Studying cancer’s causes and treatments is similar to studying one of Napoleon’s battle plans. The plot is full of deception, traitorous conversion, brute force, and surrender. To win the battle cancer cells must escape sudden death at the hands of patients’ immune systems; and it has developed clever and insidious ways to do just that, through immune evasion and immunosuppression. With recent advances in immunology and genetic engineering, however, the outcome of the battle is increasingly turning against cancer.
Successes and Challenges of Chimeric Antigen Receptors (CAR) T Therapies
Therapeutic developers have had significant success in engineering T cells to fight cancer via expression of chimeric antigen receptors (CAR) that recognize specific tumor antigens; in fact, two FDA-approved therapies now use modified CAR T cells to battle lymphoma and leukemia with impressive success rates. Additionally, more than five hundred active CAR T clinical trials aim at fighting a wide range of cancers, including lung, ovarian, breast, liver, and many others.1
As successful as CAR T cell therapies have been, the scientific community generally recognizes that significant challenges remain for widespread patient treatment. Currently, a patient’s own T cells must be harvested and shipped to a central facility, where the cells are genetically engineered to express a tumor-specific CAR, prior to reinfusion in the same patient — a time-intensive and costly manufacturing process. Moreover, a percentage of patients, especially those who have undergone chemotherapy, may not have the necessary numbers of viable T cells for engineering. While experimentation is underway to solve the manufacturing challenges and improve response rates against solid tumors using autologous T cells, scientists are increasingly turning to other cell populations as alternative adoptive cell therapies.
NK Cells Enter the Battlefield
NK cells function as part of the innate immune system and are the body’s first line of defense against cancer. They offer several incredibly important advantages over T cells as adoptive cell therapies — they recognize and rapidly kill cancer cells in an antigen-independent fashion and they lack many of the surface receptors responsible for graft-vs-host disease (GvHD) while still exhibiting graft-vs-tumor (GvT) activity. This opens the possibility of developing an off-the-shelf allogeneic product that removes the extremely costly and cumbersome nature of CAR T manufacturing, and thus presenting a promising path toward widespread cell therapy commercialization.
While human adoptive cell studies of unengineered NK cells have demonstrated their safety and modest anti-tumor activity, NK cells are far from perfect adoptive cell therapy candidates. Initial hesitance to use NK cells in cell therapy was based on their extremely short-lived persistence following adoptive transfer as well as their ability to migrate to and penetrate tumor tissues.
Developments in clinical-grade NK cell isolation, ex vivo expansion and stimulation regimens, as well as improvements in NK cell genetic engineering have significantly advanced the field of NK cell-based therapies. (Review Articles2-4)
Engineering NK Cells to Wage War
While extensive preclinical research is proving NK cells to be promising in the world of cancer therapies, many research groups are working to genetically engineer them to further enhance their efficacy — improving persistence, tumor migration, tumor targeting and cytotoxic effector functions. (Review Articles5-7)
NK cells have proven more sensitive than other immune cells to the delivery of nucleic acids, challenging researchers’ ability to produce large quantities of viable, biologically active NK cells. Recent optimization of viral transduction and mRNA electroporation technologies has revived enthusiasm for NK cell engineering. For example, MaxCyte’s ExPERT™ platform has clinical-scale electroporation capabilities that solve the challenges of low cell viability and transgene delivery of viral transduction, while delivering high transfection efficiencies.8-11
Adding NK Cells to the Arsenal
The improved ability to genetically engineer NK cells and the ever-expanding understanding of NK cell biology are allowing scientists to develop mono- and combination immunotherapies using ‘designer’ NK cells.
Following the trend of other immuno-oncology therapies, NK cells are likely not to stand alone, but instead extend to combination therapies. For example, engineering of high-affinity Fc receptors holds promise to augment currently approved biotherapeutic antibodies by increasing NK-cells’ natural antibody dependent cellular cytotoxicity.8
Like T cells, NK cells within tumors express PD-1, an immune checkpoint receptor are thus sensitive to the tumor immunosuppressive microenvironment. A recent study released by the Cancer Research Institute (CRI) highlights the importance of anti-tumor NK cell activity and the ability of checkpoint inhibitors to improve the cancer-fighting capabilities specifically of NK cells.12
Extensive preclinical evidence supports that engineered NK cells, both primary and cell lines, may be an effective cell therapy, while providing an off-the-shelf manufacturing solution. These therapies, including NK-CAR, are now starting to advance into the clinic—eleven clinical trials are in progress as of March 20191 — providing hope that clinicians may yet have another powerful weapon within their cancer-fighting arsenal.
- Bringing natural killer cells to the clinic: ex vivo manipulation. (2013) Hematology Am. Soc. Hematol. Educ. Program, 2013: 234-246.
- Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. (2015) Nat. Rev. Drug Discov., 14(7): 487-498.
- Improving natural killer cell cancer immunotherapy. (2015) Curr. Opin. Organ Transplant., 20(6): 671-680.
- Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. (2015) Front. Immunol., 6:266.
- Expanded and armed natural killer cells for cancer treatment. (2016) Cytotherapy, 18(11): 1422-1434.
- Engineering natural killer cells for cancer immunotherapy. (2017) Mol. Ther., 25(8): 1769-1781.
- Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. (2016) Front. Immunol., 7:105.
- Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method. (2009) Cancer Gene Ther 17(3):147-54.
- A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. (2012) Cytotherapy, 14(7): 830-840.
- A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. (2013) Cancer Res., 73(6): 1777-1786.
- CRI-funded study highlights the importance of natural killer cells in immunotherapy, Arthur N. Brodsky, Ph.D., Cancer Research Institute, September 12, 2018