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The Impact of Thermotherapy on Immune Response

October 5 th 2010 Evelyn Lake MBP 1028. The Impact of Thermotherapy on Immune Response. Presentation Outline. What constitutes an immune response? Range of thermotherapy temperatures: Cryotherapy Mild hyperthermia Extreme hyperthermia Summary and conclusions Questions?.

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The Impact of Thermotherapy on Immune Response

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  1. October 5th 2010 Evelyn Lake MBP 1028 The Impact of Thermotherapy on Immune Response

  2. Presentation Outline • What constitutes an immune response? • Range of thermotherapy temperatures: • Cryotherapy • Mild hyperthermia • Extreme hyperthermia • Summary and conclusions • Questions? www.physicscentral.com

  3. The Immune Response “The body's response to defend against attacks from disease-causing agents” • Ways to elicit a response = any form of stress • Cold shock (mild or extreme) • Oxidative shock • Heat shock (mild to extreme) • Heavy metals • Pathological condition (ischemia or reperfusion) • Inflammation • Tissue damage • Infection • Mutated proteins (associated with disease) www.bcm.edu.htm

  4. The Immune Response “The body's response to defend against attacks from disease-causing agents” • Ways to elicit a response = any form of stress • Cold shock (mild or extreme) • Oxidative shock • Heat shock (mild to extreme) • Heavy metals • Pathological condition (ischemia or reperfusion) • Inflammation • Tissue damage • Infection • Mutated proteins (associated with disease) www.bcm.edu.htm

  5. The Immune Response • How can you measure an immune response? • Chances for survival • Number of metastases and/or size of tumor (cancer) • Levels of Heat Shock Protein (HSP) expressed • Peptide antigen expression • T-cell response • Can be a positive or negative response • Suppression (+/-) • Enhancement (+/-)

  6. Extreme Cryotherapy • Treatment: (-40⁰C) Cryoablation • The Immune Response: Can be beneficial or detrimental • Both immune suppression and immune stimulation have been observed www.ctsnet.org

  7. Extreme Cryotherapy: Example • Many factors may effect the immune response to cryoablation: • Type of tumor • Volume of tumor • Freezing method (rate, temperature, equipment) • Example: Rate of Freeze Alters the Immunologic Response After Cryoablation of Breast Cancer • Measured immune response: • T-cells • Survival • Tumor metastases

  8. Extreme Cryotherapy: Example • Many factors may effect the immune response to cryoablation: • Type of tumor • Volume of tumor • Freezing method (rate, temperature, equipment) • Example: Rate of Freeze Alters the Immunologic Response After Cryoablation of Breast Cancer • Measured immune response: • Survival • Tumor metastases • T Cell expression

  9. T Cells • Thymus Cells • VERY large family of cells with diverse functions w.r.t. cell-mediated immunity • Type of white blood cell called lymphocytes • Effector T cells have been shown to mediate the regression of pulmonary metastases • Play a critical role in mediating tumor regression [Winter, 2007] www.daviddarling.jpg

  10. Extreme Cryotherapy: Example • Purpose: Examine the mechanism by which cryoablation may stimulate immune response w.r.t. different freeze rates • Low Freeze Rate:10% argon duty cycle (on for 1 of every 10 seconds) for a total a few minutes (until tumor is frozen) • High Freeze Rate:100% argon duty cycle for 30 seconds (until tumor is frozen)

  11. Extreme Cryotherapy: Example

  12. Extreme Cryotherapy: Example

  13. Extreme Cryotherapy: Example • Conclusion: • High freeze rate cryoablation caused a significant increase in tumor-specific T cells, a reduction in pulmonary metastases, and improved survival • Low freeze rate cryoablation caused an increase in regulatory T cells, an increase in pulmonary metastases, and was detrimental to survival • The techniques employed to freeze tissue can alter the immune response from stimulatory to suppressive

  14. Mild Hyperthermia • The Treatment: Fever (39.5-43 ⁰C for 30 mins. - 8 hrs.) • The Immune Response: Can manipulate treatment to be • Inhibitory of autoimmune or inflammatory, or • Stimulatory of malignant or infectious disease • Immune Markers: Heat shock proteins (HSP) and glucose-regulated proteins (grp)

  15. Heat Shock Proteins (HSP) • VERY large family of proteins which are over expressed when an organism is under stress • Classified by size • Two main types: • Molecular chaperones • Proteases • Have dual function (intra. vs. extracellular) alfa.di.uminho.pt/~pedrogabriel/research.htm

  16. Mild Hyperthermia: Examples • Heat shock proteins as a vaccine: • Delivered via necrotic tumor cell death • Delivered via injection • Two examples: • Heat Shock Protein 70 Gene Therapy Combined with Hyperthermia using Magnetic Nanoparticles [Ito, 2003] • Characterization of Heat Shock Protein 110 and Glucose-Regulated Protein 170 as Cancer Vaccines and the Effect of Fever-Range Hyperthermia on Vaccine Activity [Wang, 2010]

