Redirected therapies

Question 1

What is the proble with conventional monoclonal antibody therapies?

Answer 1

It can't target the many tumour antigens
Antigen loss variants
Immunosuppression
T-cell cant get to the tumour environmant and interact with the antibody
Not much tumour specifc antigens

Question 2

How does engineered antibodies provide with better solution?

Answer 2

It is samll easily diffuses through membranes
Can be designed to be really specific and target multiple antigens
Can activate alternative cell types for effector function
High affinity

Question 3

How can the structure of te antibodies be engineered?

Answer 3

Can change between mouse and human whether it is variable,CDR or constant regions. Can hybridize two different CDR regions in same antibody. Many antibody binding domain can be added in the same molecule and can alter the conformation

Question 4

What are some example of tumour antigen? What are ways to use the engineered monoclonal AB?

Answer 4

mucin, Ca55

Neutralization, growth factor receptors, can target different immune cell types such as macrophage, natural killer cells

Question 5

Problems with engineered antibodies?

Answer 5

Immunogenic but can grow tolerant to it
Because it has a short half life, have to keep replinishing
Toxicity

Question 6

What are some examples of the types of engineered antibodies?

Answer 6

TCR from HLA transgenic mouse
CART
TCR engineered t-cell

Question 7

How do each TCR from HLA trangenic mouse, TCR engineered t cells and CART work

Answer 7

1. It takes tumour cells inject it into the mouse that is transgenic with human HLA isolate that mouse t-cell that is specific for the antigen with MHC class 1. Clone mouse TCR in reteroviral vector in reteroviral create human t-cells expressing mouse TCR
2. They take a chimeric motif(TCRwith endogenous signalling and antigen binding domain that is specific) clone in reteroviral vector, then inject it into t-cell
3. Take t-cells from tumour and then isolate these specifc TCR clone it in a reteroviral vector inject into a t-cell

Question 8

How do you expand t-cells from patients?

Answer 8

Take tumour cells with t-cells, isolate these t-cells activate it by adding CD28 and CD80 induction and then let them proliferate and expand then infuse some of the tumor specific t-cell into patient, immunosuppress and irradiate

Question 9

How do you make CAR T cells?

Answer 9

Leukapherisis
Take the suitable subtype of t-cells using centrifugation
Inject t-cells with chimeric receptor, inject back into patients

Question 10

What are CAR T cells exactly?

Answer 10

Chimeric receptor that is specific for a tumour antigen but also has endogenous signalling that activates effector function it when it recognizes the antigen, It doesn’t need to be presented on MHC

Question 11

What is the endogenous signalling found in t-cells?

Answer 11

ZAP70+LAT

Question 12

What are the problems with CART tharapy?

Answer 12

Tumour lysis syndrome

Cytokine secretion/ release syndrome

Question 13

What are some example of next generation CART cells?

Answer 13

TRUCK- endogenous signalling that releases cytokines

Self destruct CAR- once activated will self destruct to limit toxicity