Cell Products Approved for Marketing

Cell therapy is currently one of the most studied treatment modalities in preclinical and clinical settings, and many cell therapy products have been approved. Currently, there are 32 approved cell therapy products worldwide , including 11 types of immune cells and 21 types of stem cells . Notably, many approved cell therapies are being developed for new indications.

Below, we will introduce cell therapy products that have been approved for marketing by regulatory agencies in various countries.

Clinically Approved Cell Products Worldwide: For immune cells, currently only T cell and DC products are approved for marketing . Most of these T cell products are CAR-T therapies for hematological malignancies , while DC products are vaccines for solid tumors .

Clinically Approved Immune Cell Products: At present, a total of 8 T cell-related products have been approved worldwide, including 5 CAR-T products approved by the US FDA and 2 CAR-T products approved by the Chinese NMPA . Interestingly, Korea KFDA approved 1 CIK product .

The two basic parts of CAR include the extracellular target-binding domain for recognizing cancer cell surface antigens and the intracellular signaling part, which consists of co-stimulatory and activation domains, which initiate processes including activation, amplification and cell killing. Notably, all approved CAR-T products are autologous and contain CARs targeting CD19 ( CD19 is a B cell surface marker ) .

1. CAR-T cell therapy

At present , a total of 7 CAR-T products have been approved for marketing in the global market . In 2017, the US FDA approved Kymriah, the world's first CAR-T cell therapy. Kymriah is suitable for relapsed, refractory and juvenile B-cell acute lymphoblastic leukemia (ALL) , mainly for adolescents and children. In 2020, Tecartus, the third CAR-T product, was approved by the US FDA. Tecartus is indicated for the treatment of adults with r/r mantle cell lymphoma (MCL) , an aggressive, rare form of non-Hodgkin lymphoma.The Tecartus preparation process includes a step to enrich the T cell population and remove circulating tumor cells (CTCs ) from the patient's peripheral blood mononuclear cells (PBMCs ) . The aim is to prevent the activation and subsequent exhaustion of CAR-T cells during in vitro preparation.

2. CIK cell therapy

Currently, only one CIK product has been approved for marketing in the global market . ImmunCell-LC is an autologous cytokine-induced killer (CIK) cell therapy, which was approved by KFDA in South Korea in 2007 and granted the orphan drug designation by FDA in 2018. It is used as an adjuvant therapy after resection of hepatocellular carcinoma, brain tumors, and pancreatic cancer by removing residual tumor cells. ImmunCell-LC is prepared by isolating peripheral blood mononuclear cells (PBMC) , and then stimulating and culturing with IL-2 and anti-CD3 antibody, and finally obtains an activated mixed group of heterogeneous T cells.

3. DC cells

At present , a total of 3 DC products have been approved for marketing in the global market . DC vaccines are another active area of ​​immune cell therapy, mainly using autologous cells. In 2010, Provenge was approved by the FDA for the treatment of hormone-refractory prostate cancer . Provenge is the first DC therapy approved by the US FDA and the only DC therapy approved by the FDA. In 2007, the autologous DC therapy CreaVax was approved by Korea KFDA for the treatment of renal cell carcinoma . In 2017, the autologous DC therapy APCeden was approved by the Indian CDSCO for the treatment of prostate cancer, ovarian cancer, colorectal cancer and non-small cell lung cancer .

Clinically Approved Stem Cell Products

Up to now, a total of 21 stem cell products have been approved globally , 12 of which have been approved by the US FDA or the European EMA. The remaining 9 products are mainly approved in Asia. It is worth noting that the approved products are mainly composed of hematopoietic stem cells or mesenchymal stem cells. In addition, there is a limbal stem cell product.

Hematopoietic Stem Cells (HSCs)

There are currently 10 hematopoietic stem cell therapies approved worldwide . Among them, the US FDA has approved 8 kinds of cord blood products, all of which are used for the treatment of hematopoietic stem cell transplantation. The EU EMA approved two gene therapies based on autologous hematopoietic stem cells, Strimvelis for adenosine deaminase deficiency (ADA-SCID) , and Zynteglo for the treatment of transfusion-dependent thalassemia.

Umbilical cord blood hematopoietic stem cells have more advantages than allogeneic hematopoietic stem cells from other sources (such as bone marrow, peripheral blood) . Because cord blood is more readily available and has a higher tolerance for human leukocyte antigen (HLA) mismatches, the risk of GVHD is lower.

In addition, both Strimvelis and Zynteglo are EMA-approved gene therapies based on autologous hematopoietic stem cells.

1. In 2016, the EMA approved Strimveli for the treatment of adenosine deaminase deficiency (ADA-SCID), an immunodeficiency disorder caused by mutations in the gene encoding adenosine deaminase (ADA).
2. In 2019, the EMA approved Zyntegl, indicated for the treatment of transfusion-dependent thalassemia, an inherited disease caused by mutations in the beta-globin gene, resulting in a marked reduction or absence of hemoglobin in adults.

