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Cancer Cryo-Immunotherapy
CRITICAL TRIAL
CRyotherapy and Intra-Tumoral Immunotherapy
with Autologous Immature Dendritic Cells
(VDC2008)
Duke K. Bahn, M.D.,
The Prostate Institute of America
Community Memorial Hospital
Ventura, California
888-234-0004
www.pioa.org
Cancer Immunotherapy
• A therapy that utilizes the body’s own natural defense, the
immune system, to fight disease
• T-cells identified as the major “soldiers” capable of
eliminating cancer (Killer T-cells) “Terminators”
• Cancer cells display unique markers or flags (antigen) that
can be recognized by Dendritic Cells (DC) “Detectives”
• DC to activate T-cells = killer cells to recognize and
eradicate cancer
• Deplete regulatory T-cells (Treg)
Dendritic Cells (Detectives)
• Special kind of White Blood Cells
• 1/10th of 1 % of WBC
• DCs are potent initiators of immune response by uptake,
process and display antigens of cancer cells on their cell
surface (Antigen-Presenting Cells)
• It can be replicated into millions in laboratory culture from
blood stem cells (Leukapheresis)
• DC migrate to regional lymph nodes, where a large
population of T-cells reside and activate T-cells (Killer
Cells)
Experimental model
Day 0
Tumor cells IV
→metastases
Levy, Fuchs, Rodriquez, Johns Hopkins
Day 14
+/- Cytoxan
200 mg/kg IP
Day 15
Surgery
or
Cryoablation
Survival
Tumor cells sc
→local tumor
Tumor:
1. CT26 colon cancer
2. RENCA renal cell CA
Tumor-free survival (%)
Cy unmasks immunologic anti-tumor
effect of cryoablation
100
Surgery
Cryotherapy
Surgery + Cy
Cryo + Cy
50
0
0
25
50
75
100
125
150
175
Day after tumor inoculation
(Surg + Cy) v. (Cryo + Cy), p = .002
Cold beats hot
Survival (%)
100
50
cryo alone
cryo/Cy
cautery
cautery/Cy
0
0
10
20
30
40
50
60
day after tumor inoculation
70
Conclusions
• Local tumor cryoablation can induce
regressions of metastatic disease
• Cryoablation is more effective than
heat ablation for promoting anti-tumor
immunity
Levy, Fuchs, Rodriquez
Low Dose Metronomic Oral Cyclophosphamide for
Hormone Resistant Prostate Cancer: Phase II Study*
• Cy can lead to enhanced immunity against a variety
of antigens possibly by targeting regulatory T
cells/or tumor angiogenesis
• Two cycles of Cy (8 weeks), 50 mg/ sq. meter, p.o.
• 34.5% PSA response rate
• Median duration of response 7.5m (3-18)
* Lord et al., J of Uro June 2007
HUMAN PHASE I TRIALS IN PROGRESS
Tumor Damage Followed by Intratumoral Injection of Autologous DCs
• Stanford University (liver cancer, thermal ablation).
• Moffitt Cancer Center (prostate cancer, radiation)
A HUMAN PILOT STUDY
• Sangretech Asia/Haakon Ragde Foundation,
• Prostate Institute of America, CMH, Ventura, CA. USA
• Asian Hospital & Medical Center, Manila, Philippine
Human (Pilot) Studies, November 2005,
May, September, and November 2006
• 12 advanced prostate cancer patients & 1 early
stage PCa patient.
• Most of them have >T3b or T4 stage prostate
cancer with Metastasis.
• Most of them have had failed radiation therapy,
hormone therapy and chemotherapy.
• All had cryoablation with intratumoral infiltration
of autologuous Dendritic cells:
• No T-reg depletion.
Observations (1)
• Long-lasting symptoms of an exaggerated immune
response: Fatigue, profuse perspiration, and
arthralgia/myalgia (up to 2 months)
• PSA reduction
• High risk disease may show bone scan flare with
temporary bone pain
• Reduction of pain in bone metastases with objective
regression of the cancer
• Reduction of rebounded PSA by low dose Cy
Observations (2)
•Five advanced patients: Disease progression and Death.
•Three patients: T3&4N0M0, PSA 5 -48, NED up to 4 years.
•One patient: T2aN0M0, Focal Cryo with DC, Unfrozen
Atypia became Gleason 6, on active surveillance.
