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

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2

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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