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Wei R. Chen, Ph.D. Professor Department of Engineering and Physics, University of Central Oklahoma Edmond, Oklahoma, USA

Targeted therapy + immunotherapy: a biomedical engineering approach for the treatment of metastatic cancers . Wei R. Chen, Ph.D. Professor Department of Engineering and Physics, University of Central Oklahoma Edmond, Oklahoma, USA Fulbright Scholar and Visiting Professor (2011-2012)

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Wei R. Chen, Ph.D. Professor Department of Engineering and Physics, University of Central Oklahoma Edmond, Oklahoma, USA

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  1. Targeted therapy + immunotherapy: a biomedical engineering approach for the treatment of metastatic cancers Wei R. Chen, Ph.D. Professor Department of Engineering and Physics, University of Central Oklahoma Edmond, Oklahoma, USA Fulbright Scholar and Visiting Professor (2011-2012) Institute of Biophotonics, National Yang Ming University, Taipei, Taiwan Hungkuang University, Taichung, Taiwan, May 23, 2012

  2. Outlines • Cancer History, Cancer Death, and Metastatic Cancer • Innovations in Cancer Treatment – • Surgery, chemotherapy, radiation, and targeted therapy • Laser Immunotherapy (LIT) for Metastatic Cancers • Laser photothermal targeted therapy + immunotherapy • In situ autologous cancer vaccination (inCVAX) • Development of LIT – A Brief History • A simple idea in 1995 • Clinical trial: melanoma in 2004; late-stage breast cancer in 2009 • Major Results of LIT • Pre-clinical work • Recent clinical trials • Mechanistic Studies • Summary: Challenges and Questions

  3. History of Cancer • The First Written Record of Cancer • A papyrus (纸莎草) with transcription of early Egyptian text in 2500 BC • Edwin Smith – part scholar and part huckster, an antique forger and self-made Egyptologist • In 1862, Smith bought (or, some say, stole) a fifteen-foot-long papyrus from an antiques seller in Luxor in Egypt • Written perhaps in 1700 BC • A transcription of a manuscript dated back to 2500 BC • Translated in 1930, considered as collected teaching of Imhotep, a great Egyptian physician around 2625 BC • A surgical textbook with 48 medical cases, broken bones, abscess of skin, with anatomical glossary, diagnosis, summary, treatment method, and prognosis

  4. History of Cancer • The First Written Record of Cancer • The description of breast cancer in Case #45 • “If you examine a case having bulging masses on the breast…they have spread over the breast” • “If you place your hand upon the breast…find them to be cool without fever” • “They have no granulations, contain no fluid, give rise to no liquid discharge” • “Bulging tumors of breast mean the existence of swellings on the breast, large, spreading, and hard…” • “Touching them is like touching a ball of wrapping… unripe hemat fruit, which is hard and cool to the touch.” • Cure for cancer? • Under the section titled “Therapy”: None

  5. History of Cancer Papyrus Plant and Papyrus Paper Egyptian text on cancer on papyrus (纸莎草) (2500 BC) Papyrus with Writings

  6. History of Cancer • The First Written Record of Cancer Operation • The Histories, by the Greek historian Herodotus, 440BC (Book III of his nine books of history) • Persia Queen Atossa, daughter of Cyrus the Great, 550-475 BC • Suddenly Struck by an unusual illness, in the middle of her reign • A bleeding lump in her breast, maybe a form of breast cancer labeled inflammatory • Wrapped herself in sheets, self-imposed quarantine • Ultimately, a Greek slave named Democedes persuaded her to allow him to excise the tumor • After the operation, Atossa vanished from Herodotus’ text • Atossa lived; to thank Democedes, who wants to return to Greek, Atossa persuaded her husband, King Darius, to invade Greek, the series of Greco-Persian wars followed • Hence, a tumor quietly launched > 1000 warships! • CANCER KILLS!!

