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Transfusion Medicine Fellowship > Cellular Therapies > Flashcards

Cellular Therapies Flashcards

1
Q

What percentage of patients have an HLA-matched sibling?

A

30%

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2
Q

How many allo-transplants have ABO incompatibility?

A

50%

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3
Q

What are the consequences of major ABO incompatibility in allo-HSCT?

A

Hemolysis
Pure red cell aplasia
Delayed engraftment

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4
Q

What are the consequences of minor ABO incompatibility in allo-HSCT?

A 
Increased GVHD (controversial)
Delayed hemolysis (passenger lymphocyte syndrome)
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5
Q

When should ABO type be switched in HSCT?

A

No consensus, but maybe:
+100d
Donor cells present at 2+ typing
Based on presence of isohemagglutinins

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6
Q

What is the significance of RhD matching in stem cell transplant?

A

It is only of concern in young women. Even then, only 10% of D+ recipients getting D+ donors will develop anti-D.

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7
Q

Why is it important to minimize platelet transfusions in the peritransplant period?

A

Excessive platelet transfusion will stimulate alloimmunization; anti-HLA antibodies can cause graft failure.

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8
Q

What isohemagglutinin titers are recommended for ABO-incompatible SOLID ORGAN transplant?

A

Titers should be less than or equal to 16, at least in young children?

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9
Q

How can ABO-incompatible solid organ transplant cases be supported by the blood bank?

A

Try to give blood that is compatible for both organ and recipient (eg. O pt receiving A liver should get A plasma and O red cells). No need to irradiate. MINIMIZE pre-transplant transfusions.

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10
Q

How significant are A subgroups in transplant settings?

A

Not at all; can treat A2 as O and A2B as B.

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11
Q

What is passenger lymphocyte syndrome, and what drives its relative risk?

A

Transfer of established B-cell lineages that generate anti-host antibodies (usually A/B, but also D, K, Fya). The risk correlates to the degree of lymphoid tissue present in the transplanted tissue.

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12
Q

What disorders are best treated with autologous transplant?

A

Those with a high dose-treatment response curve, such as B-cell lymphomas and plasma cell myelomas.

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13
Q

What are the 8 required loci for HSCT matching?

A

HLA-A
HLA-B
HLA-C
HLA-DRB1

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14
Q

How do cord transplants compare to non-cord?

A

Lower-dose, slower engrafting. Best in children. High concentration of CD34+ cells.

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15
Q

What is the benefit of conditioning chemotherapy in transplant? What is used to condition?

A

Autologous: Eliminate as much tumor as possible
Allogeneic: Suppress native immunity (and eliminate tumor).
Bone marrow failure conditions do not require conditioning.

Condition with purine analogs and anti-T-cell therapy (formerly cyclophosphamide, busulfan, TBI)

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16
Q

What is the minimum dose of CD34+ cells required for stem cell transplant?

A

2.5 x 10^6 CD34+ cells per kilogram.

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17
Q

How do HPC(A) transplants compare to HPC(M)?

A

HPC(A) engrafts faster but is associated with more reactions and GVHD due to higher CD3+ load.

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18
Q

What markers allow HPCs to interact with their bone marrow niche?

A 
VLA-4
MAC-1
CXCR44
CD44
CD62L
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19
Q

How does G-CSF promote mobilization? When is the peak?

A

It increases expression of MMP-9 and other proteolytic enzymes. 5d to peak.

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20
Q

How does Plerixafor promote mobilization? When is the peak?

A

Disrupts CXCR4-CXCL12 interactions. Peak is rapid; 6 hours

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21
Q

What are alternatives to G-CSF and plerixafor for mobilization?

A

Chemo

EPO, TPO, GM-CSF, PT? Lithium? Natalizumab…all meh.

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22
Q

What happens to circulating CD34+ count during harvest?

A

It does NOT fall, it actually holds steady or even increases as a response to harvest.

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23
Q

What happens to platelet count during harvest

A

It does fall, and patients can become transiently thrombocytopenic.

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24
Q

How are donors screened before stem cell transplant?

A

There is a DHQ-equivalent and medical records are reviewed. IDMs are performed up to 30d BEFORE harvest.

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25
Q

Can you collect from an ineligible donor?

A

Yes, if the medical need is great.

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26
Q

When should an HPC sample be drawn for culturing?

A

After collection but before processing & cryopreservation.

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27
Q

How can neoplastic cells in the product bag be reduced?

A

Harvest using chemo prime
Select/enrich for stem cells
Direct treatment in bag (doesn’t work well?)

