CYTORI’S FOCUS ON SPECIALTY THERAPEUTICS BEGINS AND ENDS WITH THE PATIENT

Cytori Cell Therapy is for investigational use in the United States.

WHAT IS CYTORI CELL THERAPY?

Cytori is developing cell therapies that harness the unique attributes of living cells that are present in an adult human patient’s own adipose tissue, also known as Adipose-Derived Regenerative Cells (ADRCs). Cytori Cell Therapy is the collective name given to the fresh, heterogeneous population of ADRCs prepared with the proprietary Celution® System platform technology and administered to a patient for a specific disease or medical condition, all within a single day:

Cytori Cell Therapy is designed to repair injured tissue, preserve function, improve quality of life, and modify disease progression.

WHY USE AN ADULT HUMAN PATIENT’S OWN ADIPOSE TISSUE?

Physicians and scientists have demonstrated the frequency of stem cells in adipose tissue to be 2,500 times greater than the frequency of similar cells in bone marrow.1,2,3 Further, adipose tissue can be more easily collected than bone marrow via a small volume liposuction procedure.

Since Cytori technology prepares ADRCs exclusively from an adult human patient’s own adipose tissue, treatment with these cells avoids common transplantation issues, such as cell rejection or disease transmission, and does not require anti-rejection or immunosuppressant drugs.

HOW DOES IT WORK?

While the exact mechanism of action is unknown, pre-clinical publications suggest the use of ADRCs has been associated with improvements in angiogenesis, inflammation, and fibrosis.

Angiogenesis/Vasculopathy

In pre-clinical studies, ADRCs have been shown to promote angiogenesis, or the creation of new blood vessels from pre-existing vessels. Application of these cells has also been associated with improvement of vasomotor function.4,5,6,7,8

Inflammation

In pre-clinical studies, use of ADRCs has been shown to be associated with modulation of inflammation through expression of factors that regulate both pro- and anti-inflammatory cells. This includes processes such as polarization of macrophages and inhibition of T cell activation.6,9,10,11,12

Fibrosis/Wound Repair

In pre-clinical studies use of ADRCs has been associated with reduction and remodeling of fibrosis. This is mediated by modulation of expression of extracellular matrix components and remodeling enzymes.5,13,14

Cytori Cell Therapy is a novel approach that has the potential to harness the power of a patient’s own cells to promote healing.

WHY CYTORI CELL THERAPY?

Cytori Cell Therapy is comprised of an autologous, heterogeneous, readily accessible cell population that is the result of more than a decade of rigorous research and development. 15,16,17,18,19

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Advanced Technology, Convenient For the Patient

Cytori Cell Therapy is being developed as a therapy to be delivered in a single treatment, designed to avoid the need for frequent re-treatment.


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Same-Day Cell Therapy

Cytori Cell Therapy eliminates the requirement for cells to be shipped to off-site facilities. Cells can be harvested in the hospital and processed on-site for faster care.


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Safety Profile

The use of ADRCs in pre-clinical and clinical studies has been shown to be well-tolerated. Hundreds of patients have been treated with ADRCs in multiple clinical trials across the world. Cytori’s approach to cell therapy avoids the risk of rejection.