•Four patients: good initial PSA drop, sustained
few months, disease progression, treated with various
modalities: Cy, Cryoablation with Cy, Neutron Beam (1),
Second line ADT: Slowing PSA doubling time.
Mr. TM, 76 yo, G 10, ADT, Orchiectomy, HDR, Chemo,
(Cryo-Immunotherapy November 28, 2005)
8/12/05
1/23/06
4/27/06
Cryo-immunotherapy Conclusions
based on Manila Experience
• Cryo-immunotherapy is a promising investigational
approach for stimulating antitumor immunity in the
cancer patient without inducing toxic side effects.
• Cryo-immunotherapy has the potential be used as an
adjunct in high risk patients; also, perhaps, as a
stand-alone focal treatment in patients who have an
early organ confined disease and maintaining the
quality of life is a major concern.
• Cryo-immunotherapy offers a most positive concept
for local and systemic disease control.
“CRITICAL” Trial
Treatment Strategy
1. Cryoablation of the prostate, followed by
2. Intra-tumoral (into the cryoablated prostate)
injection of a known number of patients’ own
immature dendritic cells (VDC2008)
3. Pre- and post-cryoablation low dose
cyclophosphamide administration to reduce
regulatory T cells temporarily
Treatment Strategy: Critical Trial
Temporary Reduction of Regulatory T Cells
A Healthy Immune System is a Balancing
Act Between Its Two Arms
ARM 1:
Stimulatory
• Activates immune response
• E.g., killer T cells (CTL),
helper T cells (TH)
Arm 2:
Regulatory
• Inhibits immune response
• E.g., regulatory T cells (Treg)
Treatment Strategy: Critical Trial
Temporary Reduction of Regulatory T Cells (cont.)
What Happens When Balance is Disrupted?
ARM 1:
Stimulatory
Arm 2:
Regulatory
Autoimmunity
Inflammation
Allergic Reactions
ARM 1:
Stimulatory
Arm 2:
Regulatory
Immune Deficiency
Infection
Cancer Growth
Treatment Strategy; Critical Trial
Temporary Reduction of Regulatory T Cells (cont.)
Regulatory T Cells in Cancer Patients
• are present in higher numbers in cancer tissues and blood
• can “protect” cancer from immune surveillance
Temporary Reduction of Regulatory T Cells
• may improve efficacy of cancer vaccination
• will be achieved in this study using administrations of low
dose cyclophosphamide pre- and post- cryoablation
Prostate Cancer Immunotherapy and Trials
• Provenge: PAP-Autologous DC, fused with GMCSF: FDA
approved, 4.1 months survival benefit
• Critical Trial: Cryoablation-Autologous DC, mutiplied, with T-reg
depletion.
• Prostvac: Two weakened Pox viruses programmed to produce
irregular PSA to induce vigorous immune attack. Not patientspecific, 8.5 month survival benefit.
• GVAX: P/Ca cells genetically modified to secrete GM-CSF, an
immune stimulatory hormone. Not patient-specific: Prematurely
terminated.
PROVENGE
FDA
Leukapheresis
Multiply DC
Induce Cancer
Cell Damage
Antigen Used
T-reg Depletion
Delivery
Approved
Yes
No
No
PAP
No
IV Infusion
Survival Benefit 4.1 months
CRITICAL TRIAL
Phase l/ll
Yes
Yes
Yes by Cryo
All Available Cancer
Specific Antigens
Yes
Direct Intra-tumoral
Infiltration
Unknown
FDA Approved Selection Criteria
(Study Population)
1. Men who have proven recurrent cancer in the prostate
after organ-preserving therapy (I.e., nonprostatectomy)
2. Men whose cancers are determined to be androgenindependent.
3. Men with known prostate cancer with metastasis
limited to three sites (Lymph nodes or Bones).
4. Chemo-naïve men
Approved T-reg Depletive Therapy
• Minus 4 days from the Cryoimmunotherapy
procedure: 300 mg/m2 Cytoxan IV
• Plus 2 weeks from the procedure:
25 mg Cytoxan, p.o., BID for 7 days
7 days off
• This oral regimen be continued for six one-month
cycles
Study Objectives
• Primary Objective:
• Data to be collected includes adverse events related
to Cryoablation, DC product administration,
Cyclophosphamide therapy.
• Secondary Objective:
Time to objective disease progression by Imaging
studies, PSAs and Biopsies.
• Tertiary Objective:
Estimation of cohort survival