Hematopoietic stem cells transplantation is a FDA-approved stem cells based therapy whereby it is usually performed for cancer patients. For an example, Multiple Myeloma.
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FDA-APPROVED HEMATOPOIETIC STEM CELLS TRANSPLANTATION FOR MULTIPLE MYELOMA
1. FDA-APPROVED
HEMATOPOIETIC STEM
CELLS TRANSPLANTATION
FOR MULTIPLE MYELOMA
SCT 60103
GENES AND TISSUE CULTURE TECHNOLOGY
Chan Ping Rol 0329220
Hing Ren Hau 0329811
Lee Wan Ning 0328745
Ling Yun Jye 0329321
Natalie Vivien Gunter 0329843
2. Introduction to stem cells
What are stem cells?
- Cells capable of proliferation for an indefinite amount of time, giving
rise to specialised cells (National Institute of Health 2016)
Unique properties of stem cells:
- Able to divide and renew for a long period of time
- Unspecialised
- Gives rise to specialised cell
Types of stem cells potency:
1) Totipotent
● Gives rise to all
types of
differentiated
cells in an
organism
● Placenta and
embryo
included
2) Pluripotent
● Descendant of
totipotent cells
● Capable of
differentiating
into all tissues
but not
extraembryoni
c cell types
(Bindu &
Srilatha 2011)
3) Multipotent
● Developed
from
pluripotent
cells
● Differentiation
potential is
within one
particular
lineage
(Sobhani et al.
2017)
5) Unipotent
● Only produce
their own cell
type
● Difference is
the ability to
self-renew
● E.g. Epithelial
tissues
4) Oligopotent
● Differentiatio
n only into a
few cells
(Bindu &
Srilatha
2011)
● E.g.
Lymphoid
stem cells
(Mayo Clinic 2018)
3. Types of Stem Cells
Tissue-specific stem cells
● Multipotent
● E.g. stem cells from
the brain and
hematopoietic stem
cells (Bryder, Rossi &
Weissman 2006)
Induced pluripotent stem cells
● Specialised cells
engineered to elicit
pluripotency
● Via pluripotency genes
Embryonic stem cells
● Capable of producing
totipotent and pluripotent
stem cells
● Obtained from inner cell
mass of blastocyst
● Able to generate all
different types of cells in the
body
(International Society for Stem Cell Research 2017)
4. Applications: Hematopoietic Stem Cells Transplantation
- Intravenous infusion of the stem cells collected
- To reestablish hematopoietic function in patients whose immune system is defective.
- Most often performed for patients with cancers of blood or bone marrow
- eg. Multiple Myeloma.
- Hematopoietic stem cells are usually derived from:
● Peripheral blood stem cells
○ Blood collected from large vein in the arm
○ White blood cells are removed
○ Red blood cells are returned to the donor.
○ Most common
● Bone marrow stem cells
○ Collected from the hip bone with a large needle
○ Person will be given anesthesia (loss of feeling below the waist)
● Cord blood stem cells
○ Collected after a child is born from the umbilical cord and placenta (Jeevani 2011).
(National Cancer Institute 2015)
5. Types of Transplants
1. Autologous Transplant
● Patients themselves act as donors to donate their own stem cells.
● Stem cells are transfused back into their bloodstream after chemotherapy to replace destroyed
tissues and stimulate normal hematopoiesis.
● Lower risk of infection and transplanted stem cell rejection, most effective.
2. Syngeneic Transplant
● Patients receive stem cells from their identical twins.
● Lower chance of transplant being rejected.
● Rare
3. Allogeneic Transplant
● Patients receive stem cells from their siblings/parents
or unrelated donors
● Close degree of HLA matching with the patients.
● Ineffective as rejection may occur (Hatzimichael & Tuthill 2010).