  • 1. Caplan 2009. Why are MSCs Therapeutic? New Data: New Insight. J. Pathol; 318-324
  • 2. Fraser 2007. Differences in stem and progenitor cell yield in different subcutaneous adipose tissue depots, ISCT Vol 9, No 5 459-467.
  • 3. Jurgens, 2008. Adipose tissue derived stem cell yield is affected by the tissue harvesting site: implications for cell based therapies, Cell and Tissue Research
  • 4. Foubert P, Gonzalez A, Teodosescu S, Berard F, et al. Adipose-derived regenerative cell therapy for burn wound healing: a comparison of two delivery methods. Adv Wound Care. 2015;4(11). http://online.liebertpub.com/doi/abs/10.1089/wound.2015.0672?journalCode=wound
  • 5. Koh Y, Koh B, Kim H, Joo H, et al. Stromal vascular fraction from adipose tissue forms profound vascular network through the dynamic reassembly of blood endothelial cells. Arterioscler Thromb Vasc Biol. 2011;31(5):1141-50. doi: 10.1161/ATVBAHA.110.218206.
  • 6. Premaratne G, Ma L, Fujita M, Lin X, et al. Stromal vascular fraction transplantation as an alternative therapy for ischemic heart failure: anti-inflammatory role. J Cardiothorac Surg. 2011;6:43. doi: 10.1186/1749-8090-6-43.
  • 7. Morris M, Beare J, Reed R, Dale J, et al. Systemically delivered adipose stromal vascular fraction cells disseminate to peripheral artery walls and reduce vasomotor tone through a CD11b+ cell-dependent mechanism. Stem Cell Transpl Med. 2015;4(4): 369-80. doi: 10.5966/sctm.2014-0252.
  • 8. Eguchi M, Ikeda S, Kusumoto S, Sato D, et al. Adipose-derived regenerative cell therapy inhibits the progression of monocrotaline-induced pulmonary hypertension in rats. Life Sci. 2014;118(2):306-12. doi: 10.1016/j.lfs.2014.05.008.
  • 9. Feng Z, Ting J, Alfonso Z, Strem B, et al. Fresh and cryopreserved, uncultured adipose tissue-derived stem and regenerative cells ameliorate ischemia-reperfusion-induced acute kidney injury. Nephrol Dial Transpl. 2010;25(12):3874-84. doi: 10.1093/ndt/gfq603.
  • 10. Hao C, Shintani S, Shimizu Y, Kondo K, et al. Therapeutic angiogenesis by autologous adipose-derived regenerative cells: comparison with bone marrow mononuclear cells. Am J Physiol Heart and Circ Physiol. 2014;307(6): H869-79. doi: 10.1152/ajpheart.00310.2014.
  • 11. Dong Z, Peng Z, Chang Q. The survival condition and immunoregulatory function of adipose stromal vascular fraction (SVF) in the early stage of nonvascularized adipose transplantation. PLos One. 2013;8(11): e80364. doi: 10.1371/journal.pone.0080364.
  • 12. Baulier E, et al. Characterization of the porcine Stromal Vascular Fraction (SVF) and evaluation of the therapeutic potential in order to use in a preclinical model of porcine kidney transplantation. Data on file (Cytori).
  • 13. Serratrice N, Bruzzese L, Magalon J, Véran J, et al. New fat-derived products for treating skin-induced lesions of scleroderma in nude mice Stem Cell Res Ther. 2014;5(6):138. doi: 10.1186/scrt528.
  • 14. Boissier R, Karsenty G. Réunion de travail tissu graisseux-fraction vasculaire stromale. Applications en urologie incontinence urinaire. Data on file (Cytori).
  • 15. Granel B, Daumas A, Jouve E, Harlé J. et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2014;0:1–8. doi: 10.1136/annrheumdis-2014-205681.
  • 16. Guillaume-Jugnot P, Daumas A, Magalon J, Jouve E, et al. Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatol. 2016:55(2):301-6. doi: 10.1093/rheumatology/kev323.
  • 17. Gotoh M, Yamamoto T, Kato M, Majima T, et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients. Intl J Urol. 2014;21(3):294-300. doi: 10.1111/iju.12266.
  • 18. Perez-Cano R, Vranckx J, Lasso J, Calabrese C, et al. Prospective trial of adipose-derived regenerative cell (ADRC)-enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial. Eur J Surg Onc. 2012;38(5): 382-9. doi: 10.1016/j.ejso.2012.02.178.
  • 19. Daumas, A. et al. “Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients.” Current Research in Translational Medicine. 2016.

WHAT IS CYTORI NANOMEDICINE?

Cytori also develops nanomedicines using liposomal encapsulation technology designed to reduce toxicity while retaining the efficacy of both existing agents and novel compounds. For oncology patients, the size and composition of liposomal-encapsulated products are designed such that the chemotherapeutic agent can be delivered more selectively to the tumor. Clinical trials have demonstrated that encapsulation can protect organs such as the heart from the toxic effects of the chemotherapy agents such as doxorubicin leading to a safety and efficacy profile that is superior to that of the non-encapsulated drug. 20,21

It is well-known that many very common chemotherapeutic drugs have significant side effects. These side effects are usually caused by the fact that normal healthy tissues such as the heart or nervous system are sensitive to the same toxic effect that allows the drug to attack the cancer. Published studies have reported that nanomedicines used in oncology can reduce toxicity towards non-tumor cells by packaging the drug inside liposomes that create a barrier between the drug and tissues.21 These liposomes are essentially very tiny bubbles of lipid with a water-filled interior containing the drug.

