L31 T-Cell Therapies

Question 1

We were practicing T cell therapies for cancer before we realized because…..

Answer 1

of bone marrow transplants (these are now stem cell transplants)

Question 2

TILs

Answer 2

• Tumor infiltrating lymphocytes
• grow T cells from tumor and then reinfuse them in patient
• if you give chemo before it can be really effective
• TILs can expand in the peripheral blood and there is access to homostatic cytokines that allows them to expand and get into tumors

Question 3

Efficacy potentiated by lymphodeletion

Answer 3

• if you give it and facilitate expanison of infused cells, good outcomes by patient

Question 4

TCR-engineered T cells

Answer 4

-introduce genes by e.g. using viral vectors or delete genes by editing the genomes
- editing genes has really increased the applicability of immunotherapy treatments because its a lot easier to create targetting treatments

Question 5

HLA system

Answer 5

most polymorphic genetic system that we have
issue because the TCR-engineered treatments have to be targetted at a specific HLA

Question 6

HLA-A2

Answer 6

most commonly focues
class 1 antigen that 40% of white people have
the TCR-engineered T cell therapies made for HLA-A2 only work for it

Question 7

CAR

Answer 7

• synthetic solution created to reprogram specificity of a T cell so that it can recognize tumors that express a particular target
• synthetic fusion receptor that contains gentic material from different sources but it recognizes a peptide from a degraded antigen
• directed to natural cell curface antigen on the tumor

Question 8

CEA

Answer 8

• carcino-embryonic antigen
• commonly on GI malignancies such as colorectal cancer
• people made CARs that target CEA in order to target the malignancies

Question 9

HER2

Answer 9

• herceptin
• cell surface antibody that a CAR can be made for

Question 10

parts of a CAR

Answer 10

• antibody fragment on the outside that binds to CEA or HER-2 for example
• followed by a spacer domain which separates

Question 11

How were CARs developed

Answer 11

• first CARs took one variable domain and substituting the variable antigen domain of an antibody fragment
• NOT HLA RESTRICTED bc can recognize the target of whatever the antigen was
• BUT problem with this design was that it was hard to change genes at the time that this was developed

Question 12

The TCR recognizes peptide generally presented in the groove of a HLA molecule (but there are diff types of receptors and the alpha beta t cell receptor is on most T cell receptors)

Answer 12

and the antigen is from degredation
- its activated because CD3

Question 13

CD3

Answer 13

• contains motifs called itoms that activate a T cell
• in the development of CAR,

Question 14

Second development of T cells….

Answer 14

• the first were hard becuase it was hard to fuse genes
• so this developemnt used single chain antibody fragments (ScFv)
• consists of variable light and heavy chains joined together with a linker peptide
• by joining them you can fuse it to the spacer of the domain
• creates a SINGLE POLYPEPTIDE FUSION which means you only need to introduce a single

Question 15

1G CAR

Answer 15

• ScFv
• T cell recieved activating signal when it comes in contact with tumor that gives the signal
• works good in the LAB
• BUT need a 2nd signal/co-stim to be developed into fully active and for it to proliferate when
  (2 imp in CAR- CD28 and 411B)

Question 16

IMP for co-stim of T cell in CARs

Answer 16

CD28 and 411B)

Question 17

2G CAR

Answer 17

• 2 types: CD28 and TNFr (depending on which co-stim is being targeted)
• solved the issue of 1G Car by adding the costim
• added upstream of the acedation domain
• when you add it, these T cells also recieve a co-stim signal when they encounter tumor and so then they can proliferate
• these forms were LEGENDS (in the clinic NOW)
• CD28 form: super fast blast of proliferation, but signal doesnt last long
• the 4-1BB form: slower more durable burn
• the different qualities = 3rd gen

Question 18

3G CAR

Answer 18

• merged the 2G generation types to have 1 type with BOTH CD28 and 4-1BB costim
• but NON YET APPROVED
• downstream of co-stim isnt in natural position, it doesn’t work so well