Cancer Immunotherapy

The field of immuno-oncology (or cancer immunotherapy) has exploded in the past decade. Cancer immunotherapies generally work by interfering with the inhibitory signals produced by tumors against certain elements of the immune system. Because such inhibitory signals are mediated by “immune checkpoint” cell-surface molecules, the first generation of cancer immunotherapies are generally known as checkpoint inhibitors. The remarkable clinical efficacy (measured as long-term tumor control or even complete disappearance of tumor lesions) of some checkpoint inhibitors appears to be associated with the activity of effector lymphocytes, mainly tumor-infiltrating effector T cells. There remains, however, a significant unmet medical need.

Medical Need

In spite of the pronounced benefit derived by some patients from treatment with immune checkpoint inhibitors, the unfortunate reality is that a large segment of patients fail to benefit from such medicines. Likely reasons include the heterogeneity of the mechanisms by which tumors interfere with what would otherwise be an appropriate and tumor-eradicating immune response. Effective application of cancer immunotherapies against ever larger segments of the patient population will likely require an understanding of the diversity of tumor-triggered immunosuppression mechanisms and access to drugs that have been specifically designed to interfere with such mechanisms. These approaches will be supplemented by agents that selectively activate and stimulate the function of tumor-infiltrating immune cells such as T cells, natural killer (NK) cells and inflammatory macrophages. Each of these types of agents will address one or more immunotherapy therapeutic nodes*.

Combination Treatments

Available clinical and preclinical knowledge supports the expectation that cancer immunotherapies will be most beneficial when utilized as part of combination treatments, which may include novel immunotherapies in addition to well-established staples such as chemotherapy or radiation. The science behind the design of such combination treatments reflects the need to “fix” those elements of the immune response that are being directly or indirectly inhibited by certain types of cancer but also the desire to stimulate a robust and appropriate immune response against the tumor. While we anticipate that, individually, each drug in our therapeutic portfolio will correct particular immune deficiencies that drive certain tumors, we envision that our overall portfolio will cover the full spectrum of therapeutic nodes. This will create multiple drug combination opportunities within our own pipeline for addressing an ever-larger segment of the patient population.

Therapeutic Nodes

Each stage in the “immune response cycle” represents a therapeutic opportunity in immuno-oncology. We refer to these as Therapeutic Nodes*. Key therapeutic nodes include the triggering of immunogenic cancer cell death, the activation of dendritic cells, the reversal of active immune suppression, and the direct stimulation of effector immune cells (such as T and NK cells). Arcus is building a wide portfolio of immune-focused cancer therapies that target one or more therapeutic nodes. This therapeutic portfolio will enable us to create, study and develop combination treatments that address the pathways of immune dysregulation most prevalent in particular malignancies or patient subgroups. Several drug discovery programs are ongoing and expected to produce optimized compounds for clinical development within the next 12-18 months.

* Smyth, Ngiow, Ribas & Teng; Nat. Rev. Clin. Oncol. (2016) 13(3): 143

Modality Independence

Arcus is pursuing its therapeutic portfolio in a modality-independent fashion. We have selected some biological pathways that are best suited to modulation by small-molecule drugs (which are being designed entirely by our internal drug discovery team). Other biological targets in our drug discovery portfolio will be best addressed with protein-based therapeutics (which will be created in collaboration with external expert organizations). Both types of drug candidates will converge into the biological / preclinical / clinical development organization that we are presently building within Arcus.

Drug Discovery Programs

We have several drug discovery programs (see Drug Pipeline) aimed at restoring the vigor and functionality of tumor-infiltrating T and NK cells, while other projects aim to find tumor-selective ways to stimulate such cell populations. We have also initiated drug discovery efforts with the objective of stimulating the maturation and activation of tumor antigen-presenting dendritic cells (DC). We are conducting this work in a modality independent manner. Each of these drug discovery programs addresses one or more therapeutic nodes and will gradually increase the breadth and depth of our growing therapeutic portfolio.