Modified T cells in prevention of cancer

1. T-CELL ENGINEERING IN
THERAPEUTICS
Presented by:-
Susmita Sen

2. WHAT IS T CELL?
A T cell, or T lymphocyte, is a type
of lymphocyte that plays a central role
in cell-mediated immunity.
 T cells can be distinguished from other
lymphocytes, such as B cells and natural
killer cells, by the presence of a T-cell
receptor on the cell surface.
 They are called T cells because they
mature in the thymus from thymocytes.
Scanning electron
micrograph of a
human
T cell

3. T CELL ENGINEERING
 T lymphocytes express on their surface a heterodimeric αβ
receptor, called the T cell receptor (TCR), which recognizes
foreign antigens.
 The recognition requires both an antigenic peptide epitope
and a protein encoded by the major histocompatibility
complex (MHC).
 In the past 10 years, there have been significant efforts to
engineer TCRs in various formats, which would allow
improved recognition and destruction of virus-infected cells
or cancer.
 The proposed therapeutic approaches involve the use of
engineered TCRs whose genes are reintroduced into

4. Types Of Engineered T cell therapies:
There are various methods of
T cell engineering. Some of them are:
1.TCR gene transfer
2.CAR gene transfer

5. Engineered T cell therapies: TCR gene
transfer
•Transfer of genes encoding a TCR
•Endow patient T cells with tumour-
reactivity of a defined Ag-specificity
•Destroy tumours without damaging
normal tissues
Antigen specificity of a T cells is
determined by the TCR. It
expresses :

6. Ag-receptor engineered T cell therapy
Cancer patient
Removal of peripheral
blood lymphocytes
Infusion of autologous TCR
gene modified T cells
Ex vivo transduction process

7. Engineered T cell therapies: CAR gene
transfer
T cell specificity can be
redirected towards cell
surface antigens by
engineering T cells with
a Chimeric Antigen
Receptor (CAR)
CAR:
Artificial T cell receptor
that combines the
antigen recognition
domains of an antibody
fused to T cell
activating signaling
domains

8. CAR T-Cells – A New Paradigm in the
Treatment of Cancer

9. Chimeric Antigen Receptor (CAR)
Step 1: Create monoclonal
antibodies
○ mice or human tumor cells in
lab Step 2: Create single chain
variable fragments (scFv’s)
 VH and VL obtain from
antibodies to make scFv
 Step 3: Zeta chain from T-Cell
signaling complex attached by
spacer.

10. Effects of CAR
• Recognition of tumor associated antigen (TAA) on
target cell via CAR sends activating signal
• Once activated it triggers release of perforin and
granzymes along with cytokines by other immune
cells

11. CAR T-Cell Mechanism of Action

12. Delivery Method
 Mainly through viral vectors (adenovirus and retrovirus are
most common)
1.method of infecting
host cell by adenovirus
2.retrovirus method of
integration

13. Correct Vector is Dependent
on Event
 Type of target cell (dividing or non-
dividing)
 Short-term or long-term expression
 Retrovirus:
▪ Long-term expression
▪ Infect dividing cells
▪ Integrates into target cell genome
 Adenovirus:
▪ Can infect dividing and non-dividing cells
▪ Short-term gene expression
▪ Does not integrate into target cell genome

14. Patient Involvement
• Isolate WBCs from patient
• Genetically modified T-cells in
vitro
• Expand modified T-cells
• Reintroduce patients own
modified T-cells with CAR
back into circulation
• Monitor and run tests for
proliferation in vivo

15. Might this technology make chemotherapy
obsolete?
Probably not. It should be noted that this
approach required pre-conditioning with
chemotherapy to allow the
"programmed-to-kill" t-cells to be
accepted by the body and to allow them
to multiply.

16. Is there a reason to be optimistic?
 Yes, we think so, because in this case the clinical results are
dramatic in patients with very advanced disease, and the
regressions are causally linked to the activity of the engineered t-
cells by findings from samples taken from the bone marrow.
 Further, unlike chemical therapeutics, the programmed cells
have no half-life limitation and the killing of malignant cells has
very good specificity - targeting mainly mature b-cells, a type of
immune cell that one can live without and that could regenerate
once the programmed t-cells are disabled or eliminated.
 Finally, we can hope that resistance might be futile - the cancer
cells may not be able to escape or survive them.

17. THANK YOU