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Immunology > Hematologic Malignancies and Stem Cell Transplantation > Flashcards

Hematologic Malignancies and Stem Cell Transplantation Flashcards

1
Q

Where do HSCs reside?

Signals promote what two fates?

A

In stem cell niches of the bone marrow where they receive signals that either promote quiescence or cell division

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2
Q

When a HSC divides, what two cells does it give rise to?

A
  1. A HSC (self-replication)

2. A cell committed to differentiation

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3
Q

What 3 cell types does common lymphoid progenitor cells give rise to?
Where are these cells produced?

A

T, B and NK cells in the bone marrow and thymus (primary lymphoid organs)

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4
Q

What are the tertiary lymphoid tissues?

A

Skin, organ sites, etc

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5
Q

What cells do the common myeloid progenitors give rise to? Where does this occur?

A 
Macrophages, monocytes
granulocytes 
RBC
Platelets 
They differentiate in marrow and mature in the blood
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6
Q

How many HSCs are in the body?

How many RBCs are made per day?

A

100,000

200billion RBC/day

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7
Q

What three signals/pathways are crucial for maintaining homeostasis so hematopoesis doesnt proceed at too fast a rate?

A
  1. cell signals to ENHANCE growth/proliferation
  2. Signals to CHECK growth/proliferation
  3. Signals to CONTROL differentiation
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8
Q

Malignancies to lymphohematopoetic system can lead to what three disorders?

A
  1. Leukemia- in bone marrow and blood
  2. Lymphoma- in lymph nodes
  3. plasma cell dyscrasias
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9
Q

What are the 4 ways that hematologic malignancies can be categorized?

A
  1. By where they occur (blood, lymph node)
  2. By cell type (lymphoid, myeloid)
  3. Acute (early precursors) vs. chronic (late precursors involving mature or differentiated cells)
  4. Historical figures (Hodgkins)
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10
Q

How are each of the over 100 hematologic malignancies unique? (5 ways)

A
  1. cell of origin
  2. histologic appearance
  3. Cell surface markers
  4. Cytogenetic features
  5. Molecular abnormalities
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11
Q

Acute myeloid leukemia is characterized by the malignant transformation of an _____________ in the _________ section of the lymphohematopoetic cascade.
The malignant cells are characterized by:
1.
2.

A

early precursor in the myeloid section

The cells have:

  1. excessive proliferation
  2. impaired differentiation
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12
Q

AML causes ___________________ because of its excessive numbers of myeloid progenitors and infiltration. This results in decreased numbers of :
1.
2.
3.

A

impaired bone marrow function

RBC, Granulocytes, platelets

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13
Q

What do leukemia cells do in the periphery?

A

Clog vessels in pulmonary and cerebral circulation thus is rapidly fatal

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14
Q

Acute T-lymphoblastic leukemia is caused by a malignant transformation of ________. These cells are characterized by their (2 things)

A

early precursors of the lymphoid lineage.

They have excessive proliferation and failure to differentiate

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15
Q

What structure to T-lymphoblastic leukemias infiltrate, causing mediastinal masses that impinge on the trachea?

A

Thymus

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16
Q

What are the two phases of Chronic Malignant Leukemia?

A
  1. Chronic phase- where the early myeloid precursor has a malignant transformation so it has excessive proliferation but is able to differentiate into mature granulocytes
  2. Blast phase- after about 5 years another transformation causes impaired differentiation so the same affects of acute myeloid leukemia ensue
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17
Q

What is mantle cell lymphoma a subtype of ?

A

Non-Hodgkin’s lymphoma

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18
Q

What causes mantle cell lymphoma?

A

mutation in a more mature B cell in the mantle area of the lymph node that have excessive proliferation.
This tumor grows excessively in lymph nodes and causes excessive proliferation of malignant cells that invade other tissues

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19
Q

What feature of chemotherapy and radiation makes it relatively undesirable as a cancer treatment?

A

It does non-specific DNA damage of normal and cancer cells so it can be damaging to the host manifest by:

  1. loss of hair, nausea, vomiting
  2. Bone marrow suppression
  3. organ damage which can result in secondary malignancies
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20
Q

Why do secondary malignancies arise after chemo and radiation?
What are two common secondary malignacies?

A

They arise because the radiation/chemo can cause DNA damage in normal cells that may result in malignant transformation

  1. Bone marrow cancer- AML
  2. Solid tumors
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21
Q

What disease is the exemplar for using molecular-targeted therapy to treat cancer?
What is the molecular mechanism of this form of cancer?

