July 15, 2024

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How to Design the Next Generation of Cell Therapies?

How to Design the Next Generation of Cell Therapies?

How to Design the Next Generation of Cell Therapies?

Cell-based therapies, involving the use of cells as active agents to treat diseases, have experienced explosive growth in both clinical applications and the pharmaceutical market in recent years.

Notably, some therapies have entered commercial applications, with the FDA approving tisagenlecleucel and Axicabtagene ciloleucel in 2017 for the treatment of acute lymphoblastic leukemia (ALL) and large B-cell lymphoma (LBCL), respectively.

Other recent successes include the approval of using patient-derived limbal stem cells to repair damaged corneal epithelium and using adult stem cells to treat fistulas associated with Crohn’s disease.

Currently, the number of clinical trials is expanding, and there is a growing array of commercially approved treatment methods.

However, despite recent significant clinical and commercial success, cell-based therapies still face numerous challenges, limiting their widespread translation and commercialization.

These challenges include determining appropriate cell sources, producing viable, effective, and safe products on a large scale to meet the specific needs of patients and diseases, and developing scalable manufacturing processes.

In response to these obstacles, scientists are employing new-generation engineering methods, including genome and epigenome editing, synthetic biology, and the application of biomaterials, to drive cutting-edge foundational research.

Advantages and Challenges of Cell Therapy

The enduring enthusiasm for cell therapy largely stems from the prospect of restoring inherent cell functions to achieve safety and efficacy beyond other treatment modalities.

While biologics, including recombinant proteins and other cell-derived biomolecules, can leverage the high molecular recognition capabilities to achieve high target specificity, they are prone to unfavorable pharmacokinetics (PK) and pharmacodynamics (PD) characteristics, limiting their safety and efficacy.

Cell therapies possess unique intrinsic features that could enhance therapeutic efficacy against diseases. For instance, cells can naturally migrate, localize, and even proliferate in specific tissues or organs. Additionally, cells can actively sense various external cues, including small molecules, cell surface marker proteins, or physical forces.

Therefore, cell-based therapies exhibit highly complex sensing and responsive functions, dynamically tracking disease states through detecting relevant molecular cues and providing multifactorial output responses, including activating intrinsic reactions or therapeutic transgene expression.

Finally, due to the ability of cells to survive in the body, consume nutrients, and influence their external environment through the secretion of factors, cell-based therapies can be utilized for sustained long-term endogenous drug delivery.

Despite progress in cell therapies for various indications, developing new products remains a daunting task, requiring treatment strategies for specific diseases to overcome a series of significant challenges to successfully produce clinically and commercially viable products.

How to Design the Next Generation of Cell Therapies?

Challenges include:

  1. Identifying cell sources to generate products with robust and stable characteristics that are amenable to genetic manipulation for engineering purposes.
  2. Ensuring cell-based products have sufficient vitality to sustain therapeutic effects for an adequate duration.
  3. Achieving predictable and determinable therapeutic efficacy levels by altering existing cell characteristics or designing new ones.
  4. Matching the PK/PD characteristics of cells with the specific physiological needs of the disease.
  5. Ensuring the safety and tumorigenicity of cell therapy products to limit adverse reactions from the host immune system and prevent tumor formation.
  6. Developing scalable manufacturing processes to efficiently and economically produce an adequate quantity of cells for patient use.

The Past and Present of Cell Therapy

Cell-based human therapies began in the 1950s with bone marrow transplants for hematologic cancer patients. The success of these treatments provided evidence of the potential of cell therapies for disease, paving the way for the approval of treatments derived from human umbilical cord blood for hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) over the past few decades. These products are widely used clinically, including various FDA-approved cell-based therapies.

However, these treatment methods faced significant obstacles in commercialization, including identifying easily procurable and manufacturable cell sources and addressing their interaction with the host immune system. These challenges posed persistent barriers to safety and efficacy, leading to only a few cell-based therapies gaining approval for market entry in the past decade.

The first groundbreaking non-HPC product was dendritic cell therapy for prostate cancer, where dendritic cells isolated from patients were exposed to recombinant tumor antigens in vitro, then reintroduced to promote T cell-mediated anti-tumor responses. While this sipuleucel-T therapy was hailed as the world’s first “personalized” cancer therapy upon FDA approval in 2010, its use was limited due to inconsistent efficacy and reimbursement uncertainty, consequences of the high cost and technical complexity of the manufacturing process. Other early-market drugs included using patient and donor-derived fibroblasts for local treatment of tissue injuries and using patient-derived chondrocytes to repair joint cartilage.

