Advanced Drug Modalities Part 1: Cell Therapies
Article summary
Cell therapies, which utilize living cells as therapeutic agents, are an advanced drug modality that represents a groundbreaking approach in medicine to treat or prevent diseases. These therapies include autologous, allogeneic, and emerging xenogeneic types, leveraging the dynamic response and complex mechanisms of living cells for therapeutic purposes, particularly in stem cell and immune cell-based applications.
Stem cells offer unparalleled potential in regenerative medicine and hematologic malignancies. The evolution of stem cell-based therapies began with bone marrow transplantation and more recently expanded to include various stem cell types like hematopoietic stem cells, mesenchymal stem cells, and pluripotent stem cells, each offering unique capabilities.
Modified immune cells like dendritic cells and T-cells are the basis for the majority of FDA-approved cell therapies currently available to patients. Pioneering therapies like Provenge and various CAR-T therapies have revolutionized cancer treatment by modifying a patient's own immune cells to target and destroy cancer cells, marking significant milestones in personalized cancer therapy.
Despite their transformative potential, cell therapies face challenges in safety, manufacturing, and regulation. Issues like undesired immune responses, manufacturing complexity, and regulatory hurdles are nevertheless being addressed through ongoing research and innovation.
Understanding Cell Therapies and Their Mechanisms of Action
Cell therapies, often hailed as a breakthrough in medicine, represent a cutting-edge living drug modality, where living cells are administered to patients for treating or preventing various diseases. Because the cells are living, they can dynamically respond to physiological changes and have complex and unique mechanisms of action. Further, cells can be manipulated outside the body and modified, for example via genetic engineering, before being administered to patients.
Cells used in cell therapies can either originate from the patient and their function is redirected to treat the patient’s disease (autologous cell therapy) or can be obtained from donors and administrated in the patient (allogeneic cell therapy). Additionally, xenogeneic cell therapies, involving cells from different species, are emerging as a novel approach, although they are still in the early stages of development.
Cell therapies can be stem cell-based and non-stem cell-based.
What are stem cells? Stem cells can be regarded as the raw material of the body. They are undifferentiated cells with the unique ability to develop into various specialized cell types. Stem cells serve as the foundation for tissue and organ formation during development and possess the capacity for self-renewal, enabling them to replicate and maintain a pool of undifferentiated cells.
Stem cell-based therapies have a major application in regenerative medicine and in treating hematologic malignancies:
In regenerative medicine, stem cell therapies are applied to repair or replace damaged tissues and organs by harnessing the ability of stem cells to differentiate into various cell types and regenerate affected areas.
In treating hematologic malignancies, stem cell therapies, particularly hematopoietic stem cell transplantation, are used to replenish the patient's blood and immune cells after chemotherapy or radiation, effectively replacing malignant cells with healthy ones.
Furthermore, stem cells have the unique capability to form organoids, which are simplified versions of organs. Organoids can be used as models of disease states and to evaluate the effects of drugs and thus offer immense potential in drug discovery.
Non-stem cell-based therapies, particularly those using immune cells, are increasingly utilized in oncology for the treatment of a wide spectrum of cancers, showing great promise in targeting and destroying cancer cells.
Tracing the Evolution of Stem Cell Therapies
The journey of cell therapies began over half a century ago with bone marrow transplantation – the transfer of cells from a healthy to a diseased patient to replace diseased bone marrow. Tracing back to 1956, the first bone marrow transplantation marked a significant milestone in treating leukemia, a type of blood cancer. 1959 witnessed the first transplant of hematopoietic stem cells (HSCs). HSCs, which are mostly found in the bone marrow and give rise to all mature blood cells, have been a standard treatment for various types of blood cancer. In recent years, stem cell focus has expanded from HSCs to mesenchymal stem cells (MSCs). The latter are of non-hematopoietic origin and are mostly present in the bone marrow, adipose tissue, placenta, and blood. While HSCs are an established modality in regenerative medicine, MSCs are at an investigational stage. MSCs are of particular interest since cell therapies based on MSCs could have a unique combination of mechanisms of action, including immunomodulatory and anti-inflammatory properties, and high potential as regenerative agents because of their ability to differentiate into different types of cells. Beyond HSCs and MSCs, pluripotent stem cells (PSCs) and induced PSCs (iPSCs), the later derived from reprogrammed differentiated adult cells, are being explored as regenerative medicine modalities.