Cutaway image of a liposome showing chemotherapy payload

HOW DOES IT WORK?

Blood vessels in tumors are different from those in normal healthy tissues in that they are leakier and will allow these small particles to pass out of the bloodstream into the tissue. As a result, the drug-filled liposomes preferentially accumulate in tumor tissue selectively sparing normal, healthy tissue. 20

Normal Tissue

Tumor Tissue

This approach is designed to retain the efficacy of the chemotherapeutic while reducing its side effects and potentially allows use of higher, more effective doses of chemotherapy without increasing side effects.

Because blood vessels in injured or inflamed tissues frequently have leakiness similar to that present in tumors, the same approach could be used to deliver regenerative payloads to injured tissues. That is, instead of delivering a chemotherapy agent to a tumor, this approach could be used to deliver molecules that promote tissue regeneration and repair thereby creating a new category of specialty therapy; regenerative nanomedicine.

  • 20. Gabizon A, Shmeeda H, and Barenholz Y (2003) “Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies” Clin Pharmacokinet. 42(5):419-36
  • 21. Rafiyath et al. 2012 “Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis” Exp Hematol Oncol 1:10-19

Awards

Cytori was the recipient of Frost & Sullivan’s 2016 North American Cell Therapeutics Technology Innovation Award in recognition of advancements made in the field of regenerative medicine for over a decade.

Frost & Sullivan’s industry research and benchmarking analysis report that Cytori’s pioneering technology platform has become the leading technology to enable the research and practice of cellular therapies that harness the potential of stem and regenerative cells from adipose tissue. Details of the full report can be found here .

Patents

To protect our proprietary Cell Therapy and Nanomedicine technologies and other scientific discoveries, we have a portfolio of 102 patents issued worldwide and over 65 applications pending.

Publications

Cytori’s technologies and investigational products have been evaluated in both pre-clinical and clinical research studies and cited in peer-reviewed publications.

Akita S et al. “Autologous adipose-derived regenerative cells are effective for chronic intractable radiation injuries.” Radiation Protection Dosimetry, 151:4; 656-660; 2012.

Akita S et al. “Noncultured Autologous Adipose-Derived Stem Cells Therapy for Chronic Radiation Injury.” Stem Cells International, 2010.

Andjelkov K et al. “A novel method for treatment of chronic anal fissure: adipose-derived regenerative cells – a pilot study.” Colorectal Disease, 19:6; 570-575; 2017.

Andjelkov K et al. “Posterior Fourchette Fissure Resolution After Injection of Autologous Adipose-Derived Regenerative Cells.” Obstetrics & Gynecology, 129:3; 497-499; 2017.

Aronowitz J et al. “Adipose Stromal Vascular Fraction Isolation: a Head-to-Head Comparison of Four Commercial Cell Separation Systems.” Plastic and Reconstructive Surgery, 132:6; 932e–939e; 2013.

Boissier R et al. “Histological and Urodynamic Effects of Autologous Stromal Vascular Fraction Extracted from Fat Tissue with Minimal Ex Vivo Manipulation in a Porcine Model of Intrinsic Sphincter Deficiency.” The Journal of Urology, 196:3; 934-942; 2016.

Borowski D et al. “Adipose Tissue-Derived Regenerative Cell-Enhanced Lipofilling for Treatment of Cryptoglandular Fistulae-in-Ano: The ALFA Technique.” Surgical Innovation, 22:6; 593-600; 2015.

Borowski D et al. “Autologous Adipose-Tissue Derived Regenerative Cells for the Treatment of Complex Cryptoglandular Fistula-in-Ano: A Report of Three Cases.BMJ Case Reports; 2012.

Calabrase C et al. “Breast Reconstruction after Nipple/Areola- Sparing Mastectomy Using Cell-Enhanced Fat Grafting.” ecancer, 3:116; 2009.

