Lecture 12 - Cell-based therapies Flashcards by Lauren Lavill

What are some examples of cell-based therapies?

HSCT
Mesenchymal stem cells
Pluripotent stem cell-derived cells
Engineered tissues and organs
CAR T cells
Antigen presenting cells
Blood cells - RBCs, platelets
Pancreatic islet cells
Skin grafts
Somatic cells, e.g. chondrocytes
Tissue and organ transplants

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What are the two types of stem cell therapies?

Autologous
Allogeneic

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Fill in the blank: Cells can be ‘wild type’ or _______.

genetically modified

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What is the process for cell therapy development?

Harvest
Selection
Amplification
(Differentiation)
Screening
Administration

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What can pluripotent stem cells (PSCs) be differentiated into?

All other types of cells, including other stem cells

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True or False: PSCs can be used to generate midbrain dopaminergic neurons.

True

Replaces those lost in Parkinson’s disease

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What significant finding was made regarding human iPSC-derived dopaminergic neurons?

They can function in a simian disease model.

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What is the FDA-approved gene therapy stem cell treatment for ADA-SCID?

Strimvelis

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What is the significance of a single nucleotide polymorphism in the β-globin gene for sickle cell disease treatment?

It allows for the transfection of autologous HSCs with an antisickling β-globin gene.

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Fill in the blank: Engineered HSCs can be used for _______ treatment.

HIV

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What are cytotoxic T cells (Tc cells) activated by?

Antigen presenting cells such as dendritic cells

Prime Tc cells with specific antigens for target cells, e.g. infected cells, cancers)

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What do Tc cells release to induce apoptosis in target cells?

Perforin
Granzyme

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What is an emerging approach in cancer immunotherapy involving antigen presenting cells?

Artificial APCs

Decorates cells or microparticles with antigens in order to prime T cells

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What are CAR T cells genetically engineered to do?

Express a chimeric antigen receptor (CAR)

Related emerging therapies:
* TCR-T cells
* CAR-M
* CAR-NK cells

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True or False: CAR T cells do not proliferate upon contact with their target antigen.

False

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What is the main advantage of artificial antigen-presenting cells?

They do not require harvesting from the patient.

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What is the role of directed differentiation in stem cell therapy?

To replicate specific signaling/contact conditions to guide cell differentiation.

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What is the outcome of the recent study on sickle cell disease with 35 patients?

High levels of therapeutic antisickling β-globin without recurrence of sickle crises.

What is Kymriah?

Autologous CAR T cells against CD19 for relapsing B-cell acute lymphoblastic leukaemia in children and young adults

Approved in Aug 2017 in the USA.

What is Yescarta?

Autologous CAR T cells against CD19 for large B-cell lymphoma in adults

Approved in Oct 2017 in the USA.

What is Tecartus?

Autologous CAR T cells against CD19 for mantle cell lymphoma and acute lymphoblastic leukaemia in adults

Approved in Jul, Dec 2020 in the USA and Europe.

What is Breyanzi?

Autologous CAR T cells against CD19 for relapsed or refractory large B-cell lymphoma

Approved in Feb 2021 in the USA.

What is Abecma?

Autologous CAR T cells against B-cell maturation antigen for adults with relapsed or refractory multiple myeloma

Approved in Mar, Aug 2021 in the USA and Europe.

What is Carvykti?

Autologous CAR T cells against B-cell maturation antigen for adults with relapsed or refractory multiple myeloma

Approved in Feb/Jun 2022 in the USA and Europe.

What is Aucatzyl?

Autologous CAR T cells against CD19 for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia ## Footnote Approved in Nov 2024 in the USA.

What are some ongoing studies related to CAR-T therapies?

Examining different tumour-specific antigens, particularly for solid tumours ## Footnote Reference to advancements in CAR-T cell applications.

What role do iPSCs play in cancer treatment?

iPSCs express a number of tumour-associated antigens and (autologous iPSCs) could act as personalised cancer vaccines ## Footnote Express tumour-associated antigens when tested against murine tumour models, vaccination with irradiated iPSCs + CpG led to tumour regression. Treatment possible within a few weeks of diagnosis.

What are some challenges in using a patient’s own cells for therapy?

* Cell damage or senescence * Genetic mutations or disease pathology * Time constraints * Insufficient cell numbers * Immune dysfunction * Difficulty in culturing or engineering cells * Comorbidities ## Footnote Factors that can prevent autologous cell use.

What is encapsulated cell therapy?

A strategy where cells are used to manufacture therapeutic proteins in situ when implanted into a patient ## Footnote Useful for delivering therapeutic proteins for various diseases.

What are some therapeutic targets for encapsulated cell therapy?

* Eye diseases * Neurodegenerative diseases * Diabetes * Cancers ## Footnote Examples of diseases that could benefit from this therapy.

What is the significance of the human leukocyte antigen (HLA) complex?

Determines whether the immune system sees cells as self or non-self ## Footnote Important for understanding transplant rejection.

What is the immune compatibility of hPSCs?

hPSCs express HLA class I antigens but not class II and require careful HLA matching ## Footnote They are not universally applicable. When differentiated, HLA class I expression changes.

What are hypoimmunogenic iPSCs?

iPSCs that maintain characteristics and can evade immune rejection in mismatched recipients ## Footnote Potential for universal transplantation - CD47 is tumour-associated antigen that is implicated in avoidance of phagocytosis.

What is the potential of off-the-shelf cells?

Clonal expansion of engineered iPSCs to generate master cell lines for well-defined treatments ## Footnote A promising avenue for standardized therapies.

What is the role of bacteria as therapeutic agents?

Bacteria can colonise hypoxic areas of tumors, which are resistant to traditional therapies ## Footnote Explored as a novel treatment approach. These bacteria classes as obligate anaerobes.

What are the challenges associated with cell-based therapies?

* Extremely expensive * Require extensive processing ## Footnote Issues that could limit widespread adoption.

Fill in the blank: Autologous iPSCs could act as _______ cancer vaccines.

personalised

What are the 7 transcription factors found which are sufficient to generate functional HSCs? ## Footnote Morphogen-directed differentiation of human PSCs into haemogenic endothelium.

1. ERG 1. HOXA5 1. HOXA9 1. HOXA10 1. LCOR 1. RUNX1 1. SPI1

How was iPSCs used as a therapy for a patient with Parkinson's disease?

iPSCs reprogrammed into 2.4 million dopamine precursor cells and implanted into dopamine activity centre of the brain

What is strimvelis?

It is an autologous CD34+ enriched cell fraction that contains CD34+ cells transducted with retroviral vector that encodes for human ADA cDNA sequence.

What does strimvelis treat?

Treatment of SCID due to adenosine deaminase deficiency (ADA) in patients who cannot be treated by bone marrow transplant as they do not have suitable donor.

How does strimvelis gene therapy work?

1. Patient bone marrow collected 1. CD34+ cells isolated and stimulated with cytokines (SCF, Flt3, TPO, IL-3) 1. Three daily rounds of retroviral supernatant addition inserted into CD34+ cells with ADA gene 1. Transduced CD34+ cells infused into patient