A

Chronic Myelogenous Leukemia (CML) was found to be due to a chromosome abnormality that placed ABL tyrosine kinase from chromosome 9 next to BCR gene on chromosome 22 resulting in a fused gene.
Overactivated tyrosine kinase ABL leads to excessive phosphorylation of signaling pathways involved in cell growth and proliferation.

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22
Q

After understanding the mechanism of BCR-ABL in CML, how were physicians able to derive a treatment pathway?
What drug do they use?

A

They developed imatinib which binds to an ATP binding site as a selective inhibitor on BCR-ABL to block it, not allow for phosphorylation and shutting off the tyrosine kinase function

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23
Q

What did scientists do in response to resistance to Imatinib?
How does resistance to the drug arise?

A

Resistance to Imatinib arises because the ABL kinase region develops mutations not allowing Imatinib to bind.
They developed second and third generation drugs to bind the imatinab resistant ATP ABL binding sites

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24
Q

Overactivation of BTK results in what?

A

Constitutive signaling in the B- cell leading to B-cell lymphomas

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25
Q

What drug has been developed to inhibit BTK?

A

Ibrutinib is a highly active BTK inhibitor used to treat B-cell malignancies

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26
Q

What are the three main steps scientists are using to develop treatments for hematologic malignancies?

A
  1. Large- scale sequencing of the genome of cancers to see whole genome, RNA, DNA methylation patterns, gene expression
  2. Identifying molecular pathways to identify the functional consequence of genetic abnormality
  3. Drug development based on these pathways
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27
Q

What does Rituximab target? What is the effect?

A

It targets CD20, a B cell marker (on malignant and normal cells)
It binds to the CD20, then its kills the B-cell by ADCC

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28
Q

What should rituximab be used in conjunction with for maximal effect?

A

chemo

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29
Q

Why is it not so severe that rituximab also kills normal B-cells?

A

patients are usually protected by already produced Ig. Also once rituxamib is removed, the B-cells can be produced again

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30
Q

What is the target of Brentuximab?

A

CD30 which is expressed on Hodgkin lymphoma malignant cells and Tcell lymphomas

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31
Q

What is the mechanism by which Brentuximab works?

A

It is an anti-CD30 antibody with anti-mitotic drug attached to it.
When it binds a Hodgkins lymphoma cell or Tlymphoma cell, it is internalized and releases the anti-mitotic drug to kill the cell

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32
Q

How do Chimeric Antigen Receptor T cells (CAR T cells) work?

A
  1. T-cells are removed from the patient
  2. They are engineered to attack “self” malignant cells by transduction (retroviral vector to deliver genes to the T-cell) that target antigens on the malignant cells (like CD19 on B-cell lymphomas)
  3. The tranduced T-cells that have IgR for the malignant cell antigen and a costimulatory molecule is infused back into the patient
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33
Q

What is transduction?

A

It is when retroviral vectors deliver genes to be incorporated in a cell.
It is used in CAR Tcells to deliver genes against an antigen on a malignant cell

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34
Q

What is the major drawback of using CAR T cells as a cancer treatment?

A

The activated T cells produce a large amount of cytokines causing severe side effects (cytokine release syndrome)

  1. leak of fluid into lungs
  2. low BP
35
Q

What was the major “offending cytokine” when cytokine release syndrome was observed as a result of CAR T cell therapy?

A

IL-6 which causes fever, inflammation, acute liver phase, etc

36
Q

When discussing Stem Cell Transplant (SCT), what is allogeneic, syngeneic, and autologous?

A

Allogeneic- from a donor
Syngeneic- from an identical twin (same genome)
Autologous- using the patients own cells

37
Q

SCT not only infuse hematopoetic stem cells, but what other cells?

A

Differentiated HSCs
differentiated myeloids
mature lymphocytes

38
Q

What is the basic schema for how SCT happens?

A
  1. The recipient receives chemo to clear room for the transplant, to kill cancer, and to immunosuppress them so they don’t reject the graft
  2. HSCs are obtained from a donor via their iliac crest (marrow) or peripheral blood
  3. HSCs are transferred to the recipient intravenously and the stem cells home to the recipients marrow
39
Q

What is aplastic anemia?

How is it treated?

A

lack of stem cells (usually because of autoimmunity) which impairs blood cell production.
It is treated by SCT

40
Q

What are the 5 basic categories of diseases treated by SCT?