Calcagni M et al.  “The novel treatment of SVF-enriched fat grafting for painful end-neuromas of superficial radial nerve.”  Microsurgery, 1-6; 2016.

Cervelli V et al. “Application of Enhanced Stromal Vascular Fraction and Fat Grafting Mixed with PRP in Post–Traumatic Lower Extremity Ulcers.” Stem Cell Research, 6:2; 103-111; 2011.

Choi J et al. “Adipose-Derived Regenerative Cell Injection Therapy for Postprostatectomy Incontinence: A Phase I Clinical Study.” Yonsei Medical Journal, 57:5; 1152-1158; 2016.

Daumas A et al. “Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients.” Current Research in Translational Medicine, in press 2016.

Domenis R et al. “Adipose tissue derived stem cells: in vitro and in vivo analysis of a standard and three commercially available cell-assisted lipotransfer techniques.Stem Cell Research & Therapy, 6:2; 2015.

Feng Z et al. “Fresh and cryopreserved, uncultured adipose tissue-derived stem and regenerative cells ameliorate ischemia–reperfusion-induced acute kidney injury.” Nephrology Dialysis Transplantation, 25:12; 3874-3884; 2010.

Foll D et al. “Successful closure of persistent oro-cutaneous fistulas by injection of autologous adipose-derived stem cells: a case report.” German Plastic, Reconstructive and Aesthetic Surgery, 3:5; 2013.

Fraser J et al. “The Celution System: Automated Processing of Adipose-Derived Regenerative Cells in a Functionally Closed System.” Advances in Wound Care, 3:1; 38-45; 2014.

Gentile P et al. “A Comparative Translational Study: The Combined Use of Enhanced Stromal Vascular Fraction and Platelet-Rich Plasma Improves Fat Grafting Maintenance in Breast Reconstruction.Stem Cells Translational Medicine, 1:4; 341–351; 2012.

Gentile P et al. “Breast Reconstruction with Enhanced Stromal Vascular Fraction Fat Grafting: What Is the Best Method?” Plastic and Reconstructive Surgery Global Open, 3:6; 2015.

Gentile P et al. “Adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical evaluation for cell-based therapies in patients with scars on the face.” The Journal of Craniofacial Surgery, 25:1; 267-272; 2014.

Gotoh M et al. “Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients.” International Journal of Urology, 21; 294-300; 2014.

Granel B et al. “Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial.” Annals of the Rheumatic Diseases, 2014.

Guillaume-Jugnot P et al. “Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up.” Rheumatology, 55:2; 301-306; 2016.

Haahr M K et al. “Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial”. EBioMedicine, 5; 204-210; 2016.

Haahr M K et al. “Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: A 12-Month Follow-Up.” The Journal of Urology, 197:4; e542; 2017.

Henry T et al. “The Athena Trials: Autologous Adipose-Derived Regenerative Cells for Refractory Chronic Myocardial Ischemia with Left Ventricular Dysfunction.” Catheterization and Cardiovascular Interventions, 2016.

Herold C et al.  “Supplementation of fat grafts with adipose-derived regenerative cells in reconstructive surgery.”  German Plastic, Reconstructive and Aesthetic Surgery, 2; 2012.

Houtgraaf J et al. “First Experience in Humans Using Adipose Tissue-Derived Regenerative Cells in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction.Journal of the American College of Cardiology, 59:5; 539-540; 2012.

Iddins CJ et al. “Case Report: Industrial X-Ray Injury Treated With Non-Cultured Autologous Adipose-Derived Stromal Vascular Fraction (SVF).” Health Physics, 111:2; 112-116; 2016.

Ito S et al. “Long-term outcome of adipose-derived regenerative cell-enriched autologous fat transplantation for reconstruction after breast-conserving surgery for Japanese women with breast cancer.” Surgery Today, 1-12; 2017.

Kakudo N et al.  “Adipose-derived regenerative cell (ADRC)-enriched fat grafting:  optimal cell concentration and effects on grafted fat characteristics.”  Journal of Translational Medicine, 11:254; 1-9; 2013.

