Please enable JavaScript.
Coggle requires JavaScript to display documents.
RADIOIMMUNOTHERAPY (RIT) (What is RIT ? (Combination of radiotherapy…
RADIOIMMUNOTHERAPY (RIT)
What is RIT ?
Combination of radiotherapy and immunotherapy in treating cancers
Enhance therapeutic response and employed to deliver radioisotopes to targeting tissue using appropriate vehicle
Cytotoxic radioisotopes are conjugated to antibody (abs) or its fragments
To reduce radiation to other tissue
Deliver adequate radiation dose at specific tumor
Immunological Technique
use of engineered monoclonal antibody and radionuclide
Monoclonal antibody
Glycoproteins secreted from plasma B-cells
Used by immune system to identify and remove foreign pathogens
Bacteria
Viruses
Cancer cells
Example and uses
Antibody
OKT3
CD 3 antigens on T-lymphocytes
Acute rejection of transplanted kidneys, hearts and livers
Rituximab
CD20 receptors on B lymphocytes
Non- hodgkin's lymphoma
Trastuzumab
HER-2 growth facors receptors
1 more item...
Infliximab
1 more item...
Target
Uses
Designed to target certain antigens that lives on surface of cancer cells
By latch onto cancer cells and act as a “call to arms” for other disease-fighting soldiers in the immune system.
+
monoclonal antibodies are paired with a radioactive substance and injected into the bloodstream
can travel and bind to cancer cells and deliver high doses of radiation directly to tumor cells
Radionuclide
Substances that follow the behaviour of various biological processes by visualisation gamma camera
Example
Radiotracers
half-life ( hrs)
Radiation
iodine-131
Yitrium-90
Rhenium-186
Rhenium-188
17
1 more item...
91
Beta
64
Beta
193
Beta or Gamma
Alpha particle emmiters
:arrow_up: LET
:arrow_up: RBE
Beta particle emmiters
Produce cellular damage
produce additional crossfire effect
Emmit gamma radiation
Dosimetry
Imaging
Evolved from spectacular growth in molecular biology and biotecnological advances
Producing highly purified monoclonal antibodies
to attack primary tumor and lesions that are systematically metastasizing
RADIOBIOLOGICAL PROCESS
Direct method
Indirect method
Definitions
Targets
Antigens of cancer cells
A place which mAbs will bind to
Killing cancer cells through apoptosis or necrosis
Example
Target/ Antigen
cancer cells
CD20
B- lymphocytes of Non-hodgkin's Lymphoma
HER-2 growth factor
Advanced breast cancers
CD52
B-cell chronic lymphocytic leukaemia
Carriers
Targeting vehicles
Helps to direct mAbs to the cancerous cells
Allows mAbs able to selectively accumulate the cytotoxic radioisotopes at affected areas
Fundamental properties of a carrier
High binding affinity to intended target
high specificity
High tumor to background ratio
High metabolic stability
Low immunogenicity
Radionuclides
Ligands that combine with mAbs
Emits therapeutic quantity of particulate radiation
Delivering tumorcidal dose to tumor mass
Release large energy during radioactive decay
causing radiation effect
Challenges and Future Direction
Challenges
Selection of radionuclides
alpha-emitters
crossfire effect
Beta-emitters
Long range in tissue allowing energy deposition in nontarget tumor
Induce less complex damage under xypoxic state
Auger-electron emitters
lower range in tissue (<1micrometer)
challenge for internalization and transport into nucleus
Selection of mAbs
IgG antibody
High molecular weight
Slow clearance of Abs from the blood and nontarget tissue
Low tumor to background ratio
Increase radiation exposure of red marrow
potentially causing myelosupression and hematologic toxicity
Accumulation in critical organs
Antibody fragments
Low molecular weight
Low affinity to tumor antigen
Lower tumor uptake
Too fast blood clearance yield less time to interact with target
Cellular biology
Tumor microenviroment
Reduced bloodflow
Increase interstitial fluid pressure
Increase hypoxic level in tumor
Reduction in tumor uptake
Increase radioresistance
Reduced potential heterogenous distribution of the conjugate across the tumor burden
Limit capacity of penetrationby large molecules
Future direction
The use of combination therapy
Improve efficacy of treatment
Use of alpha-emitting radionuclide due to highly ionising nature
highly relevant when targeting dispersed but small volume tumors
Examine role of RIT as an overall sequence of therapeutic interventions and clinical treatment protocol
Example
Adjuvant settings
Neoadjuvant settings
Advantages and Disadvantages
Advantages
Effective in killing lymphoma cancer cells
Lymphomas are sensitive to radiation
There are abundant and well characterized cell surface antigens on overexpressed tumor
Example : CD20
Radioimmunoconjugates with lymphoma cells predominantly by radioactive emmissions
Useful when patients have failed treatment with unmodified monoclonal antibodies
The ability to attack both primary tumor and metastasizing lesions
Better conformal dose to target tumor
Fewer and less severe side effects
Shorter treatment period
can be included with other treatment modality such as chemo or Radiotherapy
Highly selective in ability to adhere with cancer cells
Limit te radiation exposure to healthy tissue
Disadvantages
Beta- emitting radionuclide Increase severe risk for myelosuppression
Beta-emitter can cause collateral damage to non-targeted normal tissue
Responsed are low in solid cancer
Due to the unconventional microenviroments
Example
oxygen concentration less than 0.02% decrease the vunerability of cancer cells to radiation
Hypoxia can produce substantial level of resistance to irradiation
Risk of development of myelodysplasia
Risk of development of acute myeloid leukaemia
Group C Members
Teng
A158850
Damia
A162236
Faez
A161484
Danial
A159108
Hemma
A159079
Athirah
A158856
Cytotoxic radioIsotope
+
RadioImmunoconjugate
Slow clearance of Abs from blood and non-target tissue
In-vivo reaction
Rapid clearance rate
Therapeutic irradiation
Resulting
Lower weight molecular ABS
Mini body
Diabody
Single chain variable fragments
Resulting
Slow clearance of Abs
Higher tumor uptake
Longer duration for maximum tumor to normal radioactivity ratio
Anti-tumor mAbs
Chelator
Bispecific mAb (bs-mAb)
+
Slow clearance
Administration of radiolabelled species
Conjugation of radioisotopes to bs-mAB
Irradiation Therapy
Chelator
To remove residual streptavinated Abs from blood
clearing agent
Example
Useful for
Administration via single step
Injection of radioligand
Lag period administration of radioisotope Allowing the bs-mAbs to accumulate to target site
Binding between radioisotope and bs-mAb by treptavidin