lecture 6: cancer stem cells Flashcards
1
Q
What are some general comments about the field of stem cells and regenerative medicine?
A
- a new and rapidly growing field of biomedical research with widespread ramifications
- a potentially disruptive set of technologies whose future implications are difficult to predict
- a highly interdisciplinary field
- scientific, clinical and economic basis for product development and health care delivery in this sector is evolving and remains largely undefined
2
Q
Is the cell therapy industry growing?
A
- yes
- billion dollar industry
- growing exponentially and will continue to grow in the future
3
Q
Have there been any clinical trials involving stem cells?
A
- yes
- 2500 clinical trials in the past ten years
- 50% in phase 2-3
- diseases such as bone/cartilage, cancer, heart disease, diabetes, gastrointestinal, immune rejection/autoimmunity, neurodegenerative and other being addressed using mesenchymal stemc ells (MSC) for clincal trials
- trials undergoing with neural stem cell transplant in Pelizaeus-Merzbacher disease: a demyelinating disorder caused by deficiency in proteolipid protein 1
- neural stem cell engraftment and myelination in the human brain
4
Q
What are challenges for transplantation therapy?
A
- funding and business model
- production of required cell type in sufficient numbers and pure form
- what cell to transplant
- delivery
- problems of tissue rejection
- safety: formation of inappropriate tissue or tumour
- mechanism of action/magic issue: how do stem cell grafts actually work, cell replacement, protection of tissue, or stimulation of endogenous repair?
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5
Q
What are issues with finding the right business model for development of cell based therapies?
A
- translation into the clinic ultimately involves the investment of large amounts of money
- Geron Corporation
- largest in sector
- very strong IP portfolio
- $100 millions invested in stem cell programmes
- strong science: biotechnical firm but important contributions to public literature
- first phase 1 trial for ES derived product in spinal cord injury
- Geron corporation ends stem cell programme
- former CEO Thomas B Okarma in 2009: US authorities’ granting of approval to start the trial maked “the dawn of a new era in medical therapeutics” which placed Geron “at the forefront of the medical revolution”
- $181 million in cash and investments pa; $25 million loan from CIRM
- two cancer drugs in Phase 2 trials
- stem cells high risk, unknown, cancer drugs more solid
- there are dollars and cents decisions
- former CEO Thomas B Okarma in 2009: US authorities’ granting of approval to start the trial maked “the dawn of a new era in medical therapeutics” which placed Geron “at the forefront of the medical revolution”
6
Q
What are some Australian Stem Cell biotechs?
A
- ES Cell International/Biotime
- Stem Cell Sciences/Stem Cells Inc
- Bresagen/Viacyte
- Mesoblast: biggest company in this sector, had the product as opposed to the cool science
- all of these companies were active at the very beginning of the field
- with the exception of the last one they have all been acquired by the /comapnies
7
Q
What are new models for funding research?
A
- Old way: traditional research grants
- investigator initiated
- volunteer peer review (science)
- hypothesis driven
- academic institutions
- 2003 - 2008: Industry contracts
- Investigator and MDA initiated
- grant-like review process
- milestone driven
- academic institutions and industry
- 2008 to present: venture philanthropy
- MDA initiated (consumer driven)
- professional diligence
- milestone driven
- detailed business plan
- industry, other nonprofits
- new donor base
- e.g. California Institute of Regenerative Medicine: A unique initiative in research funding
- a major goal of CIRM strategy is to drive translation of discoveries into treatments, and a key element of this approach is to bridge the valley of death
- 20 or so disease team projects
- CIRM investment in translational and clinical research
8
Q
What is the example of stem cell therapy in macular degeneration?