A
  1. lack stem cells (aplastic anemia)
  2. lack of immune cells (SCID)
  3. abnormally functioning mature cells (sickle)
  4. Bone marrow malignancy (AML)
  5. Cancer
41
Q

Why is SCT used to treat SCID?

A

In SCID, the person is impaired in making functional immune cells and HSCs can give rise to normal immune cells

42
Q

Why is SCT used to treat sickle cell anemia?

A

Normal stem cells from a healthy donor can give rise to cells that do not sickle, because sickle cell is caused by a genetic defect, not bodily physiological conditions

43
Q

What is the most common use of allogeneic SCT?

A

To treat AML because abnormal marrow cells are killed with chemo/radiation and are replaced with normal cells from a donor

44
Q

How can cancers be killed with SCT?

A

Donor T cells (NK and B too, but to a lesser extent) attack certain types of cancer cells because the T-cell recognizes it as “non-self”.
If the T-cells were injected directly, they would be rejected by the recipients immune system. Using SCT, the donor immune cells remain in the recipient to attack cancer

45
Q

What are the 5 health requirements to be considered to be a recipient of SCT?

A
  1. right diagnosis and status of disease must be ascerned
  2. age less than 60 for normal SCT, under 70 for reduced-intensity transplant
  3. good performance status
  4. good organ function
  5. suitable donor identified
46
Q

What would be the ideal donor for a SCT?

A

An HLA-identical donor (siblings have a 1/4 chance) but if not a sibling, there are registries of unrelated donors that yield 65-70% chance of finding an HLA identical match

47
Q

If a sibling is not an HLA-identical match, what 3 other options can be explored to find someone suitable to be an SCT donor?

A
  1. Registry with HLA typing info (17 million donors, 65-70% chance of match)
  2. Umbilical cord blood- immature immune cells so more HLA mismatch can be tolerated (750,000 units worldwide)
  3. Haploidentical donors- share 3 of six HLA genes but can cause GVHD or rejection
48
Q

What do patients receive a “conditioning regimen” before SCT?

A

Chemo or radiation is given to:

  1. suppress the immune system
  2. make hematopoetic space
  3. Kill cancer cells
49
Q

What are the two ways stem cells can be gathered from the donor?

A
  1. Bone marrow harvest- aspirated from iliac crest
  2. Peripheral blood SC harvest- mobilizing agents link GM-CSF cause stem cells to be released from the marrow into the blood, then they are collected by leukapheresis (into an IV that sorts cells by size and density)
50
Q

Does bone marrow harvest or peripheral blood SC harvest yield more SC, differentiated myeloids, and immune cells?

A

Peripheral

51
Q

About how long is the hospital stay for someone receiving SCT?

A 
4 weeks
1- high dose chemo
2- Bone marrow transfer
3- supportive care because the patient will be really sick (the new blood cells haven't started working yet)
4- engraftment
52
Q

How many days does it take for new cells to be sen in blood after a SCT?

A

12-14 days

53
Q

What is engraftment?

What does the patient require in this time period?

A

the time between transplant and the appearance of new blood cells.
The patient requires frequent blood and platelet transfusion as well as prophylactic antibiotics (because their neutrophil count is low)

54
Q

Why are patients given prophylactic antibiotics during engraftment?

A

because they have low neutrophil count so are very prone to infection

55
Q

How long does it take to fully recover from a SCT?

A

a year

56
Q

Donor derived HSCs give rise to _________________ which go to the ________ to make new T cells.

A

T-lymphoid progenitor cells which travel to the thymus to make new T cells

57
Q

Donor derived T-cells are exposed to antigens from __________ and __________ in the thymus.

A

Donor and recipient

58
Q

Why are T cells from donor HSCs able to provide appropriate immunity (not autoimmune)

A

Because they go to the thymus and are educated with donor and recipient antigens and develop appropriate reactions to both tissue

59
Q

Tolerance development of donor derived T-cells work better in what patients?

A

younger because they are more likely to have a functional thymus (although the thymus can “reawaken” after transplant

60
Q

What is the most common complication of allogeneic SCT?

A

Graft vs. Host disease (GVHD)

61
Q

What causes GVHD?

A

minor histocompatability antigens that differ between donor and recipient due to polymorphic nature of HLA (they usually are identical at MAJOR HLA)

62
Q

Why do minor histocompatability antigen differences in donor and recipient cause GVHD?

