Cell Therapy in the Clinic: A Basic Overview

A Basic Overview

Cell therapy refers to the process of sending living cells into the patient's body to regulate, replace or eliminate abnormal cells, so as to achieve regenerative repair or immunotherapy. Global cell therapy products are divided into three categories: stem cells,blood cells, andtissue-specific cells (such as skin cells, chondrocytes) .

Five years ago, the number of clinical trials of mesenchymal stem cells alone exceeded the sum of the number of all immune cells. And now it is just the opposite, the number of T cell clinical trials alone exceeds the number of all stem cell trials. This is mainly due to the clinical success .

Various cell therapies in clinical trials (1705 total). T cell clinical research dominated (767 items), followed by stem cells (620 items), DC (136 items), NK cells (116 items), microorganisms (48 items), red blood cells (39 items), mononuclear cells (27 items) items) and platelets (7 items).

Tissue-specific cells are mainly used in regenerative medicine and tissue engineering applications, for example, autologous skin cells for the treatment of burns and scalds and autologous chondrocyte scaffolds for repairing cartilage defects , etc. Although this category also belongs to cell therapy products, since they are used as tissue scaffolds rather than single-cell suspensions , this is not discussed in this article.

A total of 1,705 live cell therapy clinical trials were screened and classified according to cell type, general indication, trial stage, and cell source.

Current status of cell therapies in clinical trials: All cell therapy clinical trials, including blood cells, stem cells, and microbes. Cell types include T cells, NK cells, mononuclear cells, DCs, erythrocytes, platelets, stem cells, and microorganisms. Indications include cancer, infectious disease, autoimmune disease, non-autoimmune inflammatory disease, cardiovascular disease, transplant-related disease, trauma, blood disease, degenerative disease, metabolic disorder, etc.

Clinical trials of cells in blood: Cells in the blood include white blood cells, red blood cells and platelets. Currently only T cells and DCs are approved as therapeutic products on the market. Most of the approved T cell products are CAR-T therapies for hematologic malignancies, while DC products are used as tumor vaccines for solid cancers . Although red blood cells and platelets are not medicines, they are widely used in clinical blood transfusion.

White blood cells

In white blood cell clinical trials, T cells accounted for the dominant position (45%) , followed by DC (8%) , NK cells (7%) and mononuclear cells (2%) . It is not surprising that the main indications for T cells, DCs and NK cells are cancers ( 85% in T cells ; 93% in DCs ; 95% in NK cells ) , since they are themselves in Plays a major role in anticancer immunity.

1. T cells are adaptive immune cells capable of directly clearing mutated or infected host cells, activating other immune cells, and producing cytokines to regulate immune responses.
2. NK cells are innate immune cells that destroy tumor cells and virus-infected cells through granule release of lytic molecules and rapid production of pro-inflammatory cytokines.
3. DCs are professional antigen-presenting cells (APCs) that regulate adaptive immune cells by transporting antigens to draining lymph nodes and presenting them to CTL and Th cells.

In cancer therapy, T cells and NK cells are used as cytotoxic drugs, while DCs are mainly used as cancer vaccines. From the perspective of cell sources, T cells (74%) and DCs (87%) were mainly autologous cell therapy, because allogeneic cells would increase the risk of transplant rejection.

Although the leukocytes mentioned above are mainly used in the treatment of cancer, there are also remaining mononuclear cells used in cardiovascular disease (39%) and cancer (29%) . Mononuclear cells mainly refer to: monocytes, macrophages, bone marrow mononuclear cells (BMMC) or peripheral blood mononuclear cells (PBMC).

1. Monocytes are circulating cells of the innate immune system that extravasate into tissues during inflammation, infection or injury. Once in tissues, they eventually differentiate into macrophages, a type of tissue-resident innate immune cell that (i) engulfs dead cells, debris, and foreign matter/pathogens (ii) modulates the innate immune response, and (iii ) to maintain homeostatic growth, repair and metabolism.
2. Bone marrow mononuclear cells are a heterogeneous cell population composed of lymphocytes, myeloid cells, hematopoietic stem cells and bone marrow mesenchymal stem cells. Due to their ability to differentiate into distinct lineages, they have important clinical applications in cardiovascular tissue regeneration.
3. Similar to BMMCs, PBMCs also contain a variety of cells, including lymphocytes, monocytes, and a small amount of DCs, mainly for cancer.

Currently, there are no phase 4 trials of mononuclear cell therapy . In addition, mononuclear cell therapy was predominantly autologous (89%) , possibly because of a reduced risk of graft rejection and GVHD.