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28
Q

What diseased states can have cause complications for stem cell harvesting?

A

Sickle cell: G-CSF promotes sickling.
Myeloma: Paraproteins affect the interface.
Autoimmune disorders: G-CSF can cause flares.

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29
Q

What are the adverse effects of G-CSF?

A

Bone pain, headache, nausea.
Splenomegaly is common, ruptures are rare.
Neutrophil activation syndromes are rare.

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30
Q

How do pediatric harvests differ from adult?

A

Kids have fewer complications overall, but are more likely to need CVC access and experience more vasovagal reactions and citrate toxicity.

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31
Q

What is TC(A)?

A

Therapeutic cells (usually CD3+) from apheresis, often collected in tandem with stem cells for later DLI.

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32
Q

What are the acceptance criteria for a cell processing lab to take HPCs?

A

Need IDMs, ABO/Rh, an adequate label (donor, recipient, facility, product, DIN). HPC(A) should be >60% MNCs and have >90% viability.

33
Q

How are HPCs processed to minimize major/minor ABO incompatibility issues?

A

Spin to remove red cells, wash to remove plasma. Do both in bidirectional incompatibility.

34
Q

What is the benefit of cellular selection and depletion in stem cell processing?

A

Can enrich for CD34+ cells to make a more product and select against tumor. Can also select for or against T-cells, Dendritic cells, and B-cell lineages.

35
Q

What is stem cell expansion?

A

Ex vivo culturing of stem cells with cytokines and growth factors. Can expand HPC (CB) but not HPC (A)?

36
Q

What is dendritic cell generation?

A

An ex vivo process of enriching MNCs and exposing them to IL-4 or IL-13 to generate dendritic cells, which enhances graft vs tumor effect.

37
Q

How do reactions to DMSO generaly present?

A

Very similarly to allergic transfusion reactions.

38
Q

What immunophenotypic features distinguishes a plasmacytoid dendritic cell from a conventional/myeloid dendritic cell?

A

Strong expression of CD123 and no expression of CD11c.

39
Q

What is the concept of dendritic cell vaccines?

A

Dendritic cells can be loaded with antigen and activated to generate a recipient immune response against viral or tumor antigens. In practice, this has not been very promising.

40
Q

Describe the structure of the CAR.

A

Rather than a modified TCRa/b, it consists of a zeta intracytosolic region as well as a CD28 costimulatory region affixed to an extracytosolic single-chain variable fragment which bears the target specificity.

41
Q

What are the transcription factors needed to induce pluripotency in fibroblasts?

A

c-Myc
Sox-2
Oct-4
Klf-4

42
Q

What is a real example of cellular transdifferentiation?

A

Pancreatic exocrine cells can be induced to transform into beta-endocrine cells.

43
Q

What can influence an injured tissue’s ability to undergo regeneration (rather than repair)?

A

Age of immunity (fetal tissue more able to regenerate), relative pluripotency of niche stem cells.

44
Q

What is the difference between pluripotency and multipotency?

A

Pluripotency means the ability to generate cells from all 3 germ layer lineages. Multipotency can only generate from one.

45
Q

What cellular interactions drive hematopoietic progenitor cell homing?

A

CXCL12/CXCR4, E-selectin, VLA-4/5, VCAM, and others.

46
Q

What are the four transcription factors that can induce pluripotency in fibroblasts?

A

c-Myc, Klf4, Oct4, Sox2

47
Q

What is tissue transdifferentiation?

A

Conversion of one committed cell lineage to another (eg. Pancreatic exocrine to beta-endocrine)

48
Q

What is the driving principle behind DC vaccines?

A

Dendritic cells can be prepared with an antigen to promote a robust T-cell response.

49
Q

How can an antigen presenting cell be loaded with antigen for the purpose of cellular therapy?

A

Can expose to cellular lysates, proteins, and nucleic acids. Can transfect with a viral vector.

50
Q

What is the relative occurrence rate of complications arising from mismatching of non-HLA blood groups in HSCT?

A

1-8% have complications. These are almost always to ABO, though rare complications with RhD, Kell, Kidd, and Lewis have been described.

51
Q

At what isohemagglutinin titer is hemolysis a concern in ABO incompatible transplant?

A

> 256

52
Q

What defines delayed engraftment and/or PRCA?

A

Normal engraftment should take 3-4mo to reach >2.5 x 10^9 retics per liter. If less than 1% retics after 28d, PRCA.

53
Q

What is transplant associated TMA?