With the regulatory approval of the first CAR-T therapy by the FDA, the commercialization of cell therapies has significantly accelerated in the past decade. Currently, five CAR-T products targeting refractory multiple myeloma, as well as ALL and LBCL, have been approved for marketing. More clinical trials are underway, exploring various effector cells such as NK cells for a variety of solid and hematologic tumors, with some reporting breakthrough successes.

In addition to cancer therapies continuing to garner the most attention, clinical successes in several emerging fields have also captured interest. These include the treatment of autoimmune diseases, central nervous system (CNS) and neurodegenerative diseases, cardiovascular diseases, and various orphan diseases. Some of these therapies are developed using mesenchymal stem cells (MSCs), such as darvadstrocel for treating fistulas associated with Crohn’s disease, one of the few commercialized MSC products. Another notable product is remestemcel-L, which utilizes donor-derived, cultured-expanded bone marrow MSCs for the treatment of graft-versus-host disease (GvHD).

Currently, more therapies are making progress through clinical trials, utilizing cell products derived from pluripotent stem cells. Retinal pigment epithelial cells derived from induced pluripotent stem cells (IPSCs) are used to treat acute macular degeneration and Stargardt disease. Diseases of the central nervous system are another active area for such therapies, with several studies using IPSCs to generate dopamine-producing neurons for Parkinson’s disease, and some stem cell-based approaches in preclinical studies for stroke, epilepsy, spinal cord injury, Alzheimer’s disease, multiple sclerosis, and pain.

Innovations in Cell Engineering

Currently, researchers are exploring innovations in the field of cell engineering, including genome and epigenome editing, synthetic biology, and biomaterials, to address major challenges in cell therapy. While some of these methods have successfully been used to produce commercial products, many are still in the preclinical stage.

Genome and Epigenome Editing

The use of CRISPR/CAS9 as a programmable tool to design the human genome and epigenome in live cells has propelled the latest advances in cell therapy. Cas9-mediated non-homologous end-joining (NHEJ) has been used to silence pathogenic loci, remove harmful insertions, and confer resistance to viruses.

In addition to Cas9-mediated NHEJ targeting single gene loci, compound methods targeting multiple gene loci simultaneously have made substantial progress in recent years. For instance, the use of Cas9 mRNA and gRNAs targeting T cell receptor (TCR), β2-microglobulin (β2m), and PD-1 genes in a CRISPR–Cas9-based knockout strategy enabled allogeneic CAR-T cells, demonstrating the capacity to generate immune checkpoint gene-deficient CAR-T cells, which showed significant tumor suppression in xenografts.

How to Design the Next Generation of Cell Therapies?

The development of base editors is another innovative genome-editing tool in the field. Base editors are designed to convert a single nucleotide to another without causing double-strand breaks. This approach enables efficient introduction of precise point mutations without the need for homologous recombination, providing high specificity and low off-target effects. For example, the use of adenine base editors (ABEs) for CRISPR-free gene correction in human cells demonstrated up to 30% efficiency in editing at a single site. In the context of cell therapy, base editors have been used to induce specific mutations in T cells to enhance their therapeutic efficacy, such as engineering CAR-T cells to resist exhaustion or to target specific antigens.

Epigenome editing is another promising approach to modulate gene expression without altering the underlying DNA sequence. Epigenome editing tools, such as the CRISPR/dCas9 system, are used to target specific DNA methylation patterns, histone modifications, and chromatin structure to control gene expression. This technology allows researchers to precisely control the expression of genes involved in various cellular processes, including cell differentiation, immune response, and cell cycle regulation.

Synthetic Biology

The field of synthetic biology has emerged over the past two decades with the goal of making genetic engineering results more precise, predictable, and reproducible through the application of quantitative design rules. Although its earliest breakthroughs were in microbial systems, the field has also made significant progress in engineering human cells in recent years.

Cell-based therapies can be enhanced by precisely controlling the delivery of therapeutic transgene expression or secreted therapeutic factors, or by programming cells to sense biomolecules relevant to specific tissues or disease states and respond by altering cell behavior.

How to Design the Next Generation of Cell Therapies?

Recent successes in using synthetic biology to address specificity and activity in adoptive T-cell therapies demonstrate this family of approaches. One of the most successful applications in this area is a protein-safe kill switch designed to cause apoptosis in implanted cells. The chimeric design of the switch features human caspase9 fused to a modified human FK binding domain, capable of dimerizing and activating apoptotic signaling following administration of the small molecule drug AP1903. Although this switch was originally developed to eliminate alloreactive T cells during stem cell transplantation, it was subsequently used in clinical trials of CAR-T therapy to limit the proliferation of effectors in CRS (NCT03696784 ) .