  7. History of Cancer ? Persia Queen Atossa (550-475 BC) Greek historian Herodotus (484-425BC) Greek Slave, the Surgeon Democedes No picture (???–???BC)

  8. History of Cancer • Archaeological Evidence of Cancer • Alexandrian catacombs in Egypt • 1914, a team of archaeologists found a 2000-year old Egyptian mummy with a tumor invading the pelvic bone • Southeastern Africa • Louis Leakey, an archaeologist, (who found Lucy, one of the earliest known human skeleton), discovered a jaw bone dating from 4000 BC with signs of lymphoma (not confirmed pathologically) • A thousand-year-old graveyard in south tip of Peru • A sand-swept plain at the northern edge of the Atacama Desert • Graves of the mummified remains of members of Chiribaya tribe • 1990, Prof. Arthur Aufderheide, U of Minnesota in Duluth, performed autopsies for 140 bodies • In one lady of mid-thirties, a hard “bulbous mass” in left upper arm • A clear bone cancer, an osteosarcoma

  9. History of Cancer Osteosarcoma from a mummy

  10. History of Cancer • The Name of Cancer • Karkinos • First appearance in about 400 BC, time of Hippocrates (460-370 BC), an ancient Greek physician • In medical literature, karkinos, from Greek word for “crab” • Crab dug in the sand with legs spread in a circle, like the clutch of swollen blood vessels around the tumor • Onkos • From Greek word for “a mass or load” • Origin of oncology • Metastasis • Used to describe the migration of cancer from one site to another • A curious mix of meta and stasis – “beyond stillness” in Latin • Tumor and Cancer • Tumor: Physical concept – A lump • Cancer: Abstract concept – A disease

  11. Cancer Death • 1975 to 2002: Overall death per 100,000 people in the US • 1975 to 2002: Death per 100,000 people in the US for four major cancers: • Lung, Prostate, Breast, and Colorectal cancers • Continued increase until 1992; Slight decrease since 1992 • Slight better data from 2002 to 2004 (Status of Cancer, 1975-2004, Cancer, 2007). • The death rate of late-stage cancer patient today is close to that of 1970’s

  12. 2009 Estimated US Cancer Deaths* Women713,220 Men766,130 Prostate 25% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin 5% lymphoma Kidney & renal pelvis 5% Leukemia 3% Oral cavity 3% Pancreas 3% All Other Sites 19% 27% Breast 14% Lung & bronchus 10% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 4% Thyroid 3% Kidney & renal pelvis 3% Ovary 3% Pancreas 22% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009.

  13. Metastasis Major cause of treatment failure; 90% patients died of metastasis No effective treatment modality for metastatic cancers so far Angiogenesis Signaling molecule Judah Folkman , Died Jan 14, 2008, of heart attack, at 76

  14. Cancer Treatment – A History of Innovations

  15. Innovation 1: Surgery of Cancer • 440BC, surgery of breast cancer, Queen Atossa • John Hunter, a Scottish surgeon around 1760s • Anesthesia and antisepsis, breakthroughs for surgery • Radical mastectomy in late 1880s, Halsted, an American surgeon • Mechanism: Removal of tumor mass • Toady: A mainstream therapy, but cannot work with metastatic cancers New York: A photo of radical mastectomy in the late 1800s Drawing (1595-1645) Drawing (1800s)

  16. Innovation 2: Chemotherapy of Cancer • Started with the mustard gas (芥子氣) in World War I • A colorless, blistering liquid, with smell of mustard, burnt garlic • July 12, 1917, it was first used on the battle field of World War I • Respiratory complications, burnt skin, blisters, and blindness • (Young Adolf Hitler, as a soldier, was temporarily blinded by mustard gas during WW I) • One of the major effect: White cells depletion • Target cancer cell: Leukemia (overproduction of white cells) • Father of Chemotherapy – Sydney Farber • In 1947, Farber used anti folic acid (folate) for leukemia patients • A great success, although short lived, started the era of chemo • Combination chemotherapy • Autologous (自身的) Bone Marrow Transplant (ABMT) • Solid Tumor Autologous Marrow Program (STAMP) • Mechanism: destroy dividing cells • Today: a mainstream modality, but not for metastatic cancers