(National Cancer Institute 2015)
6. Steps Involved in Hematopoietic
Stem Cell Transplantation
1. HLA Typing
❖ Human leukocyte antigen (HLA) typing is used to
determine matching between patients and donors
❖ Six main HLA markers: class I (A, B, C loci); class II (DR,
DQ, DP loci)
❖ Each sibling receives one set of antigens (A, B, C, Dr, DQ,
DP) from each parents’ chromosome 6
❖ Chances of a particular matched related allogeneic HCT can
be calculated using formula of 1-(0.75)^N, N= Number of
potential sibling donors.
❖ In general, patient with one sibling has 25% chance of
having a match
❖ A match is noted when the major class I and class II
antigens are the same as those of the donor.
❖ In matched unrelated donor cases, identification can be
accomplished by searching the computer files of the
National Marrow Donor Program and other international
registries.
❖ Serologic identity does not necessarily imply genotypic
identity since any given HLA locus has multiple alleles.
1. HLA Typing
2. Collection of the Graft
3. Transplantation
7. 3. Transplantation (3 phases)
A. Preparative phase
❖ Patients receive high-dose chemotherapy and/ or
radiation therapy
❖ Oral administration leads to unpredictable low or
increased absorption; intravenous approach is
more predictable
B. Transplant period
❖ Time period of a day or more is given after
preparative phase before reinfusion of marrow or
peripheral blood stem cells
❖ This delay allows elimination of any active drug
metabolites so that reinfused cells are not killed
by any remaining drug
C. Supportive care phase
❖ Strict attention to infectious disease (related
complications secondary to neutropenia)
2. Collection of the Graft
a. Bone marrow
❖ Harvested from posterior iliac crests
❖ Collected with heparinized syringes
❖ Marrow is filtered to remove small particles or clots before
intravenous transfusion into recipient
b. Autologous peripheral stem cells
❖ Performed via apheresis technique
❖ Efficiency and number of cells are increased if cells are
collected after administration of hematopoietic growth factors.
For example, G-CSF is administered for higher WBC count and
reduce hemoglobin production
❖ Accessed by determining cells with CD34 antigen marker (stem
cell marker)
c. Umbilical cord blood (UCB)
❖ When there is a lack of suitably matched HLA donor
❖ Donor cells are relatively immunologically naive, allows
multiple-antigen mismatches and reduces risk of GvHD
❖ Placenta and umbilical cord are suspended on a frame, and
blood in drained by ‘’standard gravity phlebotomy’’ into citrate
phosphate dextrose (CPD) anticoagulant, and are
cryopreserved and stored in cord blood banks
❖ Collection poses no donor risks if cord is appropriately clamped
8. Challenges
For Allogeneic HSCT
1. Development of Graft Versus Host Disease (GVHD)
❖ Receiving graft from HLA (human leukocyte antigen) mismatched related donor or HLA matched
unrelated donor.
❖ Graft (donated stem cells) reacts against host (recipient) by seeing the host’s cells as foreign and
attacking them.
❖ Acute GVHD (35% to 50% of HSCT patients)
- affecting skin (dermatitis), liver (hepatitis/jaundice) and GI tract (abdominal pain)
❖ Chronic GVHD (50% of AGVHD patients)
- affecting skin, liver, eyes (dry eyes), mouth (dry mouth), lungs (shortness of breath), GI tract,
neuromuscular system (fatigue) and genitourinary tract.
2. Higher early treatment-related mortality from GVHD and infectious complication
❖ Due to weaken immune system from immunosuppression
(Cancer Research UK 2017)
9. For Autologous HSCT
1. Development of Myelodysplasia
❖ Due to marrow injury from prior chemotherapy or transplant regimen.
2. No graft versus tumor effect
❖ Higher disease relapse rate
For both autologous and allogeneic HSCT
1. Development or Reactivation of Cytomegalovirus (CMV) Infection
❖ Common virus and usually asymptomatic
❖ Leading cause of significant morbidity & mortality
(Cancer Research UK 2017)
10. Advantages
For Allogeneic HSCT
❖ Graft Versus Myeloma Effect
- Due to GVHD.