Kamakura T and Ito K. “Autologous Cell-Enriched Fat Grafting for Breast Augmentation.” Aesthetic Plastic Surgery, 35:6; 1022–1030; 2011.

Karaaltin M et al.  “Adipose Derived Regenerative Cell Therapy for Treating a Diabetic Wound:  A Case Report.”  Wounds, 24:1; e1-5; 2012.

Magalon G et al. “Regenerative Approach to Scleroderma with Fat Grafting.” Clinics in Plastic Surgery, 42:3; 353-364; 2015.

Marino G et al. “Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease.” Journal of Surgical Research, 185:1; 36-44; 2013.

Mizushima T et al. “A clinical trial of autologous adipose-derived regenerative cell transplantation for a postoperative enterocutaneous fistula.” Surgery Today, 46:7; 835-842; 2016.

Peltoniemi H et al. “Stem cell enrichment does not warrant a higher graft survival in lipofilling of the breast: a prospective comparative study.Journal of Plastic, Reconstructive & Aesthetic Surgery, 66:11; 1494-1503; 2013.

Perez-Cano R et al. “Prospective Trial of Adipose-Derived Regenerative Cell (ADRC)-Enriched Fat Grafting for Partial Mastectomy Defects: The RESTORE-2 Trial.” European Journal of Surgical Oncology, 38:5; 382-389; 2012.

Perez-Meza D et al. “Hair follicle growth by stromal vascular fraction-enhance adipose transplantation in baldness.” Stem Cells and Cloning: Advances and Applications, 10; 1-10; 2017.

Perin E et al. “Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial.” American Heart Journal, 168:1; 88-95; 2014.

Prins H-J et al. “Bone Regeneration Using the Freshly Isolated Autologous Stromal Vascular Fraction of Adipose Tissue in Combination With Calcium Phosphate Ceramics.” Stem Cells Translational Medicine, 2016.

Sakai Y et al. “Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.” Regenerative Therapy, 6; 52-64; 2017.

Saxer F et al.  “Implantation of Stromal Vascular Fraction Progenitors At Bone Fracture Sites:  From A Rat Model To A First-In-Man Study.”  Stem Cells, 34:12; 2956-2966; 2016.

Shimizu S et al. “Design of a single-arm clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells for male stress urinary incontinence in Japan: the ADRESU study.” BMC Urology, 17:89; 2017.

Smyshlyaev I et al.  “Safety and Effectiveness of Intraarticular Administration of Adipose-Derived Stromal Vascular Fraction for Treatment of Knee Articular Cartilage Degenerative Damage:  Preliminary Results of a Clinical Trial.”  Traumatology and Orthopedics of Russia, 23:3; 17-31; 2017.

Sugimachi K et al.  “Novel breast reconstruction procedure- Attempts of breast regeneration using stem cells after breast cancer mastectomy.”  Japan Journal of Cosmetic Surgery, 30(3); 151-160; 2008.

Tiryaki T et al.  “Staged Stem Cell-enriched Tissue (SET) Injections for Soft Tissue Augmentation in Hostile Recipient Areas:  A Preliminary Report.”  International Society of Aesthetic Plastic Surgery, 35:6; 965-971; 2011.

Toyserkani N et al. “Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study.Stem Cells Translational Medicine, 2017.

Toyserkani N et al. “Cell-Assisted Lipotransfer Using Autologous Adipose-Derived Stromal Cells for Alleviation of Breast Cancer-Related Lymphedema.” Stem Cells Translational Medicine, 5:7; 857-859; 2016.

Tsekouras A et al. “Adipose-derived stem cells for breast reconstruction after breast surgery – preliminary results.” Case Reports in Plastic Surgery & Hand Surgery, 4:1; 35-41; 2017.

Yamamoto T et al. “Periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: Report of three initial cases.” International Journal of Urology, 19:7; 652-659; 2012.

Yokota N et al.  “Clinical results following intra-articular injection of adipose-derived stromal vascular fraction cells in patients with osteoarthritis of the knee.”  Regenerative Therapy, 6; 108-112; 2017.

Yoshimoto H et al.  “Efficacy of patients’ own adipose-derived regenerative cells for chronic intractable radiation injuries.”  Journal of Wound Technology, 10; 22-25; 2010.