FDA-approved Cell Therapies are Transforming Cancer Treatment
Most FDA-approved cell therapies are based on differentiated immune cells, using either dendritic cells (DCs) or T-cells. DCs are antigen-presenting cells that regulate the adaptive immune response by presenting antigens to other immune cells, while T-cells are adaptive immune cells that can directly eliminate other cells. Provenge, recognized as the first FDA-approved cell therapy, pioneered autologous cell immunotherapy. In this cell immunotherapy, patient’s DCs are extracted, exposed to prostate cancer antigens to activate them, and then reintroduced into the patient, where the activated DCs help develop an immune response against cancer cells (Figure 1A, left). This cell therapy can also be regarded as the first personalized cancer therapy, a major advancement in the application of personalized cell therapies in medicine.
The majority of FDA-approved T-cell therapies are chimeric antigen receptor (CAR) T-cell therapies in which T-cells are reprogrammed to attack cancer cells (Figure 1A, right). CAR-T therapies are based on extracting patient’s T-cells, genetically engineering these cells to introduce the CAR component, and then infusing the engineered cells back into the patient to fight cancer. The two essential components of a CAR are an extracellular antigen-binding domain that specifically targets cancer cell antigens and an intracellular signaling domain that activates the T-cell response and the subsequent destruction of cancer cells by the T-cell (Figure 1B).
Figure 1. Cell immunotherapies. A. On the left, the main stages of dendritic cell autologous cell therapy. Immature dendritic cells (DCs) isolated from a patient undergo maturation after which they are loaded with cancer antigens and administered into the same patient. On the right, the main stages of chimeric antigen receptor T-cell (CAR-T) therapy. T-cell isolated from patients are engineered (reprogrammed) to express a CAR for a specific cancer antigen and after CAR-T cells undergo multiplication are administered into patients. A single CAR is depicted, with its extracellular antigen binding domain in green and the intracellular signaling domain in orange. B. The overall architecture of a CAR. Colors as in A.
Currently, there about half a dozen FDA-approved CAR-T therapies, with the first such therapy approved by the FDA in 2017 (Table 1): Yescarta, Kymriah, Abecma, Tecartus, Breyanzi, and Carvykti. Building on the success of CAR-T therapies, T-cell receptor (TCR) therapies are now being developed, with the main functional distinction being that while the CAR is an engineered chimeric receptor, TCR is a naturally occurring (or minimally modified) cell surface receptor with potentially enhanced function towards solid cancer indications. The clinical success of CAR-T therapies for cancer indications has led to the ongoing development of cell-based therapies for a broad variety of indications, including autoimmune diseases, neurodegenerative disorders, and cardiovascular conditions.
Table 1. List of approved CAR-T therapies, together with their indications and year of approval.
Understanding the Advantages of Cell Therapies
Cell therapies have unique advantages over other drug modalities.
Unique and Complex Mechanisms of Action. Cell therapies have unique and complex mechanisms of action which extend well beyond the mechanisms of action of more established drug modalities such as small molecules and antibodies. For example, activation of CAR-T cells triggers a complex immune response in which T-cells undergo proliferation and secretion of various immunomodulatory molecules such as cytokines and chemokines which further amplify the immune response to cancer cells. Cytokines and chemokines also attract other immune cells to the site of action, enhancing the activation of neighboring T-cells, and exerting anti-tumor effects.
High Selectivity. Cell therapies can be highly focused, exerting their effects where they are most needed. For example, CAR-T cells specifically recognize molecules that are primarily exposed on the surface of cancer cells, allowing CAR-T cells to selectively target cancer cells.
