Haakon Ragde M.D.The Haakon Ragde Foundation
B Cell
The Star Players
Most potent cells of the immune system
T CellDendritic Cell
Antibodies
WHAT ARE ANTIGENS WHAT ARE ANTIGENS ((Kind of cell identity flags)Kind of cell identity flags)
Small parts of molecules from:mammals
VirusesBacteriaParasitesPollens
Typical Cell Surface
How does the immune “security patrol” How does the immune “security patrol” checking the body determine that all is well checking the body determine that all is well (or not well?) (or not well?)
IT INSPECTS CELL SURFACE ANTIGENS
Cells have distinct landmarks on their surfaces (antigens) that generally betray the nature of the cell within - normal or malignant, or is it infected with a virus?
Typical Cell Surface
B Cell
Preeminent Cells of The Immune System
T CellDendritic Cell
Antibodies
Humoral Immune System
Cellular Immune System
T CellsT CellsThe Major Player Responsible for Elimination of The Major Player Responsible for Elimination of both Tumors and Virusesboth Tumors and Viruses One trillion T cells in the human body One trillion T cells in the human body
Two Types of T CellsTwo Types of T Cells
The Killer T-cell (cytotoxic or cytolytic T-cell)
The Helper T-cell.
Helper T CellsHelper T Cells
Unlike Killer T-cells, helper T-cells are not assassins.
Like football quarterbacks, they are calling the plays of the immune response
They tell Killer T cells and B cells what cells to attack
Killer T CellsKiller T Cells
Ability to identify and destroy cells harboring both viruses and cancers.
Human Dendritic Cells
Cytotoxic orKiller T Cell
Tumor Cell
The Dendritic CellsThe Dendritic CellsMaster Controllers of ImmunityMaster Controllers of Immunity
Dendritic cells are specialized for: Capture of antigens Processing of antigens into small fragments (peptides) Presentation of the peptides at their cell
surfaces in association with MHC molecules so that an appropriate T cell can recognize the peptide-MHC complex and be activated
Killer T
Helper T
Cytokines
T-cells
T-cells
T-cells T-cells
T-cells
Dendritic Cell
Dendritic Cells are Professional AntigenPresenting Cells
THE PROCEDURE IS READILY ADOPTABLE THE PROCEDURE IS READILY ADOPTABLE FOR CLINICAL USEFOR CLINICAL USE
Leukapheresis
IntratumoralInjection
Dendritic Cells
Cryotherapy
1
2
3
RATIONALERATIONALE Tumor Damage (Chemo/Cryo) Followed by Tumor Damage (Chemo/Cryo) Followed by Intratumoral Injection of Dendritic CellsIntratumoral Injection of Dendritic Cells
After treatment with Cryo/Chemotherapy:
- Dying (apoptotic/necrotic) tumors cells release multiple tumor antigens and “danger signals”
- Intratumorally injected immature dendritic cells aquire tumor antigens in situ
- Dendritic cells become activated, mature and migrate to the regional lymph nodes to set in motion anti-tumor activity of Tcells
Studies of Chemotherapy + Intra-tumoral Injection of DCsStudies of Chemotherapy + Intra-tumoral Injection of DCs
1
2
3
1. Tanaka F, et al. Int J Ca 101:265-9, 2002.2. Song W, Levy R. ASCO 2004 #2509.3. Tong, et al. Ca Res 61:7530-5, 2001.
Cryotherapy
Tumor debulkingTumor debulkingReduction of Immunosuppresive factorsReduction of Immunosuppresive factorsIncrease antigen availabilityIncrease antigen availability
Intratumoral dendritic cell
injection
Uptake of tumor antigens from apoptotic & necrotic tumor cells Generation of immune response against tumor cells Systemic elimination of remaining tumors
Cryotherapy
ADVANTAGESADVANTAGESCryo/Chemotherapy + Intratumoral Cryo/Chemotherapy + Intratumoral Injection of Dendritic CellsInjection of Dendritic Cells
Multiple antigens naturally selected from patient’s tumor by patient’s own dendritic cells
Antigen-loading and maturation of dendritic cells occurs in vivo
No need to search for tumor antigens (cost reduction)
Combination with conventional cryotherapy (a standard care) which also reduce tumor burden
WHY CRYOTHERAPY?WHY CRYOTHERAPY?Freezing (cryotherapy) as a treatment for
cancer has been around since the 1930s.During the last decade, cryotherapy
technologies have been markedly improved and are becoming choice treatments for many different cancers.
Unlike radiation and chemotherapy, cryotherapy does not damage the immune system and it can be repeated time and again.
Method of ActionMethod of ActionCryotherapy results in massive tumor cell
breakdown without damaging the immune system. This gives rise to innumerable antigens. Process can be repeated.
Then, direct injection into the frozen tumor of millions of dendritic cells. The dendritic cells gobble up this mass of diverse antigens, and sensitize T cells that leads to tumor killing. Process can be repeated.
Human Phase I Trials in ProgressHuman Phase I Trials in ProgressTumor Damage Followed by Intratumoral Injection of Tumor Damage Followed by Intratumoral Injection of Autologous, Non-Loaded DCsAutologous, Non-Loaded DCs
Stanford University (liver cancer, thermal ablation).
Sangretech Asia, Manila, The Philippines (prostate cancer,
cryotherapy)
Cryoablation/Intra-Tumoral DC CombinationCryoablation/Intra-Tumoral DC Combination
cryoablation intra-tumoralDC injection
uptake ofdying tumor cells
migration to lymph nodesand tumor-specific T cell activation
tumor bed
Benjamin Tjoa 2004
ConclusionConclusionThe immunotherapy illustrated is essentially non-
toxic.
Can be added to other standard treatments
Can be repeated time and again.
Results in animals and humans are promising.
It may be the only way to control metastatic
disease?
Thank YouThank You
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