Red blood cells and platelets

Red blood cells and platelets, commonly used as cell therapy for blood disease treatment and transfusion trauma care, accounted for 2% and less than 0.4% of cell therapy trials, respectively.

Red blood cell therapy is used to replace lost or dysfunctional cells to maintain homeostasis. Red blood cells are key transporters of oxygen and nutrients to tissue cells, are also responsible for communication between major organs, and play important roles in regulating pH, redox homeostasis, and molecular metabolism. Thus, problems with red blood cell integrity and/ or number can lead to serious pathological problems and increase the incidence of vascular disease. Also, under normal conditions, platelets are key elements in blood vessels by regulating hemostasis and thrombus formation in the event of vessel injury. Thrombocytopenia (a lack of platelets) from trauma or a blood disorder can lead to bleeding into tissue or uncontrolled bleeding from a wound.

In the clinical setting, red blood cell and platelet therapy is dominated by allogeneic donor cells ( 77% and 86%, respectively) . Nonetheless, the use of allogeneic RBCs requires a blood type match between the donor and recipient. The work of clinical trials of red blood cells and platelets is currently focused on optimizing blood transfusion protocols and verifying the durability of transfused cells.

Stem Cell Clinical Trials

Currently approved stem cell therapies include hematopoietic stem cells (HSCs) , mesenchymal stem cells (MSCs) , and limbal stem cells (LSCs) . HSC products are primarily approved for the treatment of blood disorders. MSCs therapy is applicable to a variety of diseases, including cardiovascular disease, graft-versus-host disease (GVHD) , degenerative diseases, and inflammatory bowel disease. The only limbal stem cell product approved for LSC deficiency. Stem cells account for 36 percent of current cell therapy clinical trials. Stem cell therapy trials, mainly clinical trials of hematopoietic stem cells and mesenchymal stem cells, cover a wide range of indications.

Hematopoietic Stem Cells (HSCs)

Hematopoietic stem cells are a type of pluripotent stem cell capable of self-renewing and differentiating into mature blood cells, forming cells of the myeloid and lymphoid lineages. Therefore, hematopoietic stem cell transplantation (HSCT) can be used to rebuild the hematopoietic and immune system to treat inherited and acquired blood disorders. HSCT is also often used to treat blood cancers after myeloablative therapy has eliminated the cancer cells. While autologous HSCs or matched allogeneic donor HSCs are the most ideal candidates for HSCT because of the reduced risk of GvHD, graft rejection, and engraftment syndrome, allogeneic HSCs have advantages in cancer therapy because they can induce graft resistance. tumor effect.

Mesenchymal stem cells (MSCs)

Mesenchymal stem cells are also a type of pluripotent stem cells capable of differentiating in vitro into multiple cell types in mesoderm (eg, chondrocytes) , ectoderm (eg, nerve cells), and endoderm (eg, hepatocytes) . MSCs are widely used in clinical trials to treat degenerative diseases, autoimmune diseases, inflammatory diseases and trauma, etc. Notably, the majority of MSCs therapeutic trials are in the early stages, with almost equal numbers in phase 1 (44%) and phase 2 (47%) , showing their potential to have a huge impact on the future range of cell therapy.

Microbiology Clinical Trials

Recently , microbiome therapy emerged as a promising class of cell therapies for the treatment of infections and cancers. Microorganisms accounted for 3% of the total trials, with major indications including cancer (44%) , infectious disease (19%) and inflammatory disease (13%) . Although metabolic disorders-associated diseases account for only 8% of microbial indications, this unique niche is worth mentioning because few indications have been investigated for cell therapy.

Microorganisms exert therapeutic action mechanisms in two ways :

1. Displace pathogenic flora to restore symbiosis;
2. Generating therapeutic biomolecules through genetic modification.

Summary

The cell therapies presented here focus on blood cells (T cells, natural killer cells [NK], red blood cells [RBC], dendritic cells [DC], mononuclear cells, and platelets) and stem cells (hematopoietic stem cells [HSC] , mesenchymal stromal stem cells [MSCs] and limbal stem cells) . In addition, microbial therapy has recently emerged as a promising type of cell therapy for the treatment of infections and cancers.

Cell therapy is currently one of the most studied treatment modalities in preclinical and clinical settings, with many cell therapy products already approved and many more in active clinical investigation. We will continue to talk about the marketed products and clinical trials of cell therapy in the next issue.