gms | German Medical Science

The authors Fischbach et al. begin the piece by exploring how biologics and small-molecule drug discovery transformed the pharmaceutical industry. They paved the way to new applications to combat disease and now represent a large fraction of medicines being brought to market. The singular innovation of Big Pharma was their definition and mastery of the science of turning small molecules into drugs.

Biologics as an industry began in the 1980s and was built upon the molecular biology revolution. Startup companies like Genentech and Genzyme developed expertise distinct from Big Pharma by designing highly functionally optimized recombinant proteins.

The authors hypothesize that today biomedical science stands poised at the threshold of another pharmaceutical frontier: cell-based therapies, the use of human and microbial cells as therapeutic entities. Cells have therapeutic capabilities that are distinct from those of small molecules and biologics and extend beyond the arena of regenerative medicine. Cells are part drug and part device as they can move to specific sites in the body and integrate inputs to execute complex response behaviors in the context of a specific tissue environment. These cellular skills could be harnessed to treat infections and cancers as well as toward tissue repair. However the challenge of controlling cell action is monumental in scope. The authors believe the next critical step is the development of cellular engineering as a foundational science.

Of all the currently available therapeutics, only cells are capable of sensing their surroundings, making decisions, and exhibiting varied and controllable behaviors (Table 1 [Tab. 1]). Fischbach et al. offer a more complete picture of cell traits as described below.

(a) Cells naturally perform therapeutic tasks. Cells are the only one of the three natural agents, including small molecules and biologics, that can perform therapeutic tasks. (b) Cell behavior is exquisitely selective. Cells sense their environment and respond with an action only when in the presence of a specific array of molecular inputs. Engineering and controlling key cellular receptors and how their signals are processed could allow for the customization of responses such that only therapeutically relevant signals trigger the activation of a selected cellular behavior. (c) Cells are special delivery agents. Pharmacokinetics and pharmacodynamics properties and metabolism determine where in the body small molecules and biologics distribute. But the inability to limit distribution to a single cell type often results in off-target effects. This causes risks that can be serious enough to end a drug development program, even at the costly late stage. Cells, on the other hand, are less likely to have off-target effects because they can selectively recognize and migrate toward danger signals and exert their effects in a highly targeted manner. (d) Cells can handle human genetic variability. There is always a challenge determining the right dose of a drug for a diverse genetic patient population. The same dose of a small molecule in different individuals can result in widely varying amounts of the active metabolite reaching its target. Cells have the potential to be engineered to automatically adjust to differences in host metabolism by manifesting a rheostat-like circuit that produces more of a molecule when needed and less when a threshold is exceeded. Thus cells could yield therapeutic responses that are less variable in different individuals. (e) Cell behaviors can be engineered. For example, patients with autoimmune, type 1 diabetes have to monitor their blood sugar and inject insulin. Failure to control the diabetes can be dangerous, bringing on blindness, limb amputation, and death. But if a pancreatic cell could be replaced with a cell to sense glucose and produce insulin this would represent a therapeutic breakthrough.

Cell-based therapeutics, Fischbach et al. surmise, are uniquely suited to address the critical unmet needs of human disease. Here are several of their examples from various research articles. (a) Immune cells that seek and destroy cancer. A major challenge in cancer therapy is to block the growth of drug-tolerant or resistant cancer cells and to slow and kill metastatic cells that have broken free of a tumor mass and enter into the blood stream. The challenge of detecting and destroying a shape-shifting cellular target may be better suited to a cell-based therapeutic. Recent clinical studies have shown the efficacy of using engineered T lymphocytes in treating chronic lymphoid leukemia. (b) Bacterial treatment for Crohn’s disease. Recent clinical studies have demonstrated that procedures where an intact bacterial community is transplanted into the GI tract of a patient and replace the patient’s microbial community are effective treatment for recurrent infections. A single treatment could last a long time and not be as invasive as surgery. (c) Combining bacterial and mammalian cell therapeutics. Some diseases might benefit from this dual approach therapy. This example involves metabolic syndrome, for which a combination cell therapy that simultaneously decreases caloric harvest from the diet and appetite would be a powerful solution (Figure 1 [Fig. 1]).

