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CancerGen > Cancer Therapeutic Approaches > Flashcards

Cancer Therapeutic Approaches Flashcards

1
Q

What’s the issue with traditional cytotoxic drugs for cancer?

A

They are not specific to cancer cells

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2
Q

What were the original 6 hallmarks of cancer, The 6 cell-autonomous mechanisms controlling early oncogenesis?
Sustained….
Evading….
Resisting….
Inducing….
Enabling…
Activating….

A

Sustained…. proliferative signalling
Evading…. growth suppressors
Resisting…. cell death
Inducing…. angiogenesis
Enabling… replicative immortality
Activating…. invasion and metastasis

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3
Q

What are 4 hallmarks of cancer that were added later?
Deregulating CE
Avoiding ID
Genome I and M
Tumour PI

A

Deregulating Cellular energetics
Avoiding Immune destruction
Genome Instability and mutation
Tumour Promoting Inflammation

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4
Q

Which hallmark of cancer do these drugs target?
Telomerase inhibitors
Cyclin-dependent kinase inhibitors
EGFR inhibitors
PARP inhibitors

A

Telomerase inhibitors - enabling replicative immortality
Cyclin-dependent kinase inhibitors - evading growth suppressors
EGFR inhibitors - sustained proliferative signalling
PARP inhibitors - Genome instability and mutation

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5
Q

Gleevac (Imatinib) was a ground breaking drug. What was it for, and what did it target?

A

Used in CML and GIST patients to target the BCR-ABL fusion. Inhibits PDGF Receptor and c-kit TKs.

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6
Q

Previously CML was a death sentence unless you were young enough for what?

A

A successful bone marrow transplant

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7
Q

We now have second and third TKIs for BCR-ABL. Why?

A

They account for precise mutations for resistance

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8
Q

What is a big problem with creating these highly targeted therapeutics?

A

They are very expensive, and each can’t be used in everyone

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9
Q

Immunotherapy has been used in haem patients for decades. List a bunch of types of immunotherapy.
C
IS
MA
ACT

A

Cytokines
Immune suppressants
mAbs
Adoptive Cell Therapies

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10
Q

The immune synapse exists between what?

A

T cells and Antigen Presenting Cells (APCs)

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11
Q

What cells specifically bind to MHC Class 1 or 2 on Antigen Presenting Cells?

A

CD4 or CD8 cells

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12
Q

When CD4 and CD8 cells bind to MHC on Antigen Presenting cells, what relays the signal downstream?

A

CD3

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13
Q

When CD4 and CD8 cells bind to MHC on Antigen Presenting cells, CD3 relays the signal downstream, what is still needed for the activation and release of proinflammatory cytokines that have an anti-tumour effect?

A

Co-stimulatory signals. Immune checkpoint molecules. Without the co-stimulation the T-cells become less effective.

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14
Q

What are some ways that Tumour Cells can go unnoticed?

A

Disrupted presentation of antigens.
Manipulate the microenvironment with cytokines that leads to infiltration of Tregs and MDSCs that suppress T-Cells.
PD1/PD-L1 up regulation (immune checkpoint molecules) to inhibit costimulation.
Signalling to promote Tregs, inhibit APCs and reduce CD8 infiltration.

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15
Q

How do we think about making tumour cells immunologically visible?

A

Need a rational choice of antigenic target for the antibodies.
Force T cells to engage with tumour cells.
Mechanisms that encourage the release of cancer-suppressed T cells.
Engineer T cells with tumour specificity.

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16
Q

Briefly what are Bi-Specific T-Cell Engaging (BiTE) Antibodies?

A

They create a bring between T cell antigens and tumour antigens. They are highly selective with no off-target effects.

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17
Q

BiTE antibodies exist for which T cell and which Tumour antigens?

A

T cell CD3
Tumour - CD19 (ALL), BCMA (Myeloma), CD33 (AML)

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18
Q

Blinatumomab is a CD19 targeted BiTE antibody. What antigen and cells does it target specifically?

A

CD19 which is highly specific to B cells, in >90% of B cell malignancies.

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19
Q

What are the pros of BiTE antibodies?

A

Targeted at tumour antigens. Reduced off target toxicity. Tolerable. Harnesses T cells for enhanced tumour cell killing

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20
Q

What are the cons of BiTE antibodies?

A

Cancer cells are clever and you can have antigen negative escape. Also There are some immune mediated side effects. There is a lack of efficacy in heavily pre-treated patients due to their poor endogenous T cell function.

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21
Q

What does ADC stand for in terms of therapeutics?

A

Antibody-drug conjugates

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22
Q

What are antibody-drug conjugates? How do they work.

A

Monoclonal antibodies tethered to cytotoxic drugs. The chemical linker may be cleavable. They specifically bind to tumour cells, then are taken into the cell where the lyosome degrades the antibody, then the drug can take effect.

23
Q

What 4 cancers have antibody drug conjugates been approved against?

A

ALCL, AML, ALL, DLBCL.

24
Q

Inotuzumab is a CD22 directed antibody drug conjudate. What types of cancer is it good against and why?

A

It’s good for lymphoid malignancies because CD22 is highly specific to B cells, on mature and immature B cells.

25
Q

What are the pros of antibody-drug conjugates?

A

They are targeted to tumour antigens.
Deliver a large amount of drug to the tissue.
Minimal off target effects.
Good efficacy, and tolerability.

26
Q

What are the cons of antibody-drug conjugates?