A

A rare thrombotic complication of hematopoietic stem cell transplant. Diagnosed by renal biopsy, but not really well treated by plasma exchange.

54
Q

What is the role of monitoring isohemagglutinin titers pre-transplant and peri-transplant?

A

Pre-transplant: Can identify high titers that require exchange or adsorption before transplant

Peri-transplant: Can be used as a marker of native immune decline / myeloablation

55
Q

How should ABO matching be done in a major incompatible graft? Minor incompatible? Bidirectional?

A

Major: Give red cells of recipient type, plasma products of donor type.
Minor: Try to match both directions (eg AB patient getting A cells&raquo_space; Give A cells, AB plasma)
Bidirectional: Fuck it, O cells and AB plasma.

56
Q

What non-HSC cells contribute to the HSC niche?

A

Osteogenic progenitors, osteoclast, osteoblasts, adipocytes, and endothelial cells

57
Q

What infectious disease testing is required of allogeneic HPCs? Auto?

A

Allogeneic: HIV-1/2, HTLV-1/2, HBV, HCV, Syphilis, CMV
Autologous: All except CMV

58
Q

What is the maximum harvest goal in HPC-M?

A

20ml/kg.

59
Q

How are HPCs stored?

A

In vapor phase nitrogen at < -150C.

60
Q

What quality assays should be done on an HPC product upon receipt by a cell therapy lab?

A 
CBC/Diff
CD34+ flow
Sterility studies
CFU (clonogenic assay)
Viability (Trypan, 7-AAD, acridine)
61
Q

What are the features of a DMSO transfusion reaction?

A

Nausea, vomiting, cough, headache, redness

62
Q

What federal regulations oversee the handling and production of minimally manipulated HPCs? Specially altered products?

A

Minimally manipulated: Section 31 of CBER’s PHSA

Altered: Title 21, CFR pt 1271

63
Q

How does AABB recommend tissue allografts be handled?

A

By a central transfusion medicine service.

64
Q

What are the aspects of donor assessment in tissue allograft harvest?

A

Consent/authorization, review of medical history, a physical assessment, perhaps autopsy reports. IDM testing is the same as with blood…

65
Q

What types of tissue grafts does the FDA regulate?

A

Allografts, xenografts, xenotransplants. Not autografts.

66
Q

Compare and contrast freezing of tissue allografts with lyophilization.

A

Cryopreservation can preserve cellular viability if a cryoprotectant solution is used. Lyophilization does not.

67
Q

Do tissue allografts require ABO matching, HLA matching, or both?

A

Neither!

68
Q

What infectious agents can be transmitted in allografts?

A

Virtually all; viruses, bacteria, fungi, prions, and even sometimes neoplasms.

69
Q

What are the responsibilities of hospital tissue services?

A

Must handle tissue, trace/detect/report adverse events. They must handle inspection, consenting, and record-keeping.

70
Q

What is the most common tissue auto-graft?

A

Craniotomy specimens

71
Q

What are typical storage condition of most simple tissue grafts?

A

Most are stored either in fridge at 1-10C or frozen at ***

72
Q

What disease states get the most benefit from donor lymphocyte infusion (DLI)?

A

Most promising early data was in the setting of CML. AML derives some benefit, while ALL, myeloma, and lymphomas derive very little benefit.

73
Q

What are the benefits and consequences of donor lymphocyte infusions?

A

Can induce remission during relapse, can also fight off opportuistic infections. Associated with worse GVHD and can cause marrow aplasias.

74
Q

In cellular gene therapy, what are some possible methods of genetic transduction?

A

Non-viral: Injection, liposomes, electroporation.

Viral: Lentiviruses, retroviruses.

75
Q

What are the strengths and weaknesses of using a retrovirus as compared to other viral vectors?

A

Retroviruses randomly insert into the genome, causing insertional mutagenesis and requiring the cells to be actively dividing. But, response is more durable.

76
Q

What are some criteria for a disease to be targetable by cellular gene therapies?

A

The disease should have high morbidity/mortality, should not have good treatment otherwise, and should have a specific and reversible phenotype. Usually these are monogenic disorders driven by cells that are easy to harvest, modify, and administer.

77
Q

Tocilizumab

A

Anti-IL-6 antibody used to mitigate cytokine-storm-like inflammatory response in CAR-T treatment.

78
Q

Tsagenlecleucel / Kymriah

A

Novartis-based CD19 CAR-T therapy

79
Q

Axicabtagene / Yescarta

A

Gilead-based CD19 CAR-T therapy

Transfusion Medicine Fellowship (34 decks)

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