What Factors Limit the Adoption and Development of Cell Therapy?

Cell Therapy

Cell therapy can be divided into three primary categories: stem cell-based, non-stem cell-based, and multicellular therapies. Each class has unique challenges as a treatment, but common limitations connect them.

Before diving into the limitations of these treatments, it is crucial to understand what cell therapy is and which conditions it addresses. Cell therapy refers to any treatment that replaces damaged cells with healthy cells. Alternatively, cell therapy can involve reprogramming immune cells to target and remove dysfunctional cells. Cell therapy can also be combined with gene therapy for cell-based gene therapies.

The United States Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) notes that immunotherapies, cancer vaccines, and autologous or allogenic cells for therapeutic indications fall under the umbrella of cell therapy.

Cell therapies have a multitude of uses. For example, stem cell-based cell therapies have been explored for multiple kinds of leukemia, multiple myeloma, and myelodysplastic syndromes (MDS). Other applications include treatments for inherited immune system disorders, autoimmune disorders, neurological disorders, cardiovascular disease, diabetes, liver disease, kidney disease, lung disease, musculoskeletal and connective tissue disorders, gastrointestinal disorders, skin disorders, and ocular diseases.

Non-stem cell-based therapies, such as chimeric antigen receptor T-cell therapy (CAR-T cell therapy), have addressed cancers like non-Hodgkin’s lymphoma. Multi-cellular treatments such as bone marrow or stem cell transplants may address plasma cell disorders, immune deficiencies, aplastic anemia, and cancer.

General Limitations

At a glance, the multitude of applications of stem cell therapy may make it seem like a miracle therapy. However, some limitations have presented adoption barriers. These limitations may include raw material availability, procedural and manufacturing challenges, and costs.

From the biological standpoint, identifying and isolating the appropriate cell type for cell therapy can be a significant challenge. Like most clinical research and discoveries, determining the mechanisms and quantifying outcomes is particularly challenging, requiring extensive pre-clinical studies.

AstraZeneca notes, “Cell therapies also bring their own unique set of challenges. Due to their novelty, their production typically requires non-conventional raw materials, which may result in an inconsistent supply of products, along with issues related to logistics surrounding low-temperature storage and shipping.”

According to an article published by the company, manufacturing challenges are some of the most significant barriers to the widespread adoption and development of cell therapies. Limitations in the manufacturing process can be divided into two categories: biological and regulatory constraints.

Case Study CAR-T Cell Therapy

CAR-T cell therapy has become a critical tool in oncology and has many applications in cancer treatment.

The treatment is an autologous cancer immunotherapy where a patient’s T-cells are modified to express chimeric antigen receptors (CARs) on the cell surface. The modified T-cells are called chimeric antigen receptor T-cells (CAR-T cells), which can target and attack cancer cells to treat cancer.

A review published in Blood Research on April 30, 2023, notes that there are six available CAR-T cell therapies in the United States:

• Axicabtagene ciloleucel
• Brexucabtagene autoleucel
• Idecabtagene vicleucel
• Lisocabtagene maraleucel
• Tisagenlecleucel
• Ciltacabtgene autoleucel

The first two FDA-approved CAR-T cell therapies in the United States were Novartis’ Kymeriah in August 2017 to treat B-cell acute lymphoblastic leukemia (ALL) and Gilead/Kite Pharma’s Yescarta to treat subtypes of non-Hodgkin’s lymphoma (NHL): diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).

There are multiple limitations of CAR-T cell therapies that present barriers to CAR-T cell therapy uptake. As CAR-T cell therapy becomes a more popular version of cell therapy, it is critical to understand how these limitations may affect its use and adoption.

Side Effects

One of the primary limitations of these treatments is the potentially life-threatening adverse side effects associated with care. For example, Kymeriah and Yescarta can cause cytokine release syndrome (CRS), a systemic inflammatory response that causes high fever, reduced blood pressure, and difficulty breathing. Additionally, the therapies can cause toxic encephalopathy characterized by confusion, delirium, seizures, and cerebral edema — collectively, this condition is called CAR-T-related encephalopathy syndrome (CRES).

Treatment Duration

Beyond the side effects linked to CAR-T cell therapy, the duration of treatment can also present an additional barrier. The time between extracting a patient’s T-cells and administrating the personalized medicine, also called the vein-to-vein time, can be 3–4 weeks. According to an article in Cell and Gene, the delayed time to treatment can be a significant barrier for patients and providers hoping to start patients on therapy promptly.

Patient Eligibility

Another current limitation of CAR-T is the necessary treatments required before patients can initiate CAR-T. For example, to be eligible for Kymriah, patients must have had two ineffective systemic therapies.

Limited eligibility of patients presents an additional barrier to care.

Additionally, limitations can depend on the type of cancer a patient has. This treatment avenue has been predominantly used for hematological malignancies and blood cancers, but more evidence is needed on its applications in solid tumors.

According to a Stem Cell Research and Therapy review, hematological malignancies typically express one unique marker. In contrast, solid tumors may express a multitude of biomarkers, making it more challenging to develop a treatment for each patient.

The review notes, “In general, a tumor microenvironment with multiple cells and inhibitory agents can restrict the influence of CAR T cell treatment. A large number of studies have focused on enhancing CAR T cell function by modifying their metabolic profiles to improve cell activity in hostile environments.”

Provider Limitations

Beyond patient-centric barriers, there are multiple limitations on the healthcare provider's end. For example, referring patients to CAR-T can be extraordinarily complicated. Oncologists must refer patients to a specialist in CAR-T before a patient can initiate treatment.

Additionally, the complexities of CAR-T cell therapy led the FDA to regulate and restrict CAR-T cell programs, requiring certifications for healthcare facilities and providers and enforcing risk evaluation mitigation strategies (REMS).

“Training of HCPs is a mandatory step toward getting a center certified as a CAR-T cell specialist center. The long training process and the increasing demand for CAR-T cells, however, are increasing patient waiting lists as new centers await certification,” noted a Cell and Gene article.

Gaps in Understanding

Additionally, a research gap in understanding the position of CAR-T cell treatment in the healthcare process presents an additional challenge. Ongoing research and clinical trials may provide further insight into treatment utility.

Manufacturing Challenges

Finally, developing personalized therapy can be difficult, littered with manufacturing challenges. For example, production failures throughout the generation of autologous CAR-T cells can cause significant delays and setbacks for patients.

In addition, because the treatment is so personalized, manufacturers and drug developers have difficulty scaling up the treatment to meet demand and maintain quality.

Costs

The cost of therapy can also be a considerable barrier to accessing care. According to Cell and Gene, CAR-T cell therapy can cost between $373,000 and $475,000 per infusion, excluding patient management and care costs. The Centers for Medicare and Medicaid Services (CMS) typically only reimburses 50–65% of the total cost of treatment.

As the cell therapy industry expands, researchers must address these limitations to widen the reach of these life-saving treatments.