  17. Innovation 3: Radiation Therapy • Started with the discovery of X-ray in 1895 by William Röntgen • Radiation therapy using radium as source until 1990s • Use of cobalt and cesium as source in 1990, now: linear accelerator as source • Mechanism: damage to DNA of cells • Today: a mainstream modality, but not for metastatic cancers

  18. Different Types of Radiation Therapy • Examples of Radiation Therapy • Gamma Knife • Cyber Knife • Brachytherapy • Proton Therapy • Photodynamic Therapy (PDT) • High Intensity Focused Ultrasound (HIFU) therapy Gamma Knife Linear Accelerator Brachytherapy Proton Therapy Cyber Knife

  19. New Cancer Therapies • Targeted therapies • New generation of drugs: • Gleevec (imatinib) • Velcad (bortezomib) • Avastin (bevacizumab) • …… • Mechanism: • Inhibiting angiogenesis • Inhibiting signal transduction • Monoclonal antibodies • Gene therapy • Inducing apoptosis • …… • Toady: Under development • Further development: targeted therapy + immunotherapy Vanneman and Dranoff, Nature Review Cancer, 12, 237-251, 2012

  20. Development of Laser Immunotherapy • Laser Immunotherapy (LIT): combination of targeted laser therapy and immunotherapy • Laser-assisted immunotherapy/ In situ photoimmunotherapy • In situ autologous whole-cell cancer vaccination (inCVAXTM) • Development of LIT • 1994 – Selective photothermal interactions using 805-nm laser and indocyanine green (ICG); • 1995 – Glycated chitosan (GC) with photothermal interactions for metastatic cancer – LIT: laser-ICG-GC • 1996 – 2004 pre-clinical studies using different animal models • 2004 – 1st LIT clinical trial for melanoma • 2010 – LIT trial for melanoma – five-year follow-up • 2009 – LIT trial for late-stage, metastatic breast cancer patients using GC WR Chen et al, Can Lett, 88, 1995; 94, 1995; 98, 1996 WR Chen et al, Can Lett, 115, 1997 WR Chen et al, Int J Can, 81, 1999; Can Res, 61, 2001; Can Res, 62, 2002; Int J Can, 107, 2003 MF Naylor et al, Br J. Dermat, 155, 2006 X Li et al, Can Bio & Therapy, 10, 2010 X Li et al, Photochem & Photobio Sci, 10, 2011

  21. Components of LIT US Patents (Nordquist, Chen, et al): 5,747,475, 1998; 6,099,554, 2000; 6,149,671, 2000; 6,290,712, 2001; 6,316,007, 2001; several pending 805-nm laser Glycated Chitosan Indocyanine Green

  22. Procedures of LIT Local administration of ICG and GC Non-invasive laser irradiation

  23. Pre-Clinical Studies Using Laser Immunotherapy

  24. Results of LIT • Pre-clinical results • Elimination of treated primary tumors • Eradication of untreated metastases • Long-term survival of treated tumor-bearing animals • Induced resistance to tumor rechallenges • Induced immunological effect at cellular level • Histochemical assays • Induced immunological effect at molecular Level • Western blot analysis • Induced immunological effect • Adoptive immunity transfer using immune spleen cells • Enhanced treatment effects combining PDT and GC • Enhanced treatment effects with other immunoadjuvants

  25. DMBA-4 Mammary Tumor in Rats • DMBA-4 Mammary Tumor • Chemical Induced --> Transplantable • Multiple Metastases along Lymphatics • Female Wistar Furth rats • Treatment: Primary tumor size: 0.2 to 0.5 cm3 • 805-nm Laser: 2 watts and 10 minutes • Indocyanine Green: 0.25%; 2.5 mg/kg • Glycated Chitosan: 1%; 10 mg/kg