A
- macular degeneration is a major cause of blindness in the ageing population
- layer of cells at the back of the eye called the retinal pigment epithelium
- these cells are not light sensing but helper - metabolism etc
- this layer of cells begins to degerate leading to loss of photoreceptors and blindness
- Establishment of ES cells
- from ICM - ES colony 10-15 days later
- by 2000 - hESC can form neural tissue in vitro
- the eye forms as an outgrowth of the embryonic brain
- place blob on a culture dish with laminin etc and let the cells spread out and begin to specialise, differentiate
- 2004: directed neural differentiation
- conservation of developmental mechanisms
- treatment with the embryonic head inducer noggin
- induces differentiation of human ES cells into primitive neural tissue
- Nestin and Sox-2, markers of early neurogenesis
- still the basis for making early neural precursors from stem cells
- sometimes observed that retinal pigment epithelium developed from human neural progenitors
- went to colleagues at eye institute and they found that yes indeed, ES-derived RPE forms a polarised epithelium that is functional: phagocytosis of rod segments
- group went on to show these grafts were beneficial in immunocompromised rats
- delivered cells on a membrane because thought to be more efficient
- macular degeneration is a promising early target
- small amount of tissue to be replaced - not many cells required
- pigment epithelium from ES cells is fully functional
- eye is highly accessible for monitoring and intervention, imaging outstanding
- localised immunosuppression is possible
- Currently in Phase 1 trials of hESC derived retinal pigment epithelium grafts in macular degeneration (ACT trial)
- proves that it is a feasible practise to do and that it’s not horrendously damaging to the patient
- will require much more work to see whether it is actually benficial or not
9
Q
What was needed to bring together the CIRM macular degeneration disease team?
A
- The california project to cure blindness-$16 million to bring the study to Phase 1 trial in four yeards
- USC Doheny Eye Institute (nlah blah)
- UCSB Macular degeneration and Stem Cell centres
- UCL London Progect to Cure Blindness
- Caltech Biology and Chemistry
- City of Hope Center for Biomedicine and Genetics GMP facility
- multidisciplinary
10
Q
What clinical trials of pluripotent stem cell derives therapeutics have occured?
A
- Macular degeneration and related disorders
- Type 1 diabetes
- Spinal cord injury
- Parkinson’s disease, myocardial infarction (soon)
11
Q
What are some of the ethics of stem cells?
A
- the debate over the use of human embryos in research is not over, but it is of diminishing relevance to the field
- the availability of over 1000 ES cell lines and iPSC technology means that arguments for the use of embryos to achieve a new advance (that cannot be achieved by other means) must be very convincing
- although iPSC provenance is ethically less challenging than embryo usage, there are many other issues around the use of human pluripotent cells in research and therapy
12
Q
What are the ethics of research with ES or iPS cells?
A
- experimentation in vitro: growth, differentiation, genetic manipulation, functional assessment, drug testing – raises issues of genetic privacy around iPS banks
- inoculation of cells into adult or foetal animals with a view towards assessment of developmental capacity (e.g. teratoma formation) or ability to incorporate into and function within normal tissue or disease model-chimeras
13
Q
What are some of the limitations of iPSC technology?
A
- complete reprogramming to pluripotent state?
- tissue of origin memory
- differentiation capacity
- genetic lesions induced during reprogramming
- tumour formation
- however iPSC still going to therapeutic research/clinical trials e.g. in japan using them for the same issue of macular degeneration
- controversial because there are still questions of safety
14
Q
What is the Global GMP iPSC Haplobank?
A
- provide matched tissue for transplantation via IPS technology
- ABO, HLA class I and II, minor histocompatibility antigens
- proposal to derive cell lines from individual homozygouse for MHC haplotypes - means less people required to make banks cf people who are heterozygous
- goal to coordinate efforts internationally
- as opposed to individual therapy
15
Q
What about stem cells derived from Human SCNT?
A
- perhaps better quality stem cells but remains problematic
- only a few groups in the world use these
- multiple refinements to the procedure enabled ES generation from a small number of oocytes
- not going to generate 10s of thousands of lines with this technology any time soon
16
Q
What is involved in the prevention of mitochondrial disease?
A
- transfer of maternal DNA from a patient with mitochondrial disease (spindle transfer) into a healthy donor egg followed by fertilisation by father’s sperm
- variant of SCNT
- mitochondrial diseases are very bad
- trials suggest that this is safe
18
Q
What is the scaleup production of pancreatic progenitors for type 1 diabetes?
A
- viacyte
- strategy focuses on expansion in the stem cell stage followed by mass differentiation
- protocol carefully optimised over years for one cell line that is particularly amenable to this differentiation lineage
- nearly but not completely xeno-free
- end cells are not functionally mature
- 3x109 progenitor cells produced, just sufficient for Phase 1 trial of 10 patients
- less than 2% are unknown cell types (concern)
- costs not specified (issue)
19
Q
What is a consideration of interpatient variability?
A
- IPS cell differentiation capacity
- e.g. interpatient variation in albumin secretion after hepatic differentiation of IPS cells
- big challenge and don’t know exactly how to overcome it
