymphokine-activated killer cells: A new approach to immunotherapy of cancer, JNCI: Journal of the National Cancer Institute, Volume 75, Issue 4, October 1985, Pages 595–603.
2. Lanier LL. Five decades of natural killer cell discovery. J Exp Med. 2024 Aug 5;221(8):e20231222.
3. Qi C, Liu Q. Natural killer cells in aging and age-related diseases. Neurobiol Dis. 2023 Jul;183:106156.
4. Liu W, Xu J, Pu Q, et al. The reference ranges and characteristics of lymphocyte parameters and the correlation between lymphocyte parameters and routine health indicators in adults from China. Immun Ageing. 2022 Sep 27;19(1):42.
5. Gurney M, Kundu S, Pandey S, O'Dwyer M. Feeder Cells at the Interface of Natural Killer Cell Activation, Expansion and Gene Editing. Front Immunol. 2022 Feb 11;13:802906
6. Angelo LS, Banerjee PP, Monaco-Shawver L, Rosen JB, Makedonas G, Forbes LR, Mace EM, Orange JS. Practical NK cell phenotyping and variability in healthy adults. Immunol Res. 2015 Jul;62(3):341-56.
7. Bennett MP, Zeller JM, Rosenberg L, McCann J. The effect of mirthful laughter on stress and natural killer cell activity. Altern Ther Health Med. 2003 Mar-Apr;9(2):38-45.
8. Fang F, Xie S, Chen M, Li Y, Yue J, Ma J, Shu X, He Y, Xiao W, Tian Z. Advances in NK cell production. Cell Mol Immunol. 2022 Apr;19(4):460-481. doi: 10.1038/s41423-021-00808-3.
9. Saultz JN, Otegbeye F. Optimizing the cryopreservation and post-thaw recovery of natural killer cells is critical for the success of off-the-shelf platforms. Front Immunol. 2023 Dec 15;14:1304689.
10. Wendel P, Reindl LM, Bexte T, Künnemeyer L, Särchen V, Albinger N, Mackensen A, Rettinger E, Bopp T, Ullrich E. Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy. Cancers (Basel). 2021 Mar 23;13(6):1481.
11. Arunachalam AK, Grégoire C, Coutinho de Oliveira B, Melenhorst JJ. Advancing CAR T-cell therapies: Preclinical insights and clinical translation for hematological malignancies. Blood Rev. 2024 Sep 12:101241. doi: 10.1016/j.blre.2024.101241.
12. Guedan S, Calderon H, Posey AD Jr, Maus MV. Engineering and Design of Chimeric Antigen Receptors. Mol Ther Methods Clin Dev. 2018 Dec 31;12:145-156. doi: 10.1016/j.omtm.2018.12.009.
13. Pende D, Falco M, Vitale M, Cantoni C, Vitale C, Munari E, Bertaina A, Moretta F, Del Zotto G, Pietra G, Mingari MC, Locatelli F, Moretta L. Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation. Front Immunol. 2019 May 28;10:1179. doi: 10.3389/fimmu.2019.01179.
14. Romero, D. Promising early results with CAR NK cells. Nat Rev Clin Oncol 21, 168 (2024).
15. Peng, L., Sferruzza, G., Yang, L. et al. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol Immunol 21, 1089–1108 (2024).
16. Pan K, Farrukh H, Chittepu VCSR, Xu H, Pan CX, Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022 Mar 31;41(1):119.