An important recent focus of CAR-T synthetic biology has been the development of strategies to enhance tumor targeting specificity. One example is the design of receptor-mediated gene regulatory circuits, in which engineered chimeric Notch receptors fused to single-chain antibodies are triggered upon binding to ligands on adjacent cell surfaces, resulting in proteolytic release of the transcriptional activator and transgenes Express. This system was originally designed to express the CAR in the presence of a second ligand, thereby enabling bispecific recognition of antigen binding. With further development of synNotch, it may be possible to differentiate between specific tumors and bystander tissue.

Another major focus of synthetic biology is the development of closed-loop regulatory circuits that monitor physiological or disease state characteristics and respond to therapeutic outcomes. Strategies using transgenic reporters to alter native signal transduction pathways have been exploited. One example is the two-stage cytokine conversion circuit, which in the first stage converts TNF-α-dependent NF-κB signaling into IL-22 production, which then activates cytokine receptors and signals through STAT3, driving anti-inflammatory cytokines Transcriptional production and secretion of IL-10 and IL-4. In experiments in mice, cells containing this circuit reduced inflammation in a mouse model of psoriasis. Similarly, β-cell mimetic cells were constructed that introduced a circuit to sense glucose by linking glycolysis-mediated calcium entry to the induction of a transcriptional circuit that drives insulin expression and secretion. When implanted into diabetic mouse models, the engineered cells secreted insulin in a glucose-responsive manner, correcting insulin deficiency and reducing hyperglycemia.


Biomaterials play a crucial role in the development of cell therapies by providing a supportive environment for the survival, proliferation, and function of therapeutic cells. These materials can be engineered to mimic the natural extracellular matrix and create a microenvironment that promotes cell adhesion, growth, and differentiation.

One application of biomaterials in cell therapy is the development of cell encapsulation systems. These systems involve encapsulating therapeutic cells within biocompatible materials to protect them from immune attack, enhance their survival, and provide controlled release of therapeutic factors. Encapsulation can be achieved using hydrogels, microcapsules, or other polymeric materials.

Biomaterials are also used to create scaffolds for tissue engineering applications. These scaffolds provide a three-dimensional structure that supports cell growth and tissue formation. In tissue engineering, biomaterials are designed to mimic the native tissue’s mechanical and biochemical properties, facilitating the regeneration of damaged or diseased tissues.

Current Challenges and Future Directions

While advancements in cell engineering offer promising avenues for the development of next-generation cell therapies, several challenges and considerations must be addressed to ensure the successful translation of these technologies into clinical applications.

  1. Off-Target Effects and Safety Concerns: Genome and epigenome editing technologies, while powerful, may lead to unintended off-target effects. Ensuring the specificity and safety of these editing tools is crucial for preventing unintended genomic alterations and potential adverse effects.

  2. Scalability of Manufacturing: One of the significant challenges in cell therapy is the scalability of manufacturing processes. As the field moves towards personalized and allogeneic therapies, developing cost-effective and scalable manufacturing methods becomes essential to meet the increasing demand.

  3. Immunogenicity and Host Interactions: Understanding the host immune response to engineered cells is crucial for predicting potential immunogenicity and ensuring the long-term safety and efficacy of cell therapies. Strategies to minimize immune recognition and improve the persistence of therapeutic cells are actively being explored.

  4. Regulatory Considerations: The regulatory landscape for cell therapies is evolving rapidly. It is essential to establish clear regulatory frameworks that ensure the safety, efficacy, and quality of next-generation cell therapies. Collaborations between researchers, clinicians, industry, and regulatory bodies are crucial for navigating the regulatory landscape.

  5. Integration of Multiple Technologies: Next-generation cell therapies often involve the integration of multiple technologies, such as genome editing, synthetic biology, and biomaterials. Coordinating these technologies to work synergistically and optimizing their combined effects present both scientific and engineering challenges.

  6. Ethical and Social Implications: The development and application of advanced cell therapies raise ethical and social considerations, including issues related to consent, privacy, and the equitable distribution of benefits. Addressing these concerns is essential for building public trust and ensuring responsible development and use of these technologies.

As researchers continue to push the boundaries of cell therapy, collaboration across disciplines, transparent communication, and a commitment to ethical considerations will be key to realizing the full potential of next-generation cell therapies.

By overcoming current challenges and addressing emerging issues, the field is poised to witness transformative breakthroughs that could revolutionize the treatment of a wide range of diseases.

How to Design the Next Generation of Cell Therapies?


1.Engineering the next generation of cell-based therapeutics. Nat Rev Drug Discov.2022 May 30 : 1–21.

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