A

Cleavable linker can lead to toxic payload release in the blood stream creating off-target effects.
Multidrug resistance… Alteration of target antigen.
Sometimes cells just kick out the drug molecule.

27
Q

What are checkpoint inhibitors designed to do?

A

Block receptor/ligand binding so that T-cells are not inhibited and can act

28
Q

PD-1 is expressed on which cells?

A

T cells

29
Q

PD-L1 and PD-L2 is expressed on which cells?

A

Antigen presenting cells, so tumour cells in this case

30
Q

Nivolumab and Pembrolizumab are both used against PD-1. What cancer are these checkpoint inhibitors good for?

A

Hodgkin lymphoma

31
Q

What is Immune Effector Cell/Adoptive T cell Therapy?

A

Harnessing the body’s immune system to create a sustained anti-tumour response. Can use T cells isolated from the patients body, modify them, then reintroduce them.

32
Q

What does CAR T cell therapy stand for?

A

Chimeric Antigen Receptor T-Cell Therapy

33
Q

CAR T cell Therapy is a living drug that is made by expanding T cells. The CARs combine what domains?

A

A cell surface binding domain for a specific antigen.
A spacer region for flexibility.
A transmembrane domain.
A cytoplasmic signalling domain to perpetuate activation response to perceived signalling.

34
Q

How did the anti-CD19 CAR construct become more sophisticated over time?

A

Adding a co-stimulatory domain in the cytoplasm like CD28, to encourage rapid expansion of those cells

35
Q

So how does CAR T-cell therapy work?
Getting the cells, and then in the body?

A

Aphoresis to collect cells from patient. Incubate them and activate. Transduce them so they expression the CAR receptor. Expand and give them to the patient.
The CAR construct gets stably expressed on T cells, they seek out the cancer antigen and do antigen-dependent tumour cell cytolysis

36
Q

What are some of the anti-CD19 CAR cytotoxic effects?
CRS ….
ICANS ….
C
BCA

A

Cytokine Release Syndrome (fevers, rigors, myalgia, nausea, hypoxia, multi-organ toxicity),
Immune effector Cell Associated Neurotoxicity Syndrome - (neurological toxicity, particularly in those with high disease burden. Tremor, speech difficulty, coma, cerebral odema)
Cytopaenia
B Cell aplasia

37
Q

How can you stabilise CRS caused by anti CD-19 CAR therapy?

A

Stabilise with IL6 blockade.

38
Q

What actually causes the cytotoxic effects of anti-CD-19 CAR therapy?

A

Rapid early expansion of CAR T cells causing a cytokine surge, leading to fatal brain swelling

39
Q

Trials for anti CD19 have been called what?

A

ZUMA1, ZUMA2, ELIANA, JULIET

40
Q

Compare autologous and allogenic T cell usage

A

Autologous will be scarcer, take time to make, but persist well and have no GvHD risk.
Allogenic can be easily harvested, be ready off the shelf, good cellular function. But unsure about persistence, and there is GvHD risk.

41
Q

What are Universal CAR T Cells (UCART19)?

A

Off the shelf CAR T cells against CD19. Used for ALL. Includes a CAR, and RQR8. RQR8 is a CD20 mimotope as a safety switch to turn it off if you see cytotoxicity with an antibody against CD20).
Further edited with TALEN to knock out endogenous T cell receptor and CD52.

42
Q

UCART have a big down side what is that?

A

Patients can decline by the time they are ready

43
Q

Myeloma is an incurable blood cancer caused by proliferation of plasma cells in the bone marrow. What other effects does it cause?

A

Skeletal damage, lesions that can cause fracture, renal failure.

44
Q

The monoclonal antibodies for treating myeloma target which proteins?

A

CD38 and SLAMF7

45
Q

What effect do mAbs have in myeloma?

A

Eliminate cells. Restore effector cell function. Mitigate immunosuppressive effects in the TME. Mediated by natural killer cells.

46
Q

What’s the downside of mAbs against myeloma?

A

Their antigenic targets are also on normal cells, so there are off target effects.

47
Q

What has superceded mAbs against CD38 and SLAMF7 myeloma due to a better specificity against tumour cells?

A

Targeting B Cell Maturation Anitgen (BCMA) because it’s in high levels in MM cells and B cells. It promotes proliferation and survival and suppresses the immune system.

48
Q

The response rate in the Cartitude trial using BCMA targeted CAR-T cell therapy was what?

A

96.7%

49
Q

What side effects are there from BCMA targeted T cell therapy?

A

Various, but more cytokine release syndrome (CRS) of grade I and II, some worse.

50
Q

BCMA ADC in the DREAMM-2 trial had what effects on the myeloma cells?

A

Selectively killed them by inhibiting proliferation, causing apoptosis, antibody dependent cell mediated cytotoxicity, and directed phagocytosis

51
Q

What are the side effects from BCMA ADC in the DREAMM-2 trial?

A

Eye toxicity. Corneal ulceration, dry eyes.

52
Q

is BCMA ADC available in the UK?

A

Through the compassionate use programme.

53
Q

BCMA bispecific antibody has been made by Jansen. It targets BCMA on MM cells and CD3 on T cells. What was the response rate and improved survival?

A

77% response. Median of 6 months improved survival.

54
Q

Why might BCMA BiTE by Jansen be the best option of myeloma treatment despite side effects.

A

Despite side effects of some neurotoxicity and cytokine release syndrome, there’s no delay making it, and the risk are overall lower.

CancerGen (18 decks)

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