Cell-Based Therapuetics 2

Question 1

Systemic admin

Answer 1

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

Question 1

Local admin

Answer 1

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

Question 2

Immune cells are infused w

Answer 2

-Cytokines

Question 3

Cytokines

Answer 3

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

Question 4

IL-2

Answer 4

-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?)

Question 5

Immune cell drug durations

Answer 5

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

Question 6

Lymphoma CD-19 immunotherapy

Question 7

Clinical responses to CAR-T therapy

Answer 7

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

Question 8

anti-CD19 CAR-T therapies

Answer 8

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

Question 9

B-cell aplasia

Answer 9

-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

Question 10

Cell therapies that are not CARs (antibody therapy)

Answer 10

-ADCC
-multi-specific engagers

-antibody therapies via CD16

Question 11

ADCC

Answer 11

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

Question 12

Multi-specific engagers

Answer 12

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

Question 13

Cell therapy responds to

Answer 13

-antibody therapy

Question 14

NK cell therapy

Answer 14

-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

Question 15

Manufacturing immune cell-based therapies

Answer 15

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

Question 16

How can we engineer genes into cells?

Answer 16

-viruses
-mRNA electroporation
-plasmid or nanoparticles

Question 17

Viruses to get genes into cells

Answer 17

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

Question 18

components of cell-based gene therapy

Answer 18

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

Question 19

Problems w CAR therapies

Answer 19

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

Question 20

Tumor evasion

Answer 20

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

Question 21

Tumor antigens are either

Answer 21

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

Question 22

Cell therapy indications are limited bc

Answer 22

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

Question 23

Targets for solid tumor tx

Answer 23

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

Question 24

Potential risks of cell-based therapies

Answer 24

-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

Question 25

Issues with targeting cancer-associated antigens w cells

Answer 25

-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

Question 26

Gene-related toxicities associated with

Answer 26

-therapies that use viral vector (CAR)

Question 27

GVHD

Answer 27

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

Question 28

Cytokine release syndrome

Answer 28

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

Question 29

deadliest cytokine

Answer 29

IL-6

Question 30

CRS symptoms

Answer 30

-fever

Question 31

severity of CRS

Answer 31

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

Question 32

Treating CRS

Answer 32

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

Question 33

inhibitory/decoys CARs

Answer 33

-suicide gene that can be shut off to prevent CRS

Question 34

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

Question 35

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

Question 36

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

Question 37

One way to clinically mitigate/manage CRS