- Increased long-term survival.
❖ Absence of contamination and injury
- No malignant cells contaminating the graft and no prior marrow injury due to chemotherapy.
For Autologous HSCT
❖ No development of GVHD
- Less morbidity and mortality.
❖ Safer for patients with upper age limit.
- Dose-intensive therapy can be used for older patients (up to 70 years old)
❖ Less risk of infection
- As no immunosuppression in used.
(Forman & Nakamura 2015)
11. Current Work and
Development
❖ In multiple myeloma mouse model, presence of MM cells in
bone marrow could attract infused mesenchymal stem cells
(MSCs) due to CCL25 chemoattractant (Xu et al. 2012)
❖ Suggests that bone marrow derived MSCs can be good
candidates to deliver therapeutic anti-tumor agents in vivo
❖ MSCs from other sources such as umbilical cord and adipose
tissues have been reported to inhibit MM growth, though not
much research has been conducted
❖ Long-term in vivo safety and efficacy requires further
investigation.
➢ Risk of in vitro transformation
➢ Use of animal-derived product may have potential safety concerns
for recipients (possible infections and severe immune reactions)
➢ Alternative: serum-free culture media such as human platelet
lysates to retain MSC characteristics (Walenda et al. 2012)
(Xu et al. 2018)
12. Current Work and
Development
❖ Induced pluripotent stem cells (iPSCs) can generate
hematopoietic cells similar to those derived from embryonic
stem cells
❖ iPSCs can be differentiated from available somatic cells such
as fibroblasts
❖ Summarizes iPSCs for dendritic cell (DC) generation
➢ DCs are types of hematopoietic cells with potent antigen
presenting activity and the ability to activate T cells in an immune
response
➢ Differentiation into DC cells requires TNFa, GM-CSF CD40L
➢ Tumour antigen presenting functions
❖ Has not been used for clinical trials
❖ Limitations:
➢ Limitation in cell growth
➢ Time and cost related problems
(Rami, Mollainezhad & Salehi 2015)
13. ❖ GRO (growth related oncogene)-beta induced rapid
movement of stem cells from marrow into blood in animal
models
❖ When combined with AMD3100, found that rapid production
of cells equals to that provided by the 5-day G-CSF protocol
❖ Only been tested in mouse models; need to test to confirm
safety and effectiveness in humans
(Hoggatt et al. 2018)
❖ Based on DNA methylation profile of MM; hypermethylation
of several potential suppressor genes
❖ DNA methylase transferase inhibitor (DNMTi) and histone
deacetylase inhibitor (HDACi) are being evaluated in clinical
trials
❖ Reprogramming of MM cells through downregulation of
IRF4 and MYC axis
(Bruyer et al. 2018)
14. Conclusion
● Stem cells therapy offer promising
treatments for many diseases.
● Many therapies are still under clinical
trial due to safety and efficacy.
● More research on stem cell biology is
required to treat more diseases effectively.
(The Guardian 2017)
15. References
1. Bruyer, A., Maes, K., Herviou, L., Kassambara, A., Seckinger, A., Cartron, G., Reme, T., Robert, N., Requirand, G., Boireau, S., Muller-Tidow, C., Veyrune, J., Vincent, L., Bouhya, S., Goldschmidt, H., Vanderkerken,
K., Hose, D., Klein, B., Dr Bruyne, E. & Moreaux, J., 2018, ‘DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells’, British Journal of
Cancer, vol. 118, no. 8, pp. 1062-1073, <DOI: 10.1038/s41416-018-0025-x>
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10.4172/2157-7633.1000115>.
3. Bryder, D, Rossi, DJ & Weissman, IL 2006, ‘Hematopoietic Stem Cells: The Paradigmatic Tissue-Specific Stem Cell’, The American Journal of Pathology, Vol. 169, Issue 2, pp.338-346, viewed 12th May 2018, <DOI:
10.2353/ajpath.2006.060312>.
