Engineering the next generation of cell-based therapeutics

Abstract

Cell-based therapeutics are an emerging modality with the potential to treat many currently intractable diseases through uniquely powerful modes of action. Despite notable recent clinical and commercial successes, cell-based therapies continue to face numerous challenges that limit their widespread translation and commercialization, including identification of the appropriate cell source, generation of a sufficiently viable, potent and safe product that meets patient- and disease-specific needs, and the development of scalable manufacturing processes. These hurdles are being addressed through the use of cutting-edge basic research driven by next-generation engineering approaches, including genome and epigenome editing, synthetic biology and the use of biomaterials.

Introduction

Cell-based therapy, which involves the administration of cells as living agents to fight disease, has in recent years experienced explosive growth in both clinical deployment and expansion within the pharmaceutical marketplace. In particular, a handful of therapies have overcome regulatory hurdles and entered commercial use, resulting in growing public recognition and excitement. These include the successful treatment of lymphoid cancers using adoptive cell transfer of genetically reprogrammed T cells, resulting in FDA approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 for the treatment of acute lymphoblastic leukaemia (ALL) and large B cell lymphoma (LBCL), respectively. Other recent successes have included approval of the use of patient-derived limbal stem cells to repair damaged corneal epithelia¹, as well as adult stem cells to treat fistulas associated with Crohn’s disease². These breakthroughs were built upon decades of basic research, and their successes as well as that of other vanguard therapies have had the effect of stimulating enormous cross-disciplinary interest from many previously disconnected basic biomedical research and engineering fields. This growth has been accompanied by an ever-expanding number of clinical trials, and a growing collection of commercially approved therapies (Table 1).

Much of the ongoing enthusiasm for cell-based therapies derives from the prospect of redirecting innate cellular function to enable safety and efficacy profiles that exceed other, more-established, modalities. Although biologics — which include recombinant proteins and other cell-derived biomolecules — can harness the recognition capabilities of macromolecules to achieve a high degree of target specificity, they are prone to unfavourable pharmacokinetic (PK) and pharmacodynamic (PD) properties that can limit their safety and efficacy^3,4. Gene therapies offer the prospect of correcting cellular genotype through therapeutic transgene delivery, usually via a viral vector. However, gene therapies face several translational challenges^5,6, which include a lack of control over the localization, distribution and magnitude of transgene expression, as well as limitations surrounding transgenic payload size of many vectors, and a well-documented inability to support repeated dosing cycles owing to the adaptive immune response^7,8. Additionally, there have been significant safety concerns in recent gene therapy clinical trials⁹.

Although cell-based therapies have many of the same translational barriers as gene therapies — including safety concerns over the potential tumorigenicity and high manufacturing costs that challenge product reimbursement — they have unique intrinsic features that offer the potential for enhanced efficacy against disease. For example, cells can naturally migrate, localize and even undergo proliferation in specific tissues or compartments¹⁰. Cell-based modalities that harness these properties therefore hold potential for biodistribution and targeted delivery advantages not only over biologics, which are subject to limitations imposed by their PK/PD profiles, but also over gene therapies, for which tropism specificity remains challenging to engineer. Furthermore, cells can actively sense a wide variety of extrinsic inputs from small molecules, cell surface marker proteins and even physical forces. Thus, cell-based therapies have the capacity for highly sophisticated sense-and-respond functions that could dynamically track disease states by detecting associated molecular cues and delivering a multifactorial output response that includes activation of an intrinsic response or the expression of therapeutic transgenes. Finally, because of the ability of cells to persist in vivo, consume nutrients and affect their extrinsic environment through production of secreted factors, cell-based therapies can be used to sustain long-term endogenous drug delivery. Although nearly every cell type in the human body (~200 in total)¹¹ harbours properties that can potentially be turned to therapeutic use, some of the highest profile contemporary clinical successes have been enabled by engineered alterations in cellular function. For example, the clinical results for haematological malignancies described above were achieved using chimeric antigen receptors (CARs), engineered DNA constructs introduced into patient T cells to redirect their cytotoxicity to tumour cells that bear CD19, a B lymphocyte-associated antigen¹².

Despite ongoing progress towards cell-based treatments for various indications, creating new products remains a formidable undertaking, as treatment strategies tailored to specific diseases must overcome a series of grand challenges, listed here, to successfully generate products that are clinically and commercially viable (Fig. 1).

• A cell source (Box 1) needs to be identified that yields a product with robust and stable properties, and, for engineering purposes, is amenable to genetic manipulation.
• A cell-based product needs to harbour sufficient viability to ensure adequate duration of therapeutic action.
• Predictable and defined levels of therapeutic potency must be achieved by either redirecting existing cellular properties or engineering new ones.
• PK/PD properties of the cell must match the specific physiological needs of the disease.
• The safety and tumorigenicity profile of the cell therapy product must be ensured to limit adverse reactions with the host immune system and prevent tumour formation.
• Scalable manufacturing processes must be developed that can efficiently and affordably generate quantities of cells adequate for dosing patients….