Abstract SY36-03: Viewing cancer as a complex adaptive system and managing immunotherapy as “homeostatic reset”
Authors: Barker Anna D. , Buetow Kenneth 
Published: August 2019

Abstract
Complex Adaptive Systems (CAS) are ubiquitous and composed of many interacting “agents” that exhibit independent properties and behaviors that function together with their environment to produce emergent properties. Emergence and emergent properties cannot be predicted by isolated understanding of these interacting agents/components; but can be demonstrated by observing the outcomes associated with dynamically changing interacting components of a CAS. Obviously, evolution also plays a key role in driving emergence as a defining feature of biological CAS. Biological CAS are highly heterogeneous and complex, both within and across broad scales of time and space. Biological CAS are also non-linear which means that predicting outcomes is difficult. Moreover, it is impossible to “fix” a CAS, rather the identification of leverage points that can alter the trajectory of the system to achieve desired outcomes is a more logical approach. Until recently, systems of such high dimensionality were not sufficiently tractable to understand and apply CAS principles to a disease as complex as cancer. However, recent progress in the development of advanced technologies such as computation, machine learning, artificial intelligence, and modeling portend a day when cancer will be viewed and managed as a CAS. These “big data” tools offer new and innovative opportunities to mine, manage, manipulate, model and simulate cancer to derive the information needed to manage it as a CAS. In terms of applying these principles at least one approach to treating cancer, immunotherapy, suggests that achieving a future state where cancer is viewed through the lens of CAS is well underway. Immunotherapy represents a paradigm shift in cancer therapy in that it targets the immune system, which is a quintessential CAS. When immunotherapy is successful the outcome is a “homeostatic reset” of what is an extraordinarily complex interaction between cancer and the immune system. Together these two complex systems comprise a CAS that promises to re-define how we treat and prevent cancer. A variety of immunotherapeutics (dominated by checkpoint inhibitors) have produced durable responses (possible cures) in a few patients against some cancers. These agents essentially block signals that the tumor employs to keep the immune system from recognizing and killing the cancer. However, the interaction of cancer and the immune system is a dynamic CAS that will ultimately require a detailed understanding of the cellular and microenvironmental changes that occur in patients in response to specific immunotherapeutic interventions. The challenges we face are significant including: identifying responders/non-responders; determining doses; predicting and controlling toxicities; developing rational combinations; and creating new targeted systems-based therapies. Fortunately, many of these challenges can be met by defining the “states” produced by some of the defining alterations observed in responsive and non-responsive patients including “omics” alterations, types of immune cells, temporal relationships, immune activation, humoral factors, etc. Although early, models and platforms to describe, annotate, model and simulate these systems alterations are emerging. In the past several years, we have developed a modeling platform that permits the study of the immune system and its interaction with cancer. “Cell Studio” is an immune-modeling engine that seeks to examine cancer and the immune response as a dynamic CAS by using real world data on the immune system and cancer to develop and inform computational models. Cell Studio permits the user to conduct in silico experiments of defined time and complexity. It combines agent-based and mathematical modeling approaches to capture multiscale dynamics within the immune system. The engine permits user creation of multiple different types of immune cells each with different classes of properties including different collections of cell surface receptors at different concentrations and affinities as well as the capacity to release and respond to cytokines. Multiple compartments corresponding to different body niches (e.g. lymph node, tumor environment) can be created. Mathematical models govern phenomena such as diffusion and cell tracking of cytokine gradients. As a CAS, based on a finite number of “rules” the system is self-organizing and can display emergent properties. User defined therapeutic interventions such as drug administration can be incorporated to assess the system’s response. Cell Studio is implemented using a gaming platform so that the in silico experiments can be visualized in 3D - in real time if desired. This permits researchers to perform experiments similar to those done using biologic model systems and visualizing the results. Like most video gaming platforms, different user views, overviews, individual cell movement, etc. are available and real-time as well as cumulative statistical outputs are captured and displayed. Unlike biologic model systems the simulations can be time reversed to identify, visualize, and manipulate key events. Experimentation using the Cell Studio modeling engine shows that it can recapitulate the longitudinal events in biologic model systems. Additionally, it can recover “immunophenotypes” observed in human studies of immunotherapy in cancer. It is anticipated that the in silico modeling can augment current biologic modeling strategies - especially since it can be run with numbers of replicates of virtual experiments that are not practical with biologic model systems. Additionally, it promises to assist in the rationale to develop combinatorial interventions hitting multiple immune targets and in understanding factors that modulate successful outcomes. In summary, the implications of viewing, studying and developing strategic approaches to fundamentally understand the cancer - immune system CAS are profound. Cell Studio is a next generation novel and powerful approach to analyze and model specific components of this dynamic and integrated CAS for the benefit of patients.
Citation Format: Anna D. Barker, Kenneth Buetow. Viewing cancer as a complex adaptive system and managing immunotherapy as “homeostatic reset” [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY36-03.