On July 2, 2015 Provectus Biopharmaceuticals reported that data from its phase 1 study of PV-10 for chemoablation of hepatocellular carcinoma (HCC) and cancer metastatic to the liver was presented at the ESMO (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer (ESMO-GI) (Press release, Provectus Pharmaceuticals, JUL 2, 2015, http://www.pvct.com/pressrelease.html?article=20150702.1 [SID:1234506021]). The main conclusion was that preliminary evidence of efficacy in treatment of liver cancers with PV-10 was observed. The poster presentation was made by Eric Wachter, Ph.D., Chief Technology Officer of Provectus.

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Provectus has previously reported data on clinical and nonclinical testing of intralesional PV-10, a 10% solution of rose bengal, as an investigational treatment for metastatic melanoma, where it has demonstrated high rates of complete response and durable local control in melanoma lesions. The current phase 1 study reported at ESMO (Free ESMO Whitepaper)-GI was designed to assess safety, pharmacokinetics, and preliminary efficacy of PV-10 in subjects with non-resectable HCC or other types of cancer metastatic to the liver.

In the phase 1 liver study, subjects having a target lesion in the liver at least 1 cm in diameter were administered a single percutaneous injection of PV-10 into their target lesion. Plasma concentrations of PV-10 from 1 hour to 28 days after injection were measured. Radiologic assessments of the injected target lesion were performed to determine response over an initial 28-day and longer term 9-15 month follow-up period. Serum levels of potential liver injury markers were measured, and adverse events recorded.

In the initial study cohort, six subjects received PV-10 injections in two successive escalating dose cohorts of 0.25 and 0.50 mL per cm3 lesion volume. Significant adverse events were limited to injection site and photosensitivity reactions that resolved without sequelae. All injected tumors were stable in size at 28 days, and among four of the initial six tumors that had longer-term assessment, two had partial response.

Based on these data, the researchers concluded that preliminary efficacy in treatment of liver tumors with PV-10 was observed with acceptable tolerability. The study is continuing at three study centers with two expansion cohorts to further assess safety and response in HCC and other cancers metastatic to the liver.

The poster is now available online at: http://www.pvct.com/publications/ESMO-2015-PV-10-LC-01.pdf.

About ESMO (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer

The ESMO (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer is the premier global event in the field, encompassing malignancies affecting every component of the gastrointestinal tract and aspects related to the care of patients with gastrointestinal cancer, including screening, diagnosis and the latest management options for common and uncommon tumors. For additional information about the ESMO (Free ESMO Whitepaper) 17th World Congress, please visit View Source

On July 2, 2015 Macrophage Therapeutics, a subsidiary of Navidea Biopharmaceuticals reported that preclinical results in Kaposi’s Sarcoma (KS) demonstrated that a cytotoxic drug, doxorubicin, linked to Manocept was targeted to and dose-dependently taken up in CD206+ KS tumor cells and tumor associated macrophages (TAMs) and caused apoptotic death of the KS tumor cells and TAMs (Press release, Navidea Biopharmaceuticals, JUL 2, 2015, View Source;p=RssLanding&cat=news&id=2064425 [SID:1234506022]). The results are being presented at the 18th International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents in Hollywood, Florida by Michael S. McGrath, M.D., Ph.D., Professor, Departments of Laboratory Medicine, Pathology, and Medicine at the University of California, San Francisco (UCSF). The study also shows that Cy3-Manocept and a Cy3-Manocept-doxorubicin conjugate quantitatively permitted the evaluation of tumor burden, tissue uptake of Manocept and tumor response to therapy in vitro and ex vivo, supporting the potential for the Manocept platform to be used not only diagnostically but as a precision targeted molecule to deliver payloads to tumor sites throughout the body.

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"Advances in the treatment of cancer such as the recently approved PD1 and PDL1 inhibitors demonstrate the benefit of disrupting the communication signals between tumors and immune cells," said Frederick O. Cope, Ph.D., FACN, Chief