Cell and Gene Therapies

THERAPY KYMRIAH® (TISAGENLECLEUCEL) BREYANZI® (LISOCABTAGENE MARALEUCE) ZOLGENSMA® (ONASEMNOGENE ABEPARVOVEC) PROVENGE® (SIPULEUCEL-T) ABECMA® (IDECABTAGENE VICLEUCEL) CARVYKTI® (CILTACABTAGENE AUTOLEUCEL) INDICATION GENE OR CELL THERAPY *This is not an exhaustive list. CAR T-cell therapy for the treatment of B-cell acute lymphoblastic leukemia. Used to treat spinal muscular atrophy. Used for the treatment of metastatic prostate cancer. For the treatment of multiple myeloma CAR T-cell therapy used to treat relapsed or refractory multiple myeloma. Used to treat different kinds of blood cancer, such as diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma. Types of Mutations TGCCTA - Unmutated DNA TGACTA - Substitution TGCCCTA - Insertion TGCTA - Deletion TGCATC - Inversion Inherited Parents can carry genetic mutations in the sperm or egg (known as germline mutations) that can be passed on to their offspring. Acquired Acquired genetic mutations (somatic mutations) are those that are not present at birth but occur during an individual’s lifetime. Disease Example: Huntington’s disease occurs due to an inherited mutation, known as a CAG trinucleotide expansion. The CAG segment within the gene is therefore increased. Disease Example: Many types of cancer occur as a result of acquired genetic mutations. Cells either autologous (from the patient) or allogenic (from a donor) are extracted and engineered outside of the body, before being reinjected back into the patient to replace those affected by a disease. Many human diseases occur because of an alteration to the genome – the collection of genes that an individual possesses. These changes to the DNA sequence are commonly referred to as mutations or gene variants. Example of autosomal Dominant inheritance of mutations Affected Father Unaffected mother Unaffected child Unaffected child Affected child Affected child Normal cell Mutation occurs Altered gene Altered cells Normal cells Cell and gene therapies are similar because they focus on the underlying cause of a disease. They are different in the way that they achieve this goal. cell therapy Treats disease by transferring whole, “living” cells to replace cells affected by disease, or to enhance an existing defense strategy in the body, such as the human immune system. gene therapy Treats disease by replacing, introducing, inactivating or silencing genes that are implicated in a disease. In vivo ex vivo Therapeutic gene is packaged inside a vector. Therapeutic gene delivered directly to patient via injection. Cells isolated from patient. Therapeutic gene Vector Modified cells are transferred back to the patient. Cells grown in culture. Therapeutic gene introduced. Are precision medicine strategies that focus on the underlying cause of a genetic or acquired disease, aiming to treat, prevent or perhaps cure it. An example of how a cell or gene therapy may work is by restoring the “normal” function of a protein that has been affected by a genetic mutation – be it acquired, or inherited. Allogeneic Autologous Cells collected Cells re-injected to patient Cells processed Cells expanded in the lab Donor Patient Cell therapy utilizes different types of cells, typically categorized as: Cancer Stem cells adult Stem cells Pluripotent Stem cells Stem cell-based cell therapy Non Stem cell-based cell therapy non-viral vectors viral vectors 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: Chondrocytes • T cells • Dendritic cells • Natural killer cells • Macrophages Fibroblasts Keratinocytes Immune cells Are being developed to overcome issues associated with viral vectors, such as immunogenic responses. Commonly researched non-viral vectors include: Utilize the capsid of a virus to transport genetic material. There are four main subcategories used in clinical practice and research: C T G A Gene • Adenoviral • Adeno-associated viral • Lentiviral • Retroviral • Polymers • Nanoparticles • Lipids • Exosomes • Inorganic materials Development and manufacturing methods for cell and gene therapies vary, depending on the type of therapy that is prescribed for a patient. Let’s take a closer look at one example: CAR T-cell therapy production. CAR T-cell therapy is an example of adoptive cell therapy (ACT), which involves the transfer of modified immune cells to trigger an immunologic response against tumors. Healthcare provider prescribes CAR T-cell therapy. Patient’s sample is cryogenically shipped to the therapy manufacturing site. These cells are grown and multiplied in the laboratory to achieve the number of CAR T cells required for the therapy. Once manufactured, the CAR T-cell therapy is shipped to the patient’s local site and the engineered T cells are infused back to the patient. While arguably a “novel” type of therapeutic, several cell-and gene-based therapies have received approval by the US Food and Drug Association (FDA) for different indications… In the laboratory, the T cells are engineered by inserting a gene that encodes a specific chimeric antigen receptor (CAR) that is unique to the antigen expressed by the patient’s cancer cells. Blood is obtained from patient to extract white blood cells called T cells CAR T cells bind to cancer cells and kill them. While several cell and gene therapy products have already been marketed, there is still a high unmet clinical to treat many diseases of genetic origin. Cell and gene therapies are expected to impact the treatment of: Neurological conditions Autoimmune diseases Opthalmic Disorders Cancer Key advancements and challenges in cell and gene therapies Achieving robust and standardized production Unlike mature medical fields, there are fewer existing standards for the research and manufacturing of cell and gene therapies. This can prove challenging for clinical translation and scale-up. Highly controlled engineering and manufacturing strategies are required across laboratories and manufacturing sites, implementing automation and process analytical technology (PAT) to ensure safety, efficiency and batch consistency. Genome-editing capabilities Novel gene-editing technologies, such as zinc finger nucleases (ZFNs) transcription activator-like effector nucleases (TALENs) and the Cas nuclease of the CRISPR/Cas9 system, enable targeted, site-specific modifications to the genome. It’s expected that such methods – with further development – will shape the future landscape of cell and gene therapies, outperforming “classical” approaches. Artificial intelligence There are commonalities in the development and manufacturing of cell and gene therapies that can be enhanced utilizing artificial intelligence. These include, but are not limited to: • Systems biology • Design and screening • Product quality testing • Design and monitoring of clinical trials • Adverse effect detection Enhanced understanding of disease pathology Cell and gene therapies require a comprehensive understanding of disease pathology at the molecular level. Advancements in single-cell sequencing capabilities have bolstered our knowledge of disease phenotypes, and further refinements of such technologies look set to take cell and gene therapies to new heights. Safe and targeted delivery of therapeutic genetic material has proven to be a key challenge for gene therapies. Gene Therapy delivery Vectors can be likened to “mini vehicles” that transport therapeutic genetic material directly into the cell. These can be categorized as viral and non-viral. Cell and gene therapies are at the forefront of innovation in modern medicine, changing the way in which we study and treat human disease.