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PT4024 > L7 Stem Cell Therapies > Flashcards

L7 Stem Cell Therapies Flashcards

1
Q

What are stem cells?

A

Undifferentiated cells that are capable of self-renewal and have the potential to differentiate into various cell types

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2
Q

Which are more potent: embryonic or adult stem cells?

A

Embryonic stem cells (pluripotent)

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3
Q

Most valuable source of embryonic SCs?

A

Amniotic fluid

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4
Q

Blood from umbilical cord consists of which stem cells?

A

Haematopoietic and mesenchymal SCs

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5
Q

Which are more potent: haematopoietic or mesenchymal stem cells?

A

Haematopoietic

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6
Q

Most frequently used source of mesenchymal SCs?

A

Bone marrow

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7
Q

Where do stem cells come from?

A
  • amniotic fluid
  • human umbilical cord
  • bone marrow
  • adipose tissue
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8
Q

First generation stem cells

A
  1. Haematopoietic (multipotent)
  2. Mesenchymal (multipotent)
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9
Q

Most commonly used stem cell type

A

HSC

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10
Q

Bone marrow transplants containing __ have been used to treat haematological cancers.

A

HSCs

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11
Q

Advantage of MSCs

A

Much easier to isolate and produce a higher yield compared to other SCs

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12
Q

What properties do MSCs possess?

A
  • immunomodulatory
  • anti-inflammatory
  • angiogenic
  • anti-apoptotic
  • trophic
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13
Q

Mesenchymal stem cell therapy used in Europe for treating fistulising Crohn’s disease

A

Alofisel

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14
Q

Second generation stem cells

A
  1. Embryonic
  2. Induced pluripotent
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15
Q

Examples of embryonic stem cell therapies

A
  • Pluripotent derived retinal pigment epithelium to treat age-related macular degeneration
  • Oligodendrocytes for spinal cord injuries
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16
Q

How are iPSCs formed?

A

When the adult cells are cultured with embryonic SCs, forming new cells with SC-like properties

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17
Q

What may occur as a result of the reprogramming process to iPSCs?

A

Chromosomal abnormalities

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18
Q

2 categories of next generation stem cells

A
  1. Use as delivery vehicles for therapeutic drugs
  2. Use as enhanced therapeutic agents themselves
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19
Q

Tools to create next generation stem cells

A
  1. Virus-mediated transduction
  2. Gene editing tools e.g. CRISPR-Cas
  3. Chemogenetics (DREADDs)
  4. Optogenetics
  5. Copper-free Click Chemistry
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20
Q

Transduction of SCs with exogenous genes can be used to…

A
  • drive expression of proteins not normally expressed in SCs
  • treat haematological cancers using CARs
  • control cell signalling pathways using optogenetic actuators
  • increase expression of proteins normally expressed in SCs
  • express WT proteins as a mechanism to functionally compensate for genetic mutations
21
Q

What is the safest viral vector to use to facilitate stable long-term expression of a given exogenous gene, and why?

A

Lentivirus because it preferentially integrates into transcriptional unit - less likely to disrupt TSGs & protooncogenes

22
Q

What is Kymriah?

A

An immunocellular therapy containing tisagenleleucel, autologous T cells genetically modified ex vivo using a lentiviral vector encoding an anti-CD19 CAR (enhances patient’s T cell response against tumour antigens)

23
Q

Kymriah indications

A
  • B cell acute lymphoblastic leukaemia in patients up to age 25 whose cancer did not respond to previous treatment, and has come back at least twice
  • Diffuse large B cell lymphoma in adults whose cancer has come back or did not respond after 2 or more previous treatments
24
Q

What is optogenetics?

A

Use of light-responsive proteins to activate cell signalling pathways when exposed to specific wavelengths of light

25
Q

Explain how Copper-free Click Chemistry works?

