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Dosage II > Cell-Based Therapuetics 2 > Flashcards

Cell-Based Therapuetics 2 Flashcards

1
Q

Systemic admin

A

-easier
-suitable for blood cancers/metastatic disease
-risk off-target toxicities
-higher risk of side effects
-potential loss of specificity

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1
Q

Local admin

A

-more suitable for many solid cancers
-fewer off-target effect
-many tumors harder to get to

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2
Q

Immune cells are infused w

A

-Cytokines

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3
Q

Cytokines

A

-support activation, maturation, and effector functions
-IL-2, 7, 15, 21

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4
Q

IL-2

A

-first immune therapy approved by FDA
-wake up immune cells
-pretty toxic
-when cell is isolated in lab, add cytokines to t cells then freeze them then add back into body (i think less cytokine then?)

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5
Q

Immune cell drug durations

A

-long lasting
-will stay in pt for years maybe even lifetime

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6
Q

Lymphoma CD-19 immunotherapy

A
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7
Q

Clinical responses to CAR-T therapy

A

-lymphoma (CD19 therapy)
-leukemia (CD19 therapy)

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8
Q

anti-CD19 CAR-T therapies

A

-usually first line
-b-cells also express CD19 tho so all b cells get killed
-loss of b-cells = successful marker of therapy

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9
Q

B-cell aplasia

A

-CD19 CAR-T side effect (leukemia tx)
-CD19 expressed on B cells
-B cells die
-but this is good it is a sign that it is working

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10
Q

Cell therapies that are not CARs (antibody therapy)

A

-ADCC
-multi-specific engagers

-antibody therapies via CD16

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11
Q

ADCC

A

-antibody interacts w CD16 on NK cells
=signal to kill

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12
Q

Multi-specific engagers

A

-synthetic BiKEs and TriKEs
-killer cell engager
-bridges to bring immune cell and cancer cell closer together
-CD16 or NKp46

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13
Q

Cell therapy responds to

A

-antibody therapy

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14
Q

NK cell therapy

A

-NK cells kill cancer without antigen needed
-activate quicker than t cells
-safer
-can expand outside of body
-can engineer like CARs
-ADCC (T cells dont)
-lack of GVHD
-no cytokine release syndrome like T cells

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15
Q

Manufacturing immune cell-based therapies

A
  1. Apheresis
  2. cell activation
  3. modification
  4. expansion
  5. infusion
16
Q

How can we engineer genes into cells?

A

-viruses
-mRNA electroporation
-plasmid or nanoparticles

17
Q

Viruses to get genes into cells

A

-most common
-dead viruses
-most efficient but most risky

18
Q

components of cell-based gene therapy

A

-isolated immune cells
-synthetic (CAR) DNA + viral vector (drug substance)
-cryopreservation media and cytokines if needed

19
Q

Problems w CAR therapies

A

-failure (tumor evasion)
-antigen modulation
-toxicities
-unmet needs

20
Q

Tumor evasion

A

-prob w cell-based therapies
-cancer cells escaping recognition
=resistance

21
Q

Tumor antigens are either

A

-not recognized by immune response (immunologically ignorant)
-resistant to/inhibit immune cytotoxic responses (suppression factors/antigen escape)

22
Q

Cell therapy indications are limited bc

A

-immune cells cannot kill tumors well
-heterogenous, immunosuppressive
-low immune cell infiltration

23
Q

Targets for solid tumor tx

A

-cytokine networks
-immunosuppressive populatioins
-immune checkpoints
-tumor stroma

24
Q

Potential risks of cell-based therapies

A

-neurotoxicity (fatal)
-cytokine release syndrome and GVDH common
-toxicity associated with viral vector of CAR-T therapy
-cells hang out in body for long time

25
Q

Issues with targeting cancer-associated antigens w cells

A

-on target, off-tumor effects
=cells target right antigen but one that is also in healthy cells
=toxicities
-fratricide (cells target antigen expressed on themselves = kill each other

26
Q

Gene-related toxicities associated with

A

-therapies that use viral vector (CAR)

27
Q

GVHD

A

-reaction to transplant
-autoreactive immune cells
-can lead to cytokine release syndrome

28
Q

Cytokine release syndrome

A

-systemic inflammatory response
-“cytokine storm”
-release of high number of cytokines that attack pt immune system
-etanercept and tocilizumab to block IL-6

29
Q

deadliest cytokine

A

IL-6

30
Q

CRS symptoms

A

-fever

31
Q

severity of CRS

A

-approx 75% of pt on T cell therapy (CAR-T)
-life threatening in 27-44%
-inc risk w high dose, bad diease, concurrtent infection

32
Q

Treating CRS

A

-antibodies against IL-6 (tocilizumab)
-avoid steroids
-use NK cells instead
-hemofiltration (filter out cytokines)

33
Q

inhibitory/decoys CARs

A

-suicide gene that can be shut off to prevent CRS

34
Q

What are some problems that could arise when developing drugs that target a single tumor antigen?

A
35
Q

What are the main safety issues associated with cell-based gene therapies?

A
36
Q

2 reasons why cell-based therapies are more successful for blood cancers but not solid tumors

A
37
Q

One way to clinically mitigate/manage CRS

A

Dosage II (20 decks)

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