Flashcards in Haematopoietic stem cell transplantation Deck (70):
what does allogenic mean?
transplants from a non identical twin transplant
what is the first immunotherapy treatment for cancer?
bone marrow transplant
when was the first bone marrows transplant performed?
how have HSCTs are performed a year?
how has the donor recruitment changed over time?
donors used to be recruited from the family but now people use donor registers
list diseases that are treated with HSCT?
aplastic anemia, sickle cell anaemia immunodeficiency disroders
what is the basic premise of the HSCT?
you transplant HSCs which can repopulate entire lineage of the blood system
are HSC rare?
what do the HSCs need to be able to do?
- the need to be able to self renew and also differentiate into al of the lineages
what percentage of the bone marrows of haematopoeitc stem cells?
what cells are really involved in the niche of the HSC niche?
the osteoblasts, osteoclasts, macrophages, CD146+ osteprogenitors, pericytes
what are autologous stem cell transplants?
donor using patients own cells- this is used to allw escalation of chemotherapy dose ( myeloma and lymphoma) so the stem cells are taken out, stored, the patient is treated by chemotherapy and then the stem cells will be put back.
what is a syngenic transplant?
cells from identical twin
what is an allogeneic transplant?
cells from another person- parent, relative, sister etc
what is the main criteria for HSCT~
the donor needs to have a complimentary HLA region on chromosome 6,
what are the two parts of the HLA system?
MHC class I (ABC) and MHC class II (DRbeta1 chain)
why is the HLA region so difficult to circumvent?
- it is so polymorphic and has to be matched
what part of the MHC class II region of the HLA region needs to be matched specifically?
the DR beta 1 chain
how are HLA haplotypes inherited? 9what does this mean about he chances of being matched?
one from you parents and one from your parents - so you have a 1 in 4 chance of being matched to your siblings
what ethnicity is most likely to get a donor and what is the chance?
70-80 chance for caucasian
how has the matching scheme improved?
donors that aren't haploidentical and are only half matchinghapolotype because the extent of matching required is less than previously thought
what are the three are sources of HSC?
bone marrow ,peripheral blood stem cells, umbilical cord
how have the sources of HSC changed over time?
related bone marrows used to be used the most but has decreased a lot, peripheral blood autologous and related peripheral blood are use the most now
what are the 4 regions why bone marrow is used and what are the downsides of using it?
- extensive clinical data are available about marrow transplant outcomes
- extensive information is available about the marrow donation experience
- lower risk of chronic graft vs host disease
- preferred option in non- maligant disorders ad children
but engraftment takes on average 21 days so the patients has to be transplanted with immune cells and blood cells during this point
what are the advantages and disadvanatges of using PBSC?
- they are easy to collect and have a rapid hematopoietic recovery time and decrease cost.
- they can cause chronic graft host disease- but the survival rate is wide the same but the risks are different. More patients get GVH but less patients relapse
how are peripheral blood stem cells removed from the peripheral blood system?
- can use granulocyte stimulating factors which stimulates myeloid cells to create proteases which interrupt the HSC with its niche- normally it is stuck to its niche. i a SDF-1 and VCAM-1 interactions hat keep it in its niche. G-CSF interrupts this and releases the stem cell
what two factors are used to release the stem cells from their niche?
- G-CSF and AMD3100
by how much as AMD3100 increase stem cell number in the PBS?
how can the PBSCs be collected?
apheresis: take blood out of arm- transfer to centrifuge- spins down mono nuclear layer which is syphoned off and the rest of the blood is returned allows a repeated rela of the blood- takes about 4 hours
why is umbilical cord blood useful? what is the downside?
- good for patients who have an uncommon HLA type
- HLA mismatch is better tolerated
- available more quickly
- reduced indigence and severity of GVHD
- but lower numbers of HS, slow or incomplete engraftment
how do the do a transplant?
