IMMUNE THERAPY AND CURRENT TREATMENTS

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IMMUNE THERAPY AND CURRENT TREATMENTS

• Israel Barken M.D.
• The Coach
• Prostate Cancer Research and Education Foundation

San Diego, CA Telephone [phone]
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WWW.VERITASMEDICINE.COM
WWW.PCREF.ORG
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Dealing With Prostate Cancer Disease
Requiresa BalancingAct
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Principles of Coaching

• TimeIndividualized approachPsychological
  supportInterpretation of medical
  informationFind and understand clinical
  studiesList of TestsList of
  OptionsCommunication with your physicians

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Prostate Cancer Research and Education
Foundation
New Dawn
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The new era in medicine

• Treating patient not according to statistics.

• Not everyone has the same biological blue print.

• Understand each unique biological features.

• Understand each individual personal make up.

• Strategic individual planning accordingly

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The Present

• The Future

• Diagnosing everyone Diagnosing only those
  with significant disease
• Doing biopsy imaging tests and
  blood tests
• Current treatments Using only non aggressive
  complications free treatments.
• Treating locally or systemically Treating both
• Using one treatment Using combinations.

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Cancer VaccineCentral hypothesis

• Preferential destruction of tumor cells by
  components of the immune system demands selective
  recognition of such cells by the immune system.
• This selective recognition requires that tumor
  cell surface molecules (antigens) be different
  from those of normal cells.

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The acquired immune system
Functional properties

• Specificity
• Discrimination self and non-self
• Memory

Key players against cancer

• T-and B lymphocytes
• Antigen presenting cells
• Cytokines
• Tumor antigens

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Cryosurgery and Immune Response
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Cryosurgery and immune response

• The main tumor was implanted on the right side.
• A small tumor was implanted on the left side.
• Immune stimulant created destruction in the
  tumor that was not treated with freezing

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Cryosurgery and immune response

• The model was created for further testing
• The number of responses was too small for
  conclusion.
• More experiments are planned

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Tumor Cryoablation Resulted in Inhibition of
Distant Tumor GrowthJoosten JJA et. al. In Vivo
Destruction of tumor tissue by Cryoablation Can
Induce Inhibition of Secondary Tumor Growth An
Experimental Study. Cryobiology 41, 49-58
(2001)
Cryoablation Or Tumor Excision
Distant tumor not treated
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Cryosurgery and Dentritic cells C.D.C

• Cryosurgery in Anti Cancer Lab
• Dentritic cells studies
• Combined Dentritic cells with Cryosurgery

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Summary of DC Vaccine Trials

• Antigen
• PSMA peptides
• PSMA peptides
• PAP/GM-CSF
• PAP/GM-CSF
• Mouse PAP
• PSA mRNA
• TERT peptides

• Patients
• 19
• 62
• 31
• 13 (12)
• 21
• 13 (7)
• 5 (4)

Institution PNCF, Seattle, WA PNCF,
Seattle, WA UCSF, San Francisco, CA Mayo Clinic,
Rochester, MN Stanford, Palo Alto, CA Duke,
Durham, NC Dana-Farber, Boston, MA
Clinical Response 5/19 PR 3/62 CR, 16/62
PR 3/31 gt 50 PSA decline 3/12 gt 50 PSA
decline 6/21 SD 6/7 in PSA velocity 4/4 SD
PR partial responder CR complete
responder SD stable disease ( )
evaluable
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Haakon Ragde M.D. The Haakon Ragde Foundation
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The Star Players Most potent
cells of the immune system
Dendritic Cell
B Cell
T Cell
Antibodies
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WHAT ARE ANTIGENS (Kind of cell identity flags)

• Small parts of molecules from
• mammals
• Viruses
• Bacteria
• Parasites
• Pollens

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Typical Cell Surface
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How does the immune security patrol checking
the body determine that all is 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?

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Typical Cell Surface
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Preeminent Cells of The Immune System
Cellular Immune System
Dendritic Cell
B Cell
T Cell
Humoral Immune System
Antibodies
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T CellsThe Major Player Responsible for
Elimination of both Tumors and Viruses One
trillion T cells in the human body
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Two Types of T Cells

• The Killer T-cell
  (cytotoxic or cytolytic T-cell)
• The Helper T-cell.

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Helper 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

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Killer T Cells

• Ability to identify and destroy cells harboring
  both viruses and cancers.

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Human Dendritic Cells
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Tumor Cell
Cytotoxic or Killer T Cell
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The Dendritic CellsMaster 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

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THE PROCEDURE IS READILY ADOPTABLE FOR CLINICAL
USE
Cryotherapy
Leukapheresis
Intratumoral Injection
Dendritic Cells
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RATIONALE Tumor Damage (Chemo/Cryo) Followed by
Intratumoral 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

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Studies of Chemotherapy Intra-tumoral Injection
of DCs

1. Tanaka F, et al. Int J Ca 101265-9, 2002.
2. Song W, Levy R. ASCO 2004 2509.
3. Tong, et al. Ca Res 617530-5, 2001.

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Cryotherapy
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Cryotherapy
Tumor debulkingReduction of Immunosuppresive
factorsIncrease 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

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ADVANTAGESCryo/Chemotherapy Intratumoral
Injection of Dendritic Cells

• Multiple antigens naturally selected from
  patients tumor by patients 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

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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.

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Method of Action

• Cryotherapy 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.

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Human Phase I Trials in ProgressTumor Damage
Followed by Intratumoral Injection of Autologous,
Non-Loaded DCs

• Stanford University (liver cancer, thermal
  ablation).
• Sangretech Asia, Manila, The Philippines
  (prostate cancer, cryotherapy)

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Cryoablation/Intra-Tumoral DC Combination
uptake of dying tumor cells
tumor bed
cryoablation
intra-tumoral DC injection
migration to lymph nodes and tumor-specific T
cell activation
Benjamin Tjoa 2004
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Conclusion

• The 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?

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IMMUNE THERAPY AND CURRENT TREATMENTS

• Israel Barken M.D.
• The Coach
• Prostate Cancer Research and Education Foundation

San Diego, CA Telephone [phone]
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Future without prostate cancer
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Thank You
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• It has long been known I didnt look up the
  original reference
• A definite trend is evident These data are
  practically meaningless.
• Three of the samples were chosen for detailed
  study The other results didnt make any
  sense.
• In my experience Once In case after case
  Twice In a series of cases Thrice
• It is believed that I think.
• According to statistical analysis Rumor has
  it.
• A careful analysis of obtainable data 3 pages
  of notes were obliterated when I knocked over my
  coffee.
• It is hoped that this study will stimulate
  further investigation in this field I quit.

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Injected DCs Uptake and Process Antigens from
Tumor Cells and Activate Tumor-Specific T Cells
Naïve CTLs
Activated CTLs
cytokines
Tumor cell lysis
Activated TH Cells
Naïve TH Cells
Benjamin Tjoa 2004
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Human Phase I Trials in ProgressTumor Damage
Followed by Intratumoral Injection of Autologous,
Non-Loaded DCs

• Stanford University (liver cancer, thermal
  ablation).
• Moffitt Cancer Center (prostate cancer,
  radiation)
• Sangretech Asia, Manila, The Philippines
  (prostate cancer, cryotherapy)