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Harnessing the Innate Immune System to Outsmart Cancer

June 03, 2021

By Chris Arendt, Head, Oncology Therapeutic Area Unit

One of the most exciting things about working in oncology today is the rapid pace of progress. The speed of scientific innovation, the speed that is possible through innovative trial designs and the speed with which regulators engage to help us advance investigational therapeutics to realize their potential for cancer patients is nothing short of astounding. Along with this acceleration has been an explosion in the number of therapeutic concepts made possible through the expansion of novel modalities, ranging from unique protein scaffolds to cell therapies to oncolytic viruses. More than ever before, we are cognizant of the opportunity and responsibility to seek out the most promising innovation – wherever it may be – and to couple this with our drug development capabilities so as to advance cancer care through medicines that provide substantial benefits beyond current treatment paradigms.

Cancer immunotherapies focused on harnessing immune cells known as T-cells in the attack against cancer have provided powerful proof-of-concept for patient benefit across a breadth of hematologic and solid malignancies with historically poor prognoses. At the same time, this class of immunotherapy medicines, which includes T-cell checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies, has exposed new gaps by way of patient populations who are either refractory to these approaches or whose cancers relapse while on therapy. For these patients, there is a desperate need for drug developers to continue to invest in novel mechanisms, including ones that build upon the awesome potential of immunotherapies.

Harnessing the Power of Innate Immunity

So that more patients can benefit from – and have access to – life-transforming medicines, we’re leveraging our increasingly refined understanding of the interplay between cancer and immunity to develop new ways to harness specific cells of the immune system. The innate immune system serves as the body’s first defense mechanism against disease and has the power to orchestrate a broad arsenal of immune cell types and mechanisms that may help to overcome cancer’s attempts to evade immune recognition.

At Takeda, and with our network of partners across the globe, we are exploring various steps in the cancer-immunity cycle to harness untapped mechanisms of the innate immune system with significant therapeutic potential. To illustrate this, think of the cancer immunity cycle as an engine that the immune system is seeking to push forward to ignite a full response against tumors, and cancer’s immunosuppressive capabilities as a frigid winter morning. The result is a “cold” engine that stalls. Immune cells with innate properties, including gamma delta (γδ) T-cells, natural killer cells, macrophages and dendritic cells, are increasingly appreciated to be central players in the cancer-immunity “engine.” These cells help determine whether the cancer-immunity cycle remains “cold” and “stalled” – suppressing immune attack, or whether it “heats up” and propels forward to tumor cell attack and clearance.

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Adaptive and Innate Cell Cycle Immune Responses within the Tumor Microenvironment

Following the Science Yields Diverse Approaches

To outsmart cancer, we are complementing our breadth of in-house capabilities with a network of symbiotic partnerships that contribute deep expertise in cutting-edge platforms and emerging scientific areas. We collaborate with trailblazing scientific teams across the globe – be they at academic medical centers, biotechs or pharmaceutical companies – to accelerate innovation and prototype the most promising science wherever it emerges. These partnerships are unlocking novel approaches to harness the immune system in the attack against cancers in two areas of focus:

Igniting the cancer immunity cycle to elicit a “cold-to-hot” tumor microenvironment transition

One area of focus within our innate immunity strategy centers on enhancing the immune system’s recognition of cancer. Referring back to the “engine” analogy, this strategy aims to deploy novel immunotherapeutic approaches to “heat up” this engine and allow it to push forward to enhanced immune activation and, ultimately, to tumor regression and clinical benefit.

Among the platforms we are studying in this focus area is SUMOylation inhibition. SUMOylation is a process that can regulate immune activation through proteins known as interferons. It is thought that SUMOylation inhibitors can reactivate interferon signaling that is deficient in a “cold” tumor setting, and potentially re-engage the immune system to fight against cancer.

Another platform we are exploring is STING modulation and targeted delivery of STING agonists, which represent another lever for modulating key interferon signaling pathways with the potential to regulate an effective immune response against cancers.

Redirecting immune cells to directly attack tumors

Under the other area of focus within our immuno-oncology strategy, we’re studying cutting-edge approaches that redirect large numbers of immune cells to carry out broad attacks against tumor cells.

We are doing this through two different approaches. We are advancing a number of cell therapy platforms, including platforms that leverage cells with innate immune properties, such as natural killer cells, γδ T-cells and induced pluripotent stem cells (iPSCs). These are allogeneic approaches, meaning the cells can be derived from a single source and serve as a treatment for many patients. This type of treatment has the potential to be delivered off-the-shelf for patients at the time they need therapy and improve upon several aspects of existing cell therapies. Additionally, we are exploring approaches with novel cell engagers, which are biologics molecules engineered to specifically activate endogenous immune attack at the tumor interface.

Looking Ahead

Takeda strives to deliver life-transforming oncology therapies to as many patients as possible, as part of our ceaseless aspiration to cure cancer. We recognize that this “takes a village,” and we are privileged to have an outstanding network of partners and collaborators across the globe who are equally passionate about succeeding in this mission. We have conviction in the power of the immune system to be foundational to new medicines of the future, and the novel mechanisms that we are pursuing represent our commitment to transformative innovation.

Immuno-oncology research and discovery is at an inflection point. Whatever role you play in the cancer community, let this encourage you. Allow the sheer number of novel approaches built on compelling science, the pace of innovation and the volume of knowledge being shared through partnerships and scientific exchange to illuminate the progress we are making together for patients in need of more options.