Mesenchymal stem cells (MSCs)

At present , there are 10 kinds of mesenchymal stem cell products approved globally , but none of them has been approved by the US FDA. According to the mechanism of action and approved indications, MSCs products can be divided into two categories: tissue repair and immune regulation .

Among them, three MSCs products have been approved for tissue repair applications.

1. In 2011, Korea KFDA approved Cellgram, a tissue repair product based on MSCs ,  for the treatment of acute myocardial infarction.
2. In 2012, the Korean KFDA approved another MSCs-based tissue repair product, Cartistem, for repetitive and/or traumatic cartilage degeneration, including degenerative osteoarthritis.
3. In 2010, the Korean KFDA approved Queencell, an autologous fat-derived cell product , suitable for the treatment of subcutaneous tissue defects. However, Queencell is not composed of a single MSCs, but a mixture of MSCs, pericytes, mast cells, fibroblasts, and endothelial progenitor cells, similar to SVF.

MSCs have immunomodulatory functions and can be used to regulate immune responses in various diseases. Among them, seven MSCs products have been approved for indications including Crohn's disease (Alofisel, Cupistem) , acute graft-versus-host disease (Prochymal, TEMCELL) , amyotrophic lateral sclerosis (NeuroNata-R) , spinal cord injury (Stemirac ) and critical limb ischemia (Stempeucel) due to Buerger's disease .

1. Alofisel, an allogeneic fat-derived MSCs product. The only MSCs product approved by EMA, the indication is complex perianal fistula in Crohn's disease. The main mechanism of action is that MSCs inhibit the proliferation of activated lymphocytes, thereby reducing the production of pro-inflammatory cytokines.
2. Cupistem, an autologous fat-derived MSCs product. It was approved by Korea KFDA in 2012, and the indication is complex perianal fistula in Crohn's disease.
3. Prochymal, an allogeneic bone marrow-derived MSCs product. It was approved by the Canadian CFIA in 2012, and the indication is steroid-refractory acute GVHD in children.

Notably, in a Phase 3 clinical trial, Prochymal was used in children with SR-aGvHD after failure of first steroid therapy, showing safety, tolerability and efficacy as first-line treatment. However, the FDA refused to approve it. The reason given by the FDA was that the trial data came from a single-arm trial rather than a randomized trial. It is recommended to do at least one more randomized trial data.

Some of these MSCs products (e.g. Cellgram, Cartistem, Prochymal) are being evaluated in current clinical trials for other indications, including alcoholic cirrhosis, acute respiratory distress syndrome (ARDS) caused by COVID-19 , and cartilage damage.

In addition to the approved hematopoietic stem cell and MSCs products, there is also a limbal stem cell (LSC) product that has also been approved . In 2015, the EU EMA approved Holoclar for the treatment of corneal stem cell deficiency caused by ocular burns. However, since Holoclar is administered as a corneal tablet rather than a single-cell suspension, we will not discuss it for now.

Other cell therapies

Red blood cells and platelets

Blood products have a long history of treating blood disorders and deficiencies, but there are currently no specific approved products for red blood cells and platelets.

Red blood cell therapy is indicated for the treatment of anemia caused by blood disorders (ie thalassemia, sickle cell disease, iron or other vitamin deficiencies, aplastic anemia) . Blood must be ABO and RhD matched prior to IV administration. Red blood cell transfusions are most commonly used, but whole blood can also be given.

Platelet transfusions are used to treat thrombocytopenia (caused by disease or cancer treatment) . Optimal storage conditions and dosing regimens of platelets are the direction of current research.

Microbial therapy

At present, there is no clinically approved microbial therapy in the world , but related therapies are used clinically. The first is fecal microbiota transplantation (FMT) , in which a fecal solution from a healthy donor is supplied to the patient's gut to alter the gut microbiome composition. Although it can be used in clinical treatment, it has not been developed as a drug. The second is probiotics , which include live flora that are widely available over-the-counter and can also be prescribed by clinicians. They are usually classified as foods, functional foods or supplements and therefore are not regulated as drugs.

Summary and Questions

Finally, to review, there are 32 approved cell therapy products in the world , including 11 types of immune cells (7 types of CAR-T cells, 3 types of DC cells, and 1 type of CIK cells) and 21 types of stem cells (10 types of umbilical cord blood hematopoietic stem cells, 10 types of mesenchymal stem cells, 1 type of limbal stem cells) . It is worth mentioning that although red blood cells and platelets, as well as microbial therapy, can be used for clinical treatment, none of them have been developed and regulated as drugs.

Overall, stem cell therapy has sprung up like mushrooms after rain, providing an effective way to treat many refractory diseases. From the early skepticism of cell therapy, it now appears to be a vibrant new industry once again. More cell therapy products are in active clinical trials , which we will continue in the next issue.