A

the T cell recognizes the antigens as different, increases cytokines and causes targeted cell death

63
Q

What are the steps of Acute GVHD?

A
  1. minor histocompatability antigens are presented to donor T-cells by recipient APCs
  2. Donor T-cells make IL-2 and upregulate IL-2R to grow and proliferate
  3. T-cells make cytokines and recruit effector cells
  4. immune attack against recipient epithelial cells
64
Q

What three site do acute GVHD usually present in?

A

skin, liver, intestine

65
Q

What causes chronic GVHD?

A

failure of tolerance to develop so it mimic autoimmune diseases

66
Q

What are the sites of involvement of chronic GVHD?

A

eyes, mouth, espophagus, skin, joints, liver

67
Q

What 4 strategies have been explored for preventing GVHD?

A
  1. Deplete T-cells in the graft
  2. Drug against T-cell activation
  3. Drug against T cell proliferation
  4. Drug against cytokine production
68
Q

Why is depleting T-cells in the graft usually not the best idea for preventing GVHD?

A

It works fine at preventing GVHD but you lose the beneficial effects of T cells like immune recovery and anti-tumor effects.
The cons outweigh the pros

69
Q

What are the MAIN problems associated with toxicity and risk of allogeneic SCT?

A

GVHD and prolonged severe immunodeficiency (induced so there is not graft rejection)

70
Q

What is the overall mortality rate for SCT?

A

20%

71
Q

Overall outcome of patients receiving SCT depend on what three clinical circumstances?

A
  1. disease and disease status (earlier> later stage)
  2. patient (younger> older)
  3. type of transplant (matched sibling >mismatched unrelated)
72
Q

What is GVL?

A

Graft-vs-Leukemia.

Allogeneic SCT has curative potential because donor derived immunologic cells can attack cancers

73
Q

Mice that received ___________________ transplants were much more likely to relapse in cancer than those that received _____________ transplants.

A

Syngeneic relapsed more than allogeneic

74
Q

What three things made patients in a GVL study less likely to relapse?

A
  1. Allogeneic transfer instead of syngeneic
  2. Those that experienced GVHD relapsed less
  3. Those that did NOT have T-cell depleted donors
75
Q

How do physicians purposefully harness the GVL effect?
When is it used?
What is the process called?

A

giving additional donor lymphocytes without the cover of immunosuppression to patients who have relapsed after a standard transplant.
This process is called “Donor Leukocyte Infusion”

76
Q

In what cancers are Donor Leukocyte Infusions given?

What is the side effect?

A

CML and AML

GVHD is the common side effect

77
Q

What type of cell is GVL due to?

A

Alloreactive cells (the same ones that attack host cells to cause GVH, but kill the leukemia as a “welcomed side effect”

78
Q

What does emphasizing GVL when doing transplants allow physicians to de-emphasize?

A

chemo and radiation prior to the transplant. They are given enough to allow engraftment without rejection

79
Q

What is the procedure of “reduced intensity transplant”?

What are the results?

A

The physician gives a low does chemo before the SCT.
After engraftment when the recipient has regenerated blood cells, the donor T cells are “unleashed” to attack the cancer cells

This results in:

  1. high response rate in malignancy
  2. overall less toxic procedure
  3. still GVHD risk
80
Q

What is graft engineering?

A

technique to develop/engineer a graft that has beneficial cells (HSCs and Tcells for specific antigens) but no harmful effects (T-cells that are alloreactive to self)

81
Q

What do unmanipulated grafts contain?

A

Beneficial elements:
1. HSCs
2. T-cells reactive to pathogenic antigens
Harmful elements:
1. T cells that are alloreactive against the recipient cells

82
Q

What is the procedure for engineering a beneficial cell only graft?

A
  1. Isolate HSCs by using immunomagnetic beads that attract CD34
  2. Incubate donor T cells with recipient normal APCs
  3. Donor alloreactive cells will be activated and start dividing
  4. Use a drug that targets dividing cells (MTX)
  5. Remaining T cells were not alloreactive so they can be increased in number (because they are anti-pathogen)
  6. Infuse the graft
83
Q

What chemokine receptor is a co-receptor on T-cells for HIV?

What are the implications of this?

A

CCR5.
If you can find CCR5 deficient donors, you could generate T-cells that are non-reactive to HIV and thus the disease can not proliferate

84
Q

What would be the perfect donor for someone that has AML and HIV?

A

An HLA identical, CCR5 negative donor

Immunology (25 decks)

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