  26. Effect of Treatment on Primary Tumor

  27. Effect of Treatment on Metastases

  28. Effects of Treatment on Animal Survival

  29. Resistance to Tumor Challenge after Laser Immunotherapy Treatment

  30. Adoptive Immunity Transfer • Immune Cells: Splenocytes • From a Laser immunotherapy cured rat • From an untreated tumor-bearing rat • From a naive rat • Dose: 40x106 spleen cells : 105 tumor cells • Inhibition of Tumor Growth using cured rat spleen cells • First cohort protection: 100% • Second cohort protection: 83%

  31. Adoptive Immunity Transfer using Spleen Cells

  32. Adoptive Immunity Transfer using Spleen Cells -- Protection of Second Cohort

  33. Laser Immunotherapy and Tumor Rechallenge

  34. Laser Immunotherapy and Adoptive Immunity Transfer

  35. Preliminary Clinical Studies Using Laser Immunotherapy

  36. Results of LIT • Clinical results –melanoma • Protocol • 5% Imiquimod topical application • Laser: 1 W/cm2; 10 minutes • Treatment of patients

  37. Components of Laser Immunotherapy Indocyanine green 805 nm laser Imiquimod

  38. Laser Immunotherapyfor Metastatic Melanoma Patient • Patient 1 • 64-year old female • Primary tumor on left arm • Bilateral lung metastases - Stage IV melanoma • Treatment • 5% Imiquimod topical 3 weeks before laser treatment • 805-nm laser + ICG treatment twice in two week • ICG: 0.25%; ½ tumor volume; Intratumor injection 30 minutes before laser • Laser: 1 W/cm2; 10 minutes • 5% Imiquimod topical 2 weeks after laser treatment

  39. 3 weeks before the laser treatment Immediately after first laser Treatment 2004-06-08 2004-06-28 1 week after second laser treatment 8 weeks after second laser treatment 2004-07-19 2004-09-10

  40. 3 days after first laser treatment 3 weeks after second laser treatment 2004-06-31 2004-08-02 8 weeks after second laser treatment 7 months after second laser treatment 2005-02-03 2004-09-07

  41. Laser Immunotherapyfor Metastatic Melanoma Patient • Patient 2 • 63-year old male • Primary tumor on head and neck • Failed surgery and radiation therapy • Multiple local metastases (Stage III) • Treatment • 5% Imiquimod topical 3 weeks before laser treatment • 805-nm laser: 1 W/cm2; 10 minutes • 5% Imiquimod topical 2 weeks after laser treatment

  42. Before Laser Immunotherapy After 1st laser treatment 01/19/05

  43. After 3rd laser treatment After 4th laser treatment 04/08/05

  44. Clinical Studies: Melanoma Five-year follow-up for 10 evaluable patients

  45. Follow up treatment - Melanoma • Patient 1 • Tumor Recurrence and Re-Treatment • One year after tumor (original and lung metastases) eradication • Tumor recurrence on the left arm (original site) • Positive melanoma by biopsy • Re-treatment – Only One Cycle • Complete success

  46. One year after the first treatment Immediately after second laser treatment 2005-08-19 2005-08-31 Immediate after one cycle of treatment 6 weeks after one cycle of treatment 2005-10-25 2005-09-13

  47. Follow up treatment - Melanoma • Patient 2 • Tumor Recurrence and Re-Treatment • Six months after tumor eradication • Tumor recurrence on the face (original site) • Positive melanoma by biopsy • Re-treatment – Only One Cycle (one laser treatment) • Complete success

  48. Six months after the first treatment Immediately after first laser treatment 2006-02-15 2006-02-28 6 weeks after laser treatment 17 weeks after one cycle of treatment 2006-04-11 2006-06-26

  49. Discussion • Acute Life-Threatening Disease vs. Chronicle Manageable Disease? • Great outcome for patients • Outstanding outcome for health care • Excellent outcome for physicians • Co-existence with Cancer? • If everyone can co-exist with cancer for 100 years, who cares? • Laser immunotherapy may be the way to help people co-exist with cancer?!

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