Chimeric Antigen Receptor T (CAR-T) cellular therapies allow a patient’s T cells to be genetically modified to display receptors for tumor cell proteins, leading to binding and destruction. This therapy has come a long way since its inception in the late 1980s by immunologist Zelig Eshhar at the Weizmann Institute of Science in Israel. In 2017 the first CAR-T therapies, focused on B cell malignancies, were approved by the U.S. Food and Drug Administration (FDA). These therapies have changed the treatment landscape for hematologic malignancies, but suffer from several significant shortcomings:
- CAR-T therapies can induce cytokine release syndrome (CRS), a potentially fatal and rapid release of cytokines
- CAR-T cells are largely distilled from the cancer patient’s own blood cells, and after successive prior rounds of chemotherapy, the patient’s T cells may have reduced function
- The manufacturing cost and time required to manufacture these autologous CAR-T therapies limit patient access to these extremely expensive treatments
- The risk of life-threatening graft-vs-host-disease (GvHD), in which the donor T cells recognize the patient as foreign and attack the host, prevents the use of donor T cells without extensive gene editing strategies
- CAR-T therapies have had limited efficacy in settings beyond hematological malignancies. 1
Natural killer (NK) cells have the potential to solve these inadequacies of T cells and are emerging as a safe and effective mode of treatment for several hard-to-treat cancers.2 Identified in the mid-1970s, NK cells were described as a separate class of lymphocytes that can spontaneously, or naturally, kill tumor cells. In the years thereafter, the scientific community focused on their important role in viral infection. Only recently has their role in tumor immunobiology come back to the forefront.
In contrast to T cells, which have a relatively limited set of receptors to recognize cancer cells, NK cells express a broad variety of unique receptors, including NKG2D, which broadly recognize oncogenic stress, and CD16, which binds to tumor-specific antibodies, as well as many others that are typically not expressed on T cells. After being triggered by these receptors, the killing pathways utilized by NK cells are remarkably similar to T cells, i.e., perforin and Granzyme-mediated cytotoxicity, and thus, the potency of killing between the two cell types is very similar. However, what sets NK cells apart from T cells are distinct abilities beyond simply killing tumor cells. NK cells are robust producers of key cytokines like IFNg that polarize the downstream immune response, and chemokines like Xcl1 and Ccl5, which can recruit other cells of the immune system, such as dendritic cells, to the cancer microenvironment and “kick-start” a broader anti-tumor response by the entire immune system.
While our understanding of the clinical utility of these cells is still in its infancy, many exciting approaches are now being tested – including induced pluripotent stem cells (iPSC)-derived NK cells, expanded cord blood or adult donor-derived NK cells and memory NK cells, which retain epigenetic signatures of prior activation and can respond more quickly to future stimuli. Here, we discuss the potential benefits of these NK cell therapies.
NK therapies: Safe and universal
Through extensive clinical testing, NK cellular therapies have proven to be remarkably well-tolerated. They have not been associated with CRS or neurotoxicity, clinically severe complications of CAR-T therapies, and do not induce GvHD when used in an unmatched setting. NK cells, therefore, represent a significant safety improvement over T-cell therapies, while still being effective across a broad range of cancers, and may allow for the treatment of patients that would otherwise be unable to tolerate T-cell therapies.
This enhanced safety profile enables additional possibilities for NK cells – including the ability to use NK cells from a universal donor. Because NK cells do not cause GvHD, donor NK cells do not need to be matched to a recipient. The efficacy of NK cells seems to be improved in the unmatched setting, likely due to altered interactions of KIR (Killer Cell Immunoglobulin-Like Receptor) with HLA (Human Leukocyte Antigen). Avoiding time-consuming matching is extremely beneficial to cancer patients, for whom every minute matters.
The enhanced safety profile of NK cells opens an additional exciting possibility: much as we "bank" blood for future use, NK cells could be "banked" and stored as an “off-the-shelf” therapy for use in cancer patients – as universal and as treasured as O- blood -thawed and infused into any cancer patient as needed.
To enable off-the-shelf utility, there are several challenges to be solved. NK cells would ideally be expanded to produce many doses of NK cells from a single donor donation. The optimal way to multiply NK cells to large numbers while maintaining their anti-tumor function is an active area of research. Additionally, NK cells do not tolerate freezing as well as other cell types, which has been a significant challenge in the field. Should these two issues be solved, the generation of vast numbers of powerful anti-tumor cells that could be inexpensively produced and infused into any cancer patient, as needed, promises to revolutionize cancer therapy.
Solid tumor therapy
One of the greatest unmet medical needs in cancer is the treatment of patients that fail to respond to checkpoint (i.e., PD1, PDL1, CTLA4, and others) inhibition. Though many mechanisms may drive a lack of response to checkpoint inhibition, a significant mechanism is tumor evasion of T cell responses through HLA. Indeed, immunoediting is a well-established hallmark of cancer, and 60-90% of cancers lose or downregulate HLA, a percentage that likely increases after the immune pressure of checkpoint therapy.3
NK cells are inhibited by the expression of HLA, and can be thought of as a counterbalance to T cell evasion. So, when tumors downregulate HLA to evade T-cell responses, they make themselves more vulnerable to NK cell killing. Therefore, these patients that fail checkpoint therapy, across many tumor types, may be enriched for potential NK response, making them a perfect fit for NK cellular therapy.
Furthermore, many solid tumor indications now have approved IgG1 monoclonal antibodies available (e.g., ERBITUX® (cetuximab) for head and neck cancer, and HERCEPTIN® (trastuzumab) for breast cancer. By virtue of CD16 expression, NK cells can use these antibodies as a "bridge" to enhance their recognition and killing of cancer cells.4 It is well-appreciated in the field that responders to these therapies often have highly active NK cells of their own – could adoptive transfer of NK cells from a universal donor fill this role for patients that do not already have highly active NK cells?
NK cells promise several strong advantages over T cells as a cellular therapy, including safety, universality, patient access and a differentiated role in immunotherapy. The best way to realize this potential is currently unknown, and further opportunities remain to identify the best NK cell therapy, including by selecting optimal donors, cell sources or by selectively inducing more active NK cell phenotypes. An exciting gamut of upcoming clinical data from several distinct approaches will tell whether the potential of NK cells can be achieved.
1. Stoiber S, Cadilha BL, Benmebarek MR, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019; 8(5):472. doi: 10.3390/cells8050472.
2. Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell–cancer cycle: advances and new challenges in NK cell–based immunotherapies. Nat Immunol. 2020; 21:835-847. doi.org/10.1038/s41590-020-0728-z.
3. Cornel AM, Mimpen IL, Nierkens S. MHC class I downregulation in cancer: underlying mechanisms and potential targets for cancer immunotherapy. Cancers. 2020; 12(7):1760. doi: 10.3390/cancers12071760.
4. Gauthier M, Laroye C, Bensoussan D, Boura C, Decot V. Natural killer cells and monoclonal antibodies: two partners for successful antibody dependent cytotoxicity against tumor cells. Crit Rev Onc / Heme. 2021; 160:103261. doi: 10.1016/j.critrevonc.2021.103261.
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