A
  • Nanoparticles loaded with chemotherapeutic paclitaxel and cyclooctyne
  • MSCs coated with azide
  • MSCs migrate to tumour site. Azide binds nanoparticles that have cyclooctyne.
  • Click chemistry reactivity with cyclooctyne ensures paclitaxel reaches tumour site efficiently
26
Q

Stem cells have a natural tropism for __

A

tumour cells

27
Q

Two types of stem cells commonly used for drug delivery

A

Neural SCs and MSCs (little to no immunogenicity)

28
Q

SCs are packaged with the following anti-cancer agents…

A
  1. Prodrug converting enzymes
  2. Apoptosis-inducing factors
  3. Oncolytic viruses
29
Q

How does using SCs for drug delivery affect systemic toxicity?

A

They reduce systemic toxicity

30
Q

Example of SCs delivering a prodrug converting enzyme

A

Retroviral transduction of NSCs and MSCs to induce expression of cytosine deaminase allows for the systemic administration of the non-toxic prodrug 5-fluorocytosine, which is converted at tumour site (to which SCs have migrated) into the highly toxic chemotherapeutic 5-fluorouracil

31
Q

3 main groups of anti-metabolites

A
  • Folate antagonists: methotrexate
  • Pyrimidine analogs: Floxuridine
  • Purine analogs: thiopurines, mercaptopurine
32
Q

Chemotherapeutic approaches to treat glioblastoma multiforme targeting __ factors have failed to produce clinical benefit.

A

angiogenic

33
Q

NSCs engineered to express __ have been shown to be well-tolerated in a small Phase I trial in patients with high grade recurrent glioma.

A

cytosine deaminase, a prodrug converting enzyme

34
Q

What is being tested in clinical trials as an alternative therapeutic approach for high grade glioma?

A

Intracerebral injection of NSCs engineered to express human carboxylesterase (hCE1m6), which converts irinotecan to the highly potent SN-38

35
Q

Examples of approved topoisomerase inhibitors

A

Irinotecan and topotecan

36
Q

An example of using SCs to deliver apoptosis-inducing drugs

A

Recent small Phase I trial used autologous bone marrow-derived MSCs engineered to express the suicide gene encoding HSV-tk in patients with advanced GI adenocarcinoma. HSV-tk converts the prodrug ganciclovir to the toxic ganciclovir triphosphate, which induces apoptosis in actively proliferating cells.

37
Q

Bystander effect of toxic metabolite ganciclovir triphosphate

A

Toxic metabolite also taken up by neighbouring cells within the TME, resulting in further tumour cell death

38
Q

How do oncolytic viruses work?

A

Viral vectors that infect solid tumour cells, replicate and cause tumour cell lysis and release viral progenies which infect neighbouring tumour cells

39
Q

Example of an onolytic immunotherapy

A

Talimogene laherparepvec (T-VEC) is a genetically modified, HSV type 1-based oncolytic immunotherapy approved for the treatment of melanoma with metastatic lesions in skin & LNs

40
Q

Advantage of packaging OVs within SCs

A

To shield the OVs from physiological mechanisms that may limit their biodistribution and effectiveness

41
Q

Use of stem cells as therapeutics

A
  • Immuno-oncology
  • Tissue repair
  • Gene therapy
42
Q

Future work using iPSCs will hopefully allow potential to…

A

create ‘off-the-shelf’ antigen-specific immunotherapies

43
Q

Modified allogeneic bone marrow-derived MSCs transfected with __ currently being investigated in Phase II trials for TBI

A

Notch intracellular domain

44
Q

NSCs that have been engineered to constitutively express __ are currently in Phase II trial for ALS

A

glial cell-derived neurotrophic factor (GDNF)

45
Q

What is Strimvelis?

A
  • Stem cell-based gene therapy approved by EMA for the treatment of ADA-SCID
  • Autologous HSCs transduced with a retrovirus which encodes ADA enzyme
46
Q

What is Zyntelgo?

A
  • EMA approved autologous HSC-based therapy for the treatment of β-thalassaemia
  • Introduces functional copies of β-globin gene→less frequent blood transfusions
47
Q

A way to reduce immunogenicity in iPSCs

A

Reduce HLA expression on the surface of stem cells to make them less recognised by NK cells, T cells & macrophages

48
Q

Why are stem cell therapies for oncology under the greatest scrutiny?

A
  • Because stem cells share common molecular features with cancer cells
  • MSCs have angiogenic and immunosuppressive properties which may promote tumour growth

PT4024 (12 decks)

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