Cell Therapy Lecture 18

• Cell Therapy is Lecture 18

Cells as Therapies

• Cells can be used as therapies via blood transfusion, or to replace cells lost to disease or treatment
• Blood transfusions replace blood lost during injury or surgery
• Blood transfusions treat acute anemia or cardiovascular events
• Cells are replaced to treat Type 1 diabetes (Edmonton protocol), corneal transplant after a disease or injury, and bone marrow or stem cell therapy after chemo/radiotherapy

Cell Therapies Currently in Use

• Hematopoietic Stem Cell Transplantation (HSCT) treats cancers of the blood and bone marrow such as leukemia or multiple myeloma
• HSCT is derived from bone marrow, peripheral blood, or umbilical core blood
• Life threatening complications that can result from HSCT include graft versus host disease

Cell Source

• In autologous transplants, cellular material is derived from the patient, such as blood withdrawn then re-infused later
• In autologous transplants, bone marrow can be withdrawn before chemotherapy/radiation therapy and re-infused
• In allogeneic transplants, cellular material is derived from a donor
• In allogeneic transplants, HLA (blood type) is usually matched, often with a close relative or sibling
• Allogeneic transplants require immunosuppression treatment subsequently
• Graft versus host disease (GVHD) can sometimes result from allogeneic transplants

Cells as Therapies - Diabetes

• Approximately 3% of Irish people are diabetic, either Type I or Type II
• Type I diabetes (IDDM) is an autoimmune disorder
• In Type 1 diabetes, the patient's immune system sees beta cells as foreign
• Beta cells are responsible for sensing blood sugar levels and secreting insulin when required
• In IDDM patients, beta cells are destroyed so no insulin is produced, therefore they are dependent upon insulin injections
• Ways to treat the condition are pancreatic transplant, islet replacement, or stem cells

Islet Replacement

• The Edmonton Protocol was developed by Dr. James Shapiro

Edmonton Protocol

• A donor pancreas is injected with digestive enzymes
• A machine shakes and breaks the pancreas into pieces
• One to three organs are needed for each transplant recipient
• Chunks of the pancreas become smaller in a recirculating chamber with heat to isolate the islets
• A surgeon injects purified islets into the patient's liver within two days of cell isolation
• Cells take up residence in the liver, but immunosuppressive drugs are needed for life to prevent rejection

"Minor" Procedure?

• Islets are comprised of 50 to 1,000 pancreatic cells including those that produce insulin, after isolation

Avoiding Rejection

• Any transplanted material will be rejected by the patient unless they take immunosuppressants
• Matching a donor to a recipient is not always perfect
• Stem cells have the potential to form many types of cells, and could use the patients own cells
• Pluripotent stem cells can differentiate into any cell type like embryonic stem cells
• Multipotent stem cells can differentiate into many cell types like adult stem cells or cord blood stem cells
• Stem cells are very rare, 1 in 10,000, but capable of self-renewal and maintenance in culture

Stem Cells

• Adult stem cells can be taken and de-differentiated to reprogram them
• Re-programming factors can be used to generate ‘induced pluripotent stem cells' - iPS cells
• Once iPS cells have been generated they can be re-differentiated to the cell type required, like beta cells

iPS Cells

• Four transcription factors switch on/repress a cascade of other genes that reverts the adult cell
• Shinya Yamanaka was awarded the Nobel prize in 2012 for the discovery of iPS cells

Combining Cell and Gene Therapy for Cancer Treatment

• Traditional pillars of cancer therapy are surgery, radiation, and chemotherapy
• More recently targeted therapies and immunotherapies, recombinant proteins e.g. mAbs were used
• Very recently combining Cell and gene therapy to activate patients' immune system like CAR-T therapy have been used

CAR-T Therapy

• Chimeric antigen receptor – T cell therapy
• CAR-T therapy seeks to ‘activate' a patient's own immune system (T cells) to attack cancerous cells
• CAR-T therapy has been used to treat blood cancers (Leukaemias, lymphomas)
• Early CAR-T trials showed very impressive results especially with childhood leukaemia (ALL) that has become resistant to usual drugs
• The FDA rarely approves a new drug for cancer in young people (<25yo) before approving for use in adults
• The first commercial CAR-T product, Kymriah™ (Novartis), was approved in 2017
• There are now six approved CAR-T products on the market

CAR-T

• Major manufacturing hurdles still need to be overcome
• Blood is collected from the patient for CAR-T
• T cells are purified from blood
• T cells are exposed to lentivirus engineered to carry a special gene
• A virus delivers the gene into the T cell nucleus where it enters the genome
• This cell daughter cells will make this protein
• The T cells are grown to make million/billions and then re-infused back into the patient
• This protein (chimeric antigen receptor) is displayed on the surface of the T cells
• The protein binds to antigens that are only present on the surface of cancerous B cells
• This triggers the T cells to launch an immune attack on these cancerous cells
• KymriahR (Novartis), and Yescorta R, Tecartus R (Gilead) are on the market with >300 more in clinical trials

Summary

• Review of Biotechnology Principles including basic building blocks of cells, energy metabolism, DNA, and Genetic Engineering
• Viruses are used as gene delivery tools in Cell and Gene Therapy