Cell Therapy

The American Society of Gene and Cell Therapy defines cell therapy as the transfer of intact, live cells into a patient to help lessen or cure a disease. This is done by either replacing cells lost through disease or promoting the repair response for damaged or diseased tissues. In this infographic, we explore how cell therapies can be made and the potential diseases that they are - and could - be used to treat. Improvements in cell therapy manufacturing processes are needed to ensure cell therapies are produced: • Safely • Reliably • Cost-efficiently The first US approval for a stem cell-based therapy came in 2011, when Hemacord was approved for hematopoietic progenitor cell transplantation procedures in patients with diseases that affect the hematopoietic system. Currently, the only stem cell-based treatments approved by the FDA are for hematopoietic stem cell transplantation. At the end of 2022, tabelecleucel (Ebvallo), an autologous T-cell based therapy, was approved for Epstein-Barr virus-positive posttransplant lymphoproliferative disease (PTLD) in the EU. PTLD is a potentially fatal complication of solid organ transplantation that results in the overproduction of lymphocytes. Worldwide, 60 non-genetically modified cell therapies have been approved for clinical use. Data obtained from the Gene, Cell and RNA Therapy Landscape Q4 quarterly report by the American Society of Gene and Cell Therapy. The majority of cell therapies in development are for either cancer or rare disease indications. *This is a non-exhaustive list Sipuleucel-T (2010): Metastatic castrate-resistant prostate cancer. (autologous, activated/expanded) Azficel-T (2011): Nasolabial fold wrinkles in adults. (autologous, expanded) Autologous cultured chondrocytes on a porcine collagen membrane (2016): Cartilage defects of the knee in adults. (autologous, expanded) Axicabtagene ciloleucel (2017): B-cell non-Hodgkin lymphoma and follicular lymphoma. (CAR T-cell therapy. Autologous, modified) Idecabtagene vicleucel (2021): Multiple myeloma. (CAR T-cell therapy. Autologous) Allogeneic processed thymus tissue–agdc (2021): Congenital athymia. (allogeneic) Elivaldogene autotemcel (2022): Early, active cerebral adrenoleukodystrophy. (autologous, modified) Motor neurons grown from iPSCs were administered to mice after their sciatic nerves were cut. The cells innervated the muscle and helped to maintain muscle mass in the mice compared to mice that did not receive the cells. Cografting astrocytes was shown to enhance neural progenitor cellbased cell therapeutic outcomes in a model of Parkinson’s disease. Research is underway to engineer microglia in a neuroprotective state to transplant into ALS patients. Treatment can be incredibly expensive. There is risk of serious adverse effects such as cytokine release syndrome. The efficacy of CAR T-cell therapy has also been questioned, with long-term benefits less clear when compared to alternate therapies. Reproducing the success seen in hematological cancers to solid tumors remains a challenge. HEMACORD (HPC, Cord Blood) (2011): Disorders affecting the hematopoietic system. (allogeneic) Allogeneic cultured keratinocytes and fibroblasts in bovine collagen (2012): Mucogingival conditions in adults. (allogeneic) Tisagenlecleucel (2017): B-cell acute lymphoblastic leukemia and B-cell nonHodgkin lymphoma. (CAR T-cell therapy. Autologous, modified) Brexucabtagene autoleucel (2020): Mantle cell lymphoma and B-cell acute lymphoblastic leukemia. (CAR T-cell therapy. Autologous, modified) Lisocabtagene maraleucel (2021): B-cell non-Hodgkin lymphoma. (CAR T-cell therapy. Autologous) Ciltacabtagene autoleucel (2022): Multiple myeloma. (CAR T-cell therapy. Autologous) Allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen- dsat (2021): Thermal burns. (allogeneic) Betibeglogene autotemcel (2022): ß-thalassemia. (autologous, modified) Number of cell therapies in preclinical through pre-registration stages of development per indication Cells originating from the patient are classed as autologous. These cells are typically collected, processed, expanded and then re-injected. Cells originating from a donor are called allogeneic cells. Allogeneic cells are used to treat blood disorders and immune system diseases, such as sickle cell anemia. Instead of using mature cells like T cells, other cell therapy approaches utilize immature stem cells. These cells are especially suited to regenerative medicine approaches, such as restoring nerve cells and preventing neurodegeneration. Stem cells can be grown into different types of nerve cells, such as motor neurons, which can then be administered to patients. Alongside gene therapies, cell therapies are increasingly being investigated for their potential to treat rare diseases. While a disease is considered rare if it affects fewer than 1 in 2000 people, collectively these diseases affect a significant proportion of the population – around 300 million people are living with a rare disease. Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) is a rare disease affecting the skin, hair, nails, teeth and other tissues, caused by a mutation in TP63. Cell therapy approaches are being considered as a treatment for skin fragility in AEC patients. Such approaches would involve the following steps: Interest in and the development of cell therapies is expected to continue to grow: The FDA predicts that it will be approving 10 to 20 cell and gene therapy products a year by 2025. The global cell and gene therapy clinical trials market is projected to reach USD 16,054.93 million by 2030. However, such approaches are expensive, time-consuming, complex and face regulatory hurdles. Of particular interest is the development of advanced CAR T-cell therapies that present a lower chance of causing severe side effects such as cytokine release syndrome or are able to recognize two targets on cancer cells, helping to overcome resistance seen with single-targeted CAR T cells. Alternative cell types, such as NK cells, could overcome some of the limitations of relying on T cells. Expressing a variety of unique receptors, NK cell therapies could offer similar potency without the associated side effects. Referred to as the “fifth pillar” of cancer treatment, immunotherapy is a growing area of interest, with promise to transform the treatment of cancer. Alongside other approaches that harness the immune system, such as monoclonal antibodies and vaccines, cell therapies are being developed to improve treatment options for cancer patients. Six CAR T-cell therapies have been approved by the FDA since 2017, all for the treatment of blood cancers and targeting CD19 or BCMA antigens on B cells. The types of cells used for cell therapies fall into one of two categories, stem cells or somatic cells. Methods of production Neurodegeneration Rare diseases The future Cell therapy applications Current uses CAR T-cell therapy FDA approved cell therapies* Despite the promise, CAR T-cell therapy is not without limitations: Autologous vs allogeneic Cancer Stem cells vs somatic cells Pluripotent stem cells: Give rise to all cell types except extraembryonic placental cells. These include embryonic stem cells (ESCs), epiblast stem cells (EpiSCs), embryonic germ cells (EGCs) and induced pluripotent stem cells (iPSCs). Adult stem cells: Include hematopoietic stem cells (HSCs), skin stem cells (SSCs), neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Are typically used to replace cells lost to disease or contribute to the healing of damaged/diseased cells. Cancer stem cells: Found within solid tumors or blood cancers and exhibit characteristics of both stem cells and cancer cells. Can be used as a target for cancer treatments. Fibroblasts: Produce extracellular matrix (ECM) and collagen. Chondrocytes: Maintain the ECM and produce the cartilage matrix. Keratinocytes: Major cell type of the outermost layers of the skin. Immune cells: T cells, dendritic cells, natural killer (NK) cells and macrophages. 350 ANTICANCER RARE DISEASES ALIMENTARY/METABOLIC MUSCULOSKELETAL NEUROLOGICAL CARDIOVASCULAR IMMUNOLOGICAL RESPIRATORY SENSORY DERMATOLOGICAL MISCELLANEOUS GENITOURINARY ANTI-INFECTIVE BLOOD AND CLOTTING NA/UNSPECIFIED HORMONAL 300 250 200 150 100 50 0 Autologous Human iPSC Stem cell-based cell therapy Allogeneic Non stem cell-based cell therapy Sponsored by: Cells collected Cells re-injected to patient Cells processed Cells expanded in the lab Donor Patient Pluripotent stem cells Adult stem cells Fibroblasts Keratinocytes Cancer stem cells Immune cells Chondrocytes Stem cells are either used, or targeted, by the cell therapy. Examples of cells used include: Somatic cells are isolated from the body (either autologous or allogenic in nature), expanded and modified in vitro before being returned to the body. Cell types used can include: • T cells • Dendritic cells • Natural killer cells • Macrophages Cell therapy utilizes dierent types of cells, typically categorized as: T cell T cell Antigens CAR T cell CAR T cell Insert gene for CAR Chimeric antigen receptor (CAR) T cells are collected from a patient or donor’s blood. The CAR T cells recognize and bind to antigens on cancer cells and kill the cancer cells The CAR T cells are grown in large numbers. The CAR T cells are administered back to patients. The T cells are engineered to express a chimeric antigen receptor (CAR) that recognizes unique tumor antigens. Cancer cell Cancer cell 1 2 3 4 Patient somatic cells obtained by skin biopsy or blood collection. 5 Reprogramming factors TP63 mutation corrected Patient specific iPSCs generated Repaired iPSCs Dierentiation into keratinocytes. Transplantation