Personalized Therapies. Autologous cell therapies enable personalized medicine strategies. Because they involve the use of patient’s own cells, autologous cell therapies reduce the risk of immune rejection and can enhance efficacy and improve safety.
What is therapeutic efficacy? Efficacy refers to the ability of a drug to produce a desired therapeutic effect or clinical benefit when administered under specific conditions. It is a measure of the drug's ability to produce the intended physiological or pharmacological response in patients.
Tissue regeneration. Stem cell-based cell therapies have the unique advantage of being able to regenerate tissues, enabling regenerative medicine approaches. Because stem cells are undifferentiated, when introduced into the patients, stem cells can differentiate into various other cell types and contribute to the repair and regeneration of damaged tissues.
Understanding and Addressing the Key Challenges and Limitations in Cell Therapy
Cell therapies have unique characteristics that clearly differentiate them from other drug modalities and allow patients to benefit from their complex mechanisms of action. To become an established therapeutic modality, cell therapies are yet to overcome a number of challenges and limitations, including but not limited to safety, manufacturing, and regulatory challenges.
Safety limitations. Allogeneic cell therapies use non-patient cells, which can be immunogenic and can cause unwanted immune responses and rejection of the cell therapy by the patient’s immune system. A strong immune response towards the cell therapy can lead to loss of efficacy and toxicity. While immunosuppression can alleviate immunogenic effects, suppression of the immune system leaves the patient susceptible to a plethora of infections. Further, even for autologous cell therapies, in which the patient’s own cells are used, the CAR itself can be immunogenic. Finally, certain types of cell therapies are associated with increased risk of uncontrolled cell division and cancer. For example, a recent announcement by the FDA underscored the potential safety limitations of certain CAR-T cell therapies:
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.”
The potential for safety issues is further underscored by the recent request from the FDA to add boxed warning to all CAR-T products prescribing information, warning patients for the risk of developing T-cell malignancies following therapy.
Manufacturing challenges. The manufacturing of cell therapies, from extraction from a donor or a patient to administration into a patient, is a highly complex process with each step having its unique challenges and complexities. For example, extracted cells can undergo a number of procedures, including culturing, cell activation, genetic engineering, selection, proliferation, and quality control. Securing a reliable source of cells, whether autologous or allogeneic, proves to be a persistent challenge, given the variation among donor sources, tissue sources, cell subpopulations, and cell functional states. Additionally, ensuring the stability of cell therapies over the long term requires careful consideration to maintain cell viability, functionality, and, safety. All these complexities add to the batch-to-batch variation which in turn complicates clinical trials. Finally, the high cost associated with manufacturing, particularly for personalized therapies, imposes a barrier to accessibility.
Regulatory challenges. The rapid pace of innovation in cell therapies makes it challenging for harmonized regulatory frameworks to develop. Because of the variability in cell sources and manufacturing idiosyncrasies associated with different cell therapies, it is challenging to establish standardized manufacturing practices. Further, batch-to-batch inconsistencies are often observed due to source and cell population heterogeneity. The fast-paced innovation in cell therapies and the application of novel cell types also means that long-term follow-up is required to monitor safety and patients for adverse effects. The personalized nature of certain cell therapies introduces further complexities in the regulatory approval.
While cell therapies indeed face challenges in safety, manufacturing, and regulation, ongoing research and innovation are actively addressing these issues, offering promising solutions to address these challenges. For example, RNA therapeutics such as small interfering RNAs (siRNAs) offer a potential way to improve the safety and efficacy of both autologous and allogeneic CAR-T-cell therapies by silencing specific RNA transcripts, potentially overcoming some of the challenges related to undesired immune reactions and off-target effects. In another example, the implementation of a continuous closed-system processing method offers a way to improve the scalability and the efficiency of cell therapy manufacturing and thus help address manufacturing challenges. This approach could lead to more consistent manufacturing and help reduce batch-to-batch variation.
As we continue to witness the remarkable evolution of cell therapies, their potential to transform medicine becomes increasingly evident. This advanced drug modality not only offers new ways for treating complex diseases but also paves the way for a more personalized and effective approach to medicine.
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