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PHAR 211 > CAR T-cell therapy > Flashcards

CAR T-cell therapy Flashcards

1
Q

What is the function of Helper T cells (CD4)?

A

Upon binding to a specific antigen, helper T cells secrete cytokines to stimulate the differentiation of B cells into plasma cells (antibody-producing cells)

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2
Q

What is the function of Cytotoxic cells (CD8)?

A

Upon activation, cytotoxic T cells bind and kill infected cells and cancer cells (or any substance marked as foreign by the immune system)

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3
Q

How are cytotoxic T cells activated?

A

By simultaneous interactions of surface molecules (TCR-MCR and CD28-CD80) between cytotoxic T cell and APC cells

These two cell stimulating interactions result in T cell proliferation and activation

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4
Q

What is the first T cell activation signal?

A

Between TCR of the cytotoxic T cell and MHC I of the APC

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5
Q

What is the second T cell activation signal?

A

Between CD28 of cytotoxic T cell and CD80 of APC

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6
Q

What are the co-stimulators for T cell activation?

A

CD80/86

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7
Q

What is the TCR-CD3 complex?

A

It is a signalling complex comprised of TCR and three CD3 subunits

When TCR-CD3 is activated by MHC I from APC, it will bind ZAP70 ro initiate the activation of T cells via TCR pathway

see slide 5

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8
Q

How do T cells actually destroy targeted cells?

A

Cytotoxic T cells release perforin, granzyme, and granulysin

All substances are involved in the destruction and breakdown of cells

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9
Q

What are the functions of perforin?

A

Forming pores on target cell membranes

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10
Q

What are the functions of granzyme?

A

Inducing apoptosis of target cells

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11
Q

What are the functions of granulysin?

A

Forming pores in microbial cell walls

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12
Q

What are some techniques used by cancer cells to evade immune response?

A
  • Overexpression of CD47 (binds to SIRPa)
  • Downregulation of MHC I molecules
  • Lack of costimulatory signals (downregulation of CD80)
  • Secretion of immunosuppressive molecules (recruited immune cells are inactivated)
  • Modulation of antigens (old T-cells can no loger bind to cancer cells)
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13
Q

What is CAR T-cell therapy?

A

Chimeric antigen receptor (targeting a specific antigen in cancer cells such as CD19)

CAR T cells are engineered T cells with CAR on the surface

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14
Q

In general, how are CAR T cell therapies designed?

A
  • Collect T cells from a patient’s blood
  • Add the chimeric gene (encoding CAR) into the T cells in a laboratory (gene should be unique to cancer)
  • Grow and collect CAR T cells in the laboratory
  • Infuse CAR T cells into the patient
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15
Q

What is the latest generation of CAR T cell therapies to be approved for regular use?

A

2nd generation CAR T cell therapies

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16
Q

What are the components of the chimeric antigen receptor (CAR)?

A
  • scFv (single-chain variable fragment)
  • Hinge
  • Transmembrane domain
  • CD3 (activates TCR signalling pathway)
17
Q

What is a single-chain variable fragment (scFv)?

A

It is a fusion protein of the variable regions of the heavy chain and light chain.

The two are combined into a single unit

18
Q

What is most significant difference between different generations of CAR T cells?

A

Newer generations have more costimulators

1st gen: 0 co-stimulators (low efficacy)

2nd gen: one co-stimulator along with CD3

3rd gen: two co-stimulators along with CD3

19
Q

What are some challenges associated with CAR T cell therapy?

A
  • Time consuming
  • High cost (about $500,000 per treatment course)
  • Hostile tumour microenvironment
  • T cell exhaustion (loss of effector function due to prolonged antigen stimulation)
  • Regulatory hurdles
20
Q

What are some characteristics of tumour cells that express CD19?

A

Biomarker for lymphoma and leukemia (universally expressed in B-cell avute lymphoblastic leukemia)

Serves as a target for CAR T-cell therapy

21
Q

What are some characteristics of B-cell maturation antigen (BCMA)?

A

Biomarker for multiple myeloma

Overexpression and activation are associated with multiple myeloma

Member of TNF-receptor superfamily

22
Q

What are some characteristics of the drug Kymriah (tisagenlecleucel)?

A
  • 4-1BB as the co-stimulator
  • Targeting CD 19 antigen

Indicated for B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma

23
Q

What are some characteristics of the drug Yescarta (axicabtagene ciloleucel)?

A
  • CD28 as the co-stimulator
  • Targeting CD19 antigen

Indicated for Diffuse large B-cell lymphoma and Follicular lymphoma

24
Q

What are some characteristics of the drug Tecartus (brexucabtagene autoleucel)?

A
  • CD28 as the co-stimulator
  • Targeting CD19 antigen

Indicated for Mantle cell lymphoma

25
Q

What are some characteristics of the drug Breyanzi (lisocabtagene maraleucel)?

A
  • 4-1BB as the co-stimulator
  • Targeting CD19 antigen

Indicated for large B-cell lymphoma

26
Q

What are some characteristics of Abecma (idecabtagene vicleucel)?

A
  • 4-1BB as the costimulator
  • Targeting B-cell maturation antigen (BCMA)

Indicated for multiple myeloma

27
Q

What are some characteristics of Carvytkti (ciltacabtagene autoleucel)?

A
  • 4-1BB as the co-stimulator
  • Targeting B-cell maturation antigen (BCMA)

Indication for relapsed/refractory multiple myeloma

28
Q

What is the advantage of using 4-1BB as a costimulator vs CD28?

A

4-1BB as a co-stimulator for CAR T cell therapies shows better survival in B-cell acute lymphoblastic leukemia

29
Q
A

PHAR 211 (18 decks)

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