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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