  17. Mild Hyperthermia: Example 1 • Mice infected with melanoma cells were treated with gene (HSP70) and hyperthermia therapy • Tumor tissue was heated to 43 ⁰C for a period of 30 minutes 24hrs. after HSP70 gene injection • Heating was insufficient to kill tumor tissue, purpose was to observe the effects of combined heating and gene therapy

  18. Mild Hyperthermia: Example 1

  19. Mild Hyperthermia: Example 1

  20. Mild Hyperthermia: Example 2 • Example: Characterization of Heat Shock Protein 110 and Glucose-Regulated Protein 170 as Cancer Vaccines and the Effect of Fever-Range Hyperthermia on Vaccine Activity [Wang, 2010] • Mice inflicted with colon cancer were treated with heat shock protein injections, a subset of which were also treated with mild hyperthermia

  21. Mild Hyperthermia: Example 2 • Awake mice were heated to 39.5 ⁰C for 6hrs. following protein injection

  22. Mild Hyperthermia: Conclusions • Treatments were each very effective • Both forms of mild hyperthermia, in conjunction with artificially stimulated immune responses

  23. Extreme Hyperthermia • The Treatment: High-intensity focused ultrasound (56-80⁰C for ~1 second) • The Immune Response: Changes in T-cell, HSP, and protein antigen expression • Observed: • Spontaneous regression of tumor metastases • Better survival after treatment • Changes in all immune response agents listed

  24. Conclusions • Thermotherapy offers an advantage over traditional surgical treatments: • Recuperation and hospital time is minimized by less invasive procedure • A beneficial immune response makes treatment more effective • Future Work: • Further study into the mechanism of immune response • Optimize immunological stimulation • Technique optimization (Ex. Freeze rate) • Response supplementation (Ex. HSP vaccination)

  25. References • Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma (2004) Akira Ito, Fumiko Matsuoka, Hiroyuki Honda, Takeshi Kobayashi. Cancer ImmunolImmunother 53: 26-32 • Heat shock protein 70 egen therapy combined with hyperthermia using magnetic nanoparticles (2003) Akira Ito, Fumiko Matsuoka, Hiroyuki Honda, and Takeshi Kobayahsi. Cancer Gene Therapy 10: 918-925 • Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy (2007) E. Schmill, M. Gehrmann, M. Brunet, G. Multhoff, and C. Garrido. Journal of Leukocyte Biology 81: 15-27 • Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity (2001) Xiang-Yang Wang, LatifKazim, Elizabeth A. Repasky, and John R. Subjeck. J. Immunol. 166: 490-497 • Regulatory potential of fever-range whole body hyperthermia on lagerhans cells and lymphocytes in an antigen-dependent cellular immune response (2001) Julie R. Ostberg, Caren Gellin, Rahul Patel and Elizabeth A. Repasky. J. Immunol. 167: 2666-2670 • Role of the heat shock response and molecular chaperones in oncogenesis and cell death (2000) Caroline Jolly, Richard I. Morimoto. Journal of the National Cancer Institute. Vol. 92, No. 19, 1564-1572 • Regulatory effects of fever-range while-body hyperthermia on the LPS-induced acute inflammatory response (2000) Julie R. Ostberg, Shannon L. Taylor, Heinz Baumann, and Elizabeth A. Repasky. Journal of Leukocyte Biology. Vol. 68 815-820 • Effects of mild perioperative hypothermia on cellular immune response (1998) Benzion Beilin, M.D., YehudaShavit, Ph.D, Jacob Razumovsky, M.D., YaacovWolloch, M.D, Alexander Zeidel, M.D., Hanna Bessler, Ph.D. Anesthesiology V.89 No. 5 1133-1140 • Investigation of the mechanism and the effect of cryoimmunology in the copenhagen rat (2000) Nathan E. Hoffmann, James E. Coad, Christopher S. Huot, David J. Swanlund and John C. Bischof. Cryobiology, Vo. 42, Issue 1 59-68 • Enhanced tumor metastases in rats following cryosurgery of primary tumor (1982) Yamashita T., Hayakawa K, Hosokawa M, Kodama T, Inoue N, Tomita K, Kobayahsi H. PMID 73(2) 222-8 • The cryobiology of cryosurgical injury (2002) Nathan E. Hoffmann, and John C. Bischof. Urology Elsevier Science Inc. (Suppl 2A) 40-49 • Rate of freeze alters the immunologic response after cryoablation (2010) Michael S. Sabel, MD, Gang Su, Kent A. Griffith, MPH, MS, and Alfred E. Chang, MD. Surgical Oncology 17: 1187-1193 • Host antitumour immune responses to HIFU ablation (2007) F. Wu, L. Zhou, W.R. Chen. Int. J. Hyperthermia 23(2): 165-171

  26. Questions?Thank you!

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