At Aethlon Medical, our focus is to create revolutionary medical devices that save lives. In the treatment of Hepatitis C (HCV) infected individuals, we have demonstrated that our Hemopurifier® synergistically combines with drug therapy to accelerate the achievement of undetectable viral load. In cancer, I envision our opportunity to save lives will be driven by the discovery that our Hemopurifier® can addresses a therapeutic target that plays a pivotal role in cancer progression, yet remains beyond the reach of drug therapies. The target? Microvesicles known as exosomes, which are particles secreted by tumors underlying a wide-range of cancers.
of cancer therapies without adding drug resistance or interaction risks.As more and more medical institutes establish exosome research programs, we benefit from new discoveries that will help us to understand which forms of cancer are most likely to benefit from our technology. In this regard, Dr. Annette Marleau (our Director of Tumor Immunology) provides the following review on recent discoveries that describe the implication of exosomes in metastatic melanoma, a form of cancer whose 5-year survival rate
is less than 20%.Exosomes As Therapeutic Targets In Metastatic Melanoma
Exosomes are nano-sized microvesicles released in large quantities by cancer cells that are key culprits in the pathogenesis of several cancer types. Exosomes are now recognized as biological delivery vehicles for communication between cells in almost every system of the body investigated to date. In the area of oncology, cancer derived exosomes are highly stable "packages" released from tumors that transport proteins and genetic material from their originating tumor cells to distant sites throughout the body to accelerate tumor progression. In melanoma patients, tumor-secreted exosomes serve as carriers of malignant proteins and their levels in circulation correlate with the aggressiveness of the cancer1. To date, cancer exosomes have been implicated in: a) immune suppression; b) enhancement of angiogenesis; and c) promotion of metastasis, which will be discussed below.
Owing to several recent publications that have defined their pathological roles in metastatic disease, melanoma exosomes are emerging as candidate therapeutic targets. Metastatic (stage 4) melanoma, the most aggressive form of skin cancer, has a five-year survival rate of only 15-20%2. This disease continues to be a challenge to treat, as the current standard treatments have proven to be ineffective and/or highly toxic. Since patients afflicted with metastatic melanoma have suppressed immune systems due to tumor- and drug-related effects, the efficacy of novel immunotherapeutic solutions
is limited and only small percentages of patients experience durable
responses and extended survival. Thus, the development of novel
treatments to reliably bolster anti-cancer immune responses remains an
urgent clinical objective.Recent scientific studies have defined the importance of melanoma exosomes in the progression of cancer, thereby providing the rationale for targeting tumor-derived nano-vesicles therapeutically. In a 2012 publication in the prestigious journal Nature Medicine, Dr. David Lynden's group at Weill Cornell Medical College and their colleagues reported that melanoma tumors release exosomes that condition metastatic sites for growth of tumors and their supporting blood vessels3. This publication also identifies a correlation between high exosome concentrations in circulation with advanced disease and poor prognosis of patients. This knowledge reinforces the concept that a strategy for eliminating circulating exosomes could be beneficial for addressing metastatic disease.
A pivotal publication by Dr. Joshua Hood and colleagues at Washington University School of Medicine showed that melanoma exosomes migrate to lymph nodes and alter the biochemical milieu to allow lodging of cancer cells in the establishment of metastatic foci4. Once again, this study suggests that systemic clearance of melanoma exosomes could interrupt the "messenger system" underlying metastasis. Along these same lines, a study by Parolini and colleagues in The Journal of Biological Chemistry demonstrated that melanoma exosomes serve as delivery vehicles for spreading malignant proteins from high aggressive metastatic cells to less aggressive cancer cells5.This article raises the concept that exosomes from a primary tumor can transfer their cargo to distant organs, thereby allowing the malignancy to spread.
Experiments have also demonstrated that the functions of immune cells are impaired by melanoma exosomes6. Since the immune system is responsible for recognizing and destroying cancer cells, exosomes thereby manipulate immunity to allow tumors to grow unchecked. Additionally, since immunotherapy is administered to bolster the patient's endogenous immune response, melanoma exosomes impair the effectiveness of these treatments. On this basis, a device strategy for removal of circulating exosomes could be implemented to reverse immune dysfunction in order to improve the effectiveness of standard of care treatments against metastatic melanoma.
Given these recent scientific developments that reveal broad tumor growth promoting and immune inhibitory effects of melanoma exosomes, there is a strong impetus for moving forward with therapeutic targeting options, which do not exist to date. Clinical studies are needed to define the impact of exosomes in metastatic melanoma and to offer promising new treatment solutions that are urgently needed.
References
1 Logozzi M, De Milito A, Lugini L, Borghi M, Calabrò L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, Santinami M, Huber V, Maio M, Rivoltini L, Fais S. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009;4(4):e5219.
2 http://www.cancer.org/cancer/ skincancer-melanoma/detailedguide/ melanoma-skin-cancer -survival-rates
3 Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012 Jun;18(6):883-91.
4 Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011 Jun 1;71(11):3792-801.
5 Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009 Dec 4;284(49):34211-22.
6 Marton A, Vizler C, Kusz E, Temesfoi V, Szathmary Z, Nagy K, Szegletes Z, Varo G, Siklos L, Katona RL, Tubak V, Howard OM, Duda E, Minarovits J, Nagy K, Buzas K. Melanoma cell-derived exosomes alter macrophage and dendritic cell functions in vitro. ImmunolLett. 2012 Nov;148(1):34-8.
About Aethlon Medical
The Aethlon Medical mission is to create innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT™ System is a revenue-stage technology platform that provides the basis for a new class of therapeutics that target the selective removal of disease enabling particles from the entire circulatory system. The Aethlon ADAPT™ product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer; HER2osome™ to target HER2+ breast cancer, and a medical device being developed under a contract with DARPA that would reduce the incidence of sepsis in combat-injured soldiers and civilians. For more information, please visit www.aethlonmedical.com.
Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that the company can successfully protect its intellectual property, that removal of exosomes from the human body will impact or lead to successful treatment of cancer, or that exosomes are the cause of tumor growth and progression, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies whether revenue or non-revenue generating of the Aethlon ADAPT™ system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer or hepatitis C therapies or as a standalone cancer or hepatitis C therapy, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result
of a variety of factors, including the risks associated with the effect
of changing economic conditions and other risk factors detailed in the
Company's Securities and Exchange Commission filings. The Company
undertakes no obligation to publicly update or revise any
forward-looking statements, whether as a result of new information,
future events, or otherwise.Contacts:
James A. Joyce
Chairman and CEO
858.459.7800 x301
jj@aethlonmedical.com
Jim Frakes
Chief Financial
Officer
858.459.7800 x300
jfrakes@aethlonmedical.com
Marc Robins
877.276.2467
mr@aethlonmedical.com
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