4. Cancer Research UK 2017, Graft versus host disease(GVHD), viewed 13 May 2018, <http://www.cancerresearchuk.org/about-cancer/coping/physically/gvhd/about>
5. Forman, S.J., Nakamura, R., 2015, ‘Haematopoietic Cell Transplantation’, Home of the Journal Oncology, viewed 13 May 2018, <http://www.cancernetwork.com/cancer-management/hematopoietic-cell-transplantation>
6. Hatzimichael, E & Tuthill, M 2010, ;’Hematopoietic Stem Cell Transplantation’, Stem Cells and Cloning: Advances and Applications, vol.3, pp.105-117, doi:10.2147/SCCAA.S6815
7. Hoggatt, J., Singh, P., Tate, T.A., Chou, B., Datari, S.R., Fukuda, S., Liu, L., Karchenko, P.V., Schajnovitz, A., Baryawno, N., Mercier, F.E., Boyer, J., Gardner, J., Morrow, D.M., Scadden, D.T. & Pelus, L.M., 2018,
‘Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell’, Cell, vol. 172, no. 1-2, pp. 191-204, <DOI: 10.1016/j.cell.2017.11.003>
8. International Society for Stem Cell Research 2017, Stem Cell Facts, viewed 12th May 2018, <http://www.closerlookatstemcells.org/docs/default-source/patient-resources/stem-cell-facts.pdf?sfvrsn=4>.
9. Jeevani, T 2011, ‘Stem Cell Transplantation - Types, Risks and Benefits’, Journal of Stem Cell Research and Therapy, vol.1, no. 3, pp. 1-2, doi: 10.4172/2157-7633.1000114
10. Mayo Clinic 2018, Stem Cells: The Body’s Master Cells, viewed 12th May 2018, <https://www.mayoclinic.org/stem-cells-the-bodys-master-cells/img-20008569>.
11. National Cancer Institute 2015 , ‘Apheresis: Harvesting Stem Cells from Peripheral Blood’, Blood Stem Cell Transplants, viewed 13 May 2018, <http://www.ubooks.pub/Books/ON/B0/E16R1616/TOC.html>.
12. National Cancer Institute 2015, ‘Stem Cell Transplants in Cancer Treatment’, Cancer Treatment, viewed 15 May 2018, <https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant>.
13. National Institutes of Health 2016, Stem Cell Basics, viewed 12th May 2018, <https://stemcells.nih.gov/info/basics/1.htm>.
14. Rami, F., Mollainezhad, H. & Salehi, M., 2016, ‘Induced Pluripotent Stem Cell as a New Source for Cancer Immunotherapy’, Genetics Research International, vol. 2016, <DOI: 10.1155/2016/3451807>
15. Sobhani, A, Khanlarkhani, N, Baazm, M, Mohammadzadeh, F, Najafi, A, Mehdinejadiani, S & Sargolzaei, AF 2017, ‘Multipotent Stem Cell and Current Application’, Acta Medica Iranica, Vol. 55, Issue 1, pp. 6-23,
viewed 12th May 2018, <https://www.ncbi.nlm.nih.gov/pubmed/28188938>.
16. The Guardian 2017, New Applications of Stem Cell Therapy, viewed 12th May 2018, <https://guardian.ng/features/new-applications-of-stem-cell-therapy/>.
17. Walenda, G., Hemeda, H., Schneider, R.K., Merkel, R., Hoffmann, B. & Wagner, W., 2012, ‘Human platelet lysate gel provides a novel three dimensional-matrix for enhanced culture expansion of mesenchymal stromal
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18. Xu, S., Menu, E., De Becker, A., Van Camp, B., Vanderkerken, K. & Van Riet, I., 2012, ‘Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favour
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19. Xu, S., Veirman, K., Becker, A., Vanderkerken, K. & Van Riet, I., 2018, ‘Mesenchyman stem cells in multiple myeloma: a therapeutical tool or target?’, Leukemia, <DOI: 10.1038/s41375-018-0061-9>