A type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. CAR T-cell therapy is being studied in the treatment of some types of cancer. Also called chimeric antigen receptor T-cell therapy.

2.  For years : cancer treatment
Surgery
Chemotherapy
Radiation therapy
 Last decade Target therapies Gleevec : Treatment of multiple cancers
Tyr kinase inhibitor
Herceptin : Treat certain breast cancers
Specific molecular changes

3. Nowadays
Immunotherapy
Immune system is the body’s defense against
infection and cancer

5.  The body’s Own immune system
 Improve : Detect and Kill cancer cells
Immune cells or Antibodies can recognize

6.  Molecules : On the surface of T cells
 Recognizing fragments of antigen as peptides bound
to (MHC)
 Many TCRs recognize : same antigen
 Many antigen peptides are recognized by
the same TCR
 TCR two different protein chains (Heterodimer)
95% (α/β)
5% (γ/δ)
 TCR engages Peptide/MHC Signal transduction Biochemical mediators
T-Cell activation

7.  Variable domain of TCR : Complementarity Determining Regions (CDRs)
 CDR
CDR 1
CDR 2
CDR 3
α Chain :
Interact with the N-terminal part of the antigenic
peptide
β Chain : Interacts with the C-terminal part of the peptide
Recognize the MHC
Main CDR : Recognizing processed antigen

8.  The signal from the T-cell : Enhanced by Co-receptor
On helper T Cells
CD4 : Specific for MHC class II
On cytotoxic T Cells
CD8 : that is specific for MHC class I

10.  Three transmembrane signalling molecules (CD3ζζ, CD3δε and CD3γε)
T-cell activation
Phosphorylation CD3 : ZAP70 (zeta associated protein) Bind to CD3
signal

11.  Engineered Receptors
 Graft an arbitrary specificity
 These receptors are used to graft the specificity of a monoclonal antibody onto a T cell
Transfer coding sequence by Retroviral Vectors and etc
 The receptors are called chimeric because they are composed of parts from different sources
 CARs : As a therapy for cancer Using a technique called adoptive cell transfer

13. CARs : fusion of single-chain variable fragments (scFv) derived from monoclonal antibodies,
fused to CD3-zeta transmembrane and endodomain

14.  Scfv fusion protein :VH and VL with a short linker peptide of 10 to about 25 amino acids
Rich in Gly for flexibility and connection to the N-Ter of the VH with the C-Ter of the VL
Enable antigen binding

18.  T cells Removed from a patient and modified
Express receptors specific to the patient's particular cancer
Recognize and kill the cancer cells
Reintroduced into the patient
Note : Modification of T-cells sourced from donors other than the patient are also under
investigation

20.  In medicine Phytohaemagglutinin ( PHA ) are useful and are used as a mitogen to trigger
T-lymphocyte cell division from human peripheral lymphocytes

21. Anti CD3 or CD28

23. Viral techniques
 Lentiviral vector
Advantage :compared with adenoviral
Low immunogenicity
Deliver larger DNA sequences
less susceptible to silencing by host restriction factors
Disadvantage
High cost
Highly specialized staff and facilities required
Risk of mutagenesis
Strict regulatory requirements

26. Nonviral techniques
 Transposons/Transposase systems
 RNA Electroporation
Advantage
Disadvantage
Cheaper and Safer
Specific terminal repeats recognized by the transposase
Insertion into the T-cell genomeRNA Electroporation
Introducing synthetic mRNA into T cells without
integration into the host genome
Not durable
Limited anti tumor activity
They have been used in early experiments

30.  Cell Expansion System Culture Cellbag bioreactor w25 filled with 5% CO2
Connected it to a reservoir of complete media
and a waste bag