Therapeutics
to another type of immune cells, NK cells, for the next breakthrough in immunotherapy. By opening the door to exploring new therapies capable of delivering improved efficacy with reduced risk, NK cell therapy has the potential to transform the bur- geoning field of immunotherapy.
The natural killer cell advantage While T-cells are considered to be part of the adap- tive immune system, NK cells are categorised as a cell within the innate immune system. Similar to cytotoxic T-cells, NK cells have the ability to recognise distressed cells (such as cancer cells) and kill them. This capability has led investigators to explore whether NK cells can be used in immunotherapy much like T-cells are used, but without the side-effects often associated with T- cell-based treatments, such as cytokine storm or GvHD (graft versus host disease). In turn, IO researchers are leveraging the knowledge they have obtained from the use of T-cell therapy and apply- ing it to NK cells, with the goal of developing immuno-oncology treatments that are efficacious while avoiding the risks associated with other immunotherapies. Three major NK cell therapy approaches have
emerged to date: Bispecific antibodies, antibody- dependent cell-mediated cytotoxicity (ADCC), and cell-and-gene-therapy with NK cells. All are in var- ious stages of investigation and testing.
l Bispecific antibodies are being developed to engage NK cells and bring them closer to their can- cer targets to cause direct killing. An example of such an approach is the bispecific antibody therapy from Innate Pharma. To activate NK cells to attack a tumour, this therapy uses an antibody to bind to an antigen on the surface of tumour cells on one end, and the NKp46 activating receptor on the sur- face of NK cells on the other end. l Induction of ADCC is another approach to using NK cells for anti-tumour activity. ADCC uses Fc receptors that are expressed on NK cells to find and kill antibody-coated target cells. Affimed is one company investigating this approach for the treatment of Hodgkin’s lymphoma. l Development of CAR-modified NK cells takes a similar approach as CAR-T therapy – leveraging the cytotoxic capabilities of NK cells. This approach is being used by Fate Therapeutics, which has entered into a two-year collaboration with the University of California San Diego to develop off- the-shelf CAR-NK cell-based immunotherapies.
These three approaches can be utilised alone as a 68
treatment or in combination. For example, Fate Therapeutics is combining cell therapy and anti- body-based therapy to induce ADCC. It announced in February 2018 that the first subject had been treated in a study of advanced solid tumour treat- ment with its FATE-NK100 markedly in combina- tion with a targeted monoclonal antibody therapy. FATE-NK100 is an NK cell therapy derived from peripheral blood NK cells expanded ex vivo with interleukin (IL)-15 and a small molecule inhibitor of glycogen synthase A kinase (GSK) 3. Combining FATE-NK100 with monoclonal antibody therapy is designed to enhance ADCC. Regardless of the specific mechanism employed,
NK cell-based cancer therapies may offer crucial treatment advantages compared to T-cell-based therapy, including less concern about the side- effects associated with T-cell-based treatments. For CAR-based NK cell therapy in particular, there are additional potential advantages. For instance, since human leukocyte antigen (HLA) matching is less of a concern with NK cells as compared to T-cells, allogeneic transplantation (transplantation from a donor that is not genetically identical) may be pos- sible, so that one donor/NK cell line could provide a cure to multiple patients. Therapy production also may be streamlined when therapies do not have to be personalised to each patient, creating cost-efficiencies.
Changing needs for animal models These rapid advancements in cell therapies indicate that harnessing various parts of the immune system yield potent treatments for common diseases such as cancer. Going forward, immune-oncology researchers will look for systems that accommo- date the complete arsenal of the immune system. To do this, better testable in vivo animal models capable of accepting, supporting and sustaining the full repertoire of human immune cell lineages are needed. Critical insights into how the host system can accommodate the unique requirements of cell therapies by providing the most appropriate envi- ronment for testing were recently published for multiple immune cell types. Recent work by Nilsson et al at the University
of Gothenburg demonstrated that transgenic expression of supportive cytokines were key for T-cell survival and effector function in a novel autologous T-cell transfer model with patient matched-melanoma xenografts1. This work has broad implications because most immune cell lin- eages source homeostatic and effector signals from their environmental cytokine milieu which may not be supplied by the rodent host system.
Drug Discovery World Spring 2018
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