Fischbach et al. identify two major challenges in developing any new therapy: safety and efficacy. Safety and cost concerns lie at the core of any skepticism about cell-based therapeutics. The development of cell-based therapeutics will be different than that of small molecules. More effort may be required to engineer these agents. But cell therapeutics is probably less likely to yield unanticipated, late-stage problems that often kill off promising new small molecule drugs. The authors argue that:

1.

The lifetime of a cell can be carefully controlled. Both cell and biologic therapeutics can be liabilities as well as opportunities, however cell-based therapeutics have the ability to be controlled by natural and unnatural (engineered) circuits. Two types of synthetic lifetime controls hold great promise. A signaling pathway could be introduced that causes a cell to destroy itself after a predefined number of cell divisions or in response to a diffusible signal. If reliable mechanisms to control cell division can be introduced, then in principle one treatment could last indefinitely. The United States Food and Drug Administration [3] has well-defined safety criteria for small molecules and these can be developed for cell therapeutics so that prospective developers know what standards have to be met. Having standards in place would encourage early movers to invest in new companies focused on developing creative cell-based therapeutics.

2.

There are better odds in the therapeutic development pipeline. The complexity of cell therapies makes researchers, investors, and regulatory agencies leery. But this same trait could make these agents more predictable in the clinic than small molecules or biologics. Complicated circuits in a cell exist to restrict its spatial and temporal activity. An aberrant toxicity that results from the actions of a drug on a target tissue could be negated by using a designed cell-based therapy to attack one cell type. Using a cell that automatically modulates its activity on the basis of a measured response could overcome the toxicity, for example, because of a rare polymorphism that alters the concentration of the active drug in circulation. Cell-based therapeutics may offer unintended side effects, but these issues may prove to be easier to fix with designer cell therapeutics. Because with cells, the designer is able to add or modify a control circuit.

In the last few decades, skilled synthetic chemists designed small molecules and protein engineers have become the face of biologics. Looking forward, the authors ask: how will cell-based therapeutics become the “third pillar” in medicine and a viable foundation for the biotechnology and pharmaceutical industries? Their suppositions are as follows:

Future of sustainable growth of the cell-based therapeutics industry. First, the industry should approach cellular engineering as a foundational science. Without a parallel cellular engineering science, cell-based therapeutics will likely rely on coincidental ad hoc solutions, with no systematic way to design or optimize cells in strategic, reproducible ways.

Essential key control modules in the cellular engineer’s toolbox. The following techniques would be essential to the success of cell-based therapeutics. (a) Control over cell death with self-regulated mechanisms and external reusable “safety-switch” mechanisms. (b) Ability to redirect cellular migration and movement toward specific signals where cells should execute their action. (c) Quantitative control of therapeutic cellular responses, including the ability to tune activation thresholds and to control the type of response the cell elicits. (d) Ability to reprogram cell communication, including cell-to-cell, small molecule-to-cell, and biologic-cell communication. (e) Ability to control type of response the cell elicits such as activation and memory cell establishment. (f) On-demand production and secretion of small molecules and biologics by engineering cells that extend beyond the natural output of molecules. (g) Development of systematic strategies and intuition for how to tune and reshape cellular behaviors. A comparative precedent is the control theory in engineering, which is used to design auto-regulated devices, including thermostats, cruise control systems, and autopilot systems (Figure 2 [Fig. 2]).

The authors Fischbach et al. close on a positive note, with a number of exciting conclusions. The capability to genomically edit human cells is growing rapidly. We must be prepared with ideas about the types of genetic changes we want by envisioning the advanced genetic engineering technologies that will be available in the next five to 10 years. Now is the time for the designers of cellular therapeutics – as did the early synthetic chemists and protein engineers before them – to take the first systematic steps to laying down the foundation for the third pillar in medicine.

Katherine H. Forsythe is Senior Publisher Relations Specialist at the American Association for the Advancement of Science, Washington, D.C., USA.