- condiitoning: empty bone marrow with chemotherapy, then prevent the patient from rejecting the infused cells- apply anti-rejection drugs
- then infused the graft from the donors. It has two ke components HSCs which will reconstitute the immune system and also contain mature immune cells from the donor
- the aim is to switch the patients immune system to that of the donor
how can the switch of the immune system from that of the host to the donor be sed to treat cancers?
the tumour is attacked by the donor immune system - the major benefit of allogeneic transplant is that you provide a platform for the rejection of the caner- this is mediated by the donor immune system
what mediates the attack on cancer cells?
why is it that donor transplants can attack the cancer when the hosts can't?
the cancer has developed mutations so that itch ant be recognised by the T cells any more, but the new donors T cells can still recognise it because the patients ad the donor are genetically distinct- so the host tumour cells will express patient antigens which means these antigens can be targeted by the donor immune system
what is the graft versus tumour effect?
the donor immune system recognises the patients antigens of the patient
what is the downside of the patient versus tumour effect
the donor T cells will eat against antigens in the patents tissues that aren't the tumour
what two reasons cause graft versus host disease?
- the donor T cells can't be attacked by the host because of the antirecession drugs
- the host and the donor are genetically distinct
what is chronic graft vs host disease?
can cause multiorgan problems
what does chronic graft vs host disease result from (2)?
- reaction of the donor against the host
- occurrence of autoimmunity because the process of graft vs host disease damages the thymus which is critical for self tolerance
do most people recover from graft vs host disease?
once the patient has recovered from graft vs host disease, what can happen and why?
- the patients immune cells become educated and stop reacting against the patients tissue- becomes educated in the thymus- this means that immunosuppressants can be stopped
what drugs are used in immunosppreences?
mTORi, calcium inhibitors such as tacrolimus and cyclosporine which inhibit a phosphotase called calcineurin which normally acts downstream of T cell receptors and when it is activated is phos a T called NFAT which binds to IL-2 which leads to T cell activation. SO you can block this pathway
- can block TOR and then bloc the cell cycle
what is the downside fof cyclosporine?
tremor, renal dysfunction, risk of infections
even after the transplant has been successful, what risks are he patients exposed to and why?
- increased infection due to the fact the immune system isn't fully reconstsutied for around 2 years herpes etc
what are the areas that have improved stem cell transplantation?
re-diected T cell therapies
suicide gene therapy
what is the nonmyleoablative process?
CAMPATH is an antibody which recognises an antigen called CD52 which is expressed on most lymphocytes and it leads to their inhibition. If one performs a transplant in the normal but fgives it this antibody, yo can deplete the T cells and this results in reduced risk of severe GVHD- it reduces the risk of transplant such that the risk of dying is reduced by about half .You can then give thehe patient T cells that are less likely to form graft vs host disease- M t cells may be less lily too. You can give modified T cells which makes them specific for cancerous cells
what drug is used in non-myeloablative therapies?
what are the main positives about using non-meloablative approaches?
the problems with transplants is that a first high chemo has to be given- this can be damaging to the patient- you can change the conditioning proton l to make it specifically anti-rejection based rather than chemo therapy based because you are relying on the T cell attack on the cancer not the chemo
what is the re-directing T cell approach?
- re-directing T cells involves taking an antibody which can recognise the cancer antigen and link it to the down stream signalling of the T cells- insert this into the T cells and you make the chimeric antigen receptor be expressed in the T cells. You link the antibody to the downstream signalling apparatus of the T cel- recognition from the antibody and intracellular from T cell receptor and you make the cells be very good killer cells
- the responses are 80% 90% success rate of response
how can yo T modify T cells?
- suicide gene technonolgy- insert a gene which confers the ability after transplant to manipulate the environment and ablate the cells- modify the T cells you transfer and if they cause graft vs host then yo can stop the process b allowing the cells to undergo apptosis- HSV gene which has the effect of converting the drug inside of it into a toxic drug which will stimulate apoptosis
what gene and drug is used in gene suicide treatment?
- HSV-TK snd then use GVC which will form GCV-PPP which halts DNA replication
how can incompletely matched transplants be carried out?
can transfer the graft from incompletely matched grafts and prevent graft vs host by 3 days after transplant injecting cyclophosphamide which kill lost rapidly dividing cells- this will target hose cells launching an immune response- so patient islet with T cells which are non reactive and just contain the virus memory cells etc for the immune response to infection
generally what is the nonmyeloablative approach and what does this process of treatment involve?
generally it relies on the role of the T cells from the donor to attack the patient tumour with graft vs tumour effect. This allows less chemotherapy which often can be damaging for the patient and can't bemused in older patients.
- there is initial use of high immunosuppressants but then these are decreased and are less than conventonal transplants, this leads to a state of mixed chimerism early after transplant were both recipient and donor HSC coexist in bone marrow space.
- the bad thing is that it is often accompanied by draft vs host effect butt his can be used as a sign that the cancer is being eradicated
in terms of inflammatory response, why has non ablative HSCT been associated with less GVHD?
- the ablative chemotherapy approach results in a 'cytokine storm' which is thought to provide a proinflammator milieu for the development of GVHD
why is using an autologous graft not good for cancer?
because you want the graft vs tumour effect
how were the effects of graft vs host first seen?
- they found that total body irradiation in mice could not eliminate leukemias in doses tolerated clinically (in mice), but that total body irradiation followed by allogenic marrow transplantation could cure leukemias in some model mice. in the 1950 i patents of transplants in the 60-s it was observed that those who suffered from GVDH suffered less rate of relapse
what causes the cytokine storm?
the radiation and chemotherapy prematurely activates antigen presenting cells and leads to an accelerated stimulation of T helper cells. These release pro inflammatory cytokines which stimulate more T heleper cells with can result in a viscous circle know a the cytokine storm - can be treated with TNA-alpha antibody which can suppress GVHD .The cytokine storms leads to increased activation of donor T cells, producing more of a immune response
ow can you produce chimerism when you are doing a transplant ?
- you carry out an eugenic transplantation with T cel ldpeletion , this cause chimerism and tolerance and then adoptive immunotherapy with donor lymphocytes
why is using GVL effect hard?
because there is a fine line between it and GVD rate increase
what does CAR stand for ?
chimeric antigen receptors
what is the general process of using CARs?
- ou introduce tumour-specfic cloned TCR genes or genes encoding chimeric Ag receptors into immune effector cells
- through this genetic reprogramming, these immune effector cells are predicted to target Ags expressed y the leukaemia cells.
- in most clinical applications to date, aa paitent's own T cells may be reprogrammed to express these tumour specific receptors, minimising the risk of GVHD related toxicity as seen in the setting go aloo-hsct
why is CAR so good in terms of its targets?
- CAR-modified T cells are applicable to any cell surface-ag, including proteins, carbohydrates, and glycolipids for which an mAB can be generated
what antigen is normally targeted for leukemias clinical trials ?
how are the genes encoding the cars normally delivered?
via lentrivirus or gamma-retrovirus
How can CAR and suicide gene technology be used together?
Although adoptive transfer of CAR-modified T-cells is a unique and promising cancer therapeutic, there are significant safety concerns. Clinical trials of this therapy have revealed potential toxic effects of these CARs when healthy tissues express the same target antigens as the tumor cells, leading to outcomes similar to graft-versus-host disease (GVHD). A potential solution to this problem is engineering a suicide gene into the modified T cells. In this way, administration of a prodrug designed to activate the suicide gene during GVHD triggers apoptosis in the suicide gene-activated CAR T cells. This method has been used safely and effectively in hematopoietic stem cell transplantation (HSCT). Adoption of suicide gene therapy to the clinical application of CAR-modified T cell adoptive cell transfer has potential to alleviate GVHD while improving overall anti-tumor efficacy
how can you try to reduce the effect of GVD by altering the cell that you use in the transplant ?
you can remove the do not T cells and then put into the patient after 21 days- they have been genetically engineered
what organ has been particularly implicated in GVHD?
Many groups demonstrated that intensity of TBI and chemotherapy used during conditioning dictated the integrity of the GI mucosa and the subsequent transfer of bacterial lipopolysaccharide22-25 and other “danger/pathogen-associated molecular patterns” (DAMPS/PAMPS) into the systemic circulation.
when using less conditioning, why do you use immunosuppressants?
because you would use chemotherapy to destroy the hosts immune system but if you dont use this then they still have immune system so you use an immunosuppressant and then gradually decrease to promote the mixed chimera formation
explain DLI and mixed chimerism?
in order to reduce the levels of chemo used and irradiation which can be damaging, you can use less and then transplant - which destroys some of the bone marrow sand suppresses the immune system to prevent host vs grft disease. you then add lower levels of the stem cell graft which results in mixed chimerism with the hope that they will all eventually be switched- this is reduced intensity allogenic transplant. You can then add for take away donor lymphocytes accordingly (donor lymphcoyte infusion) - this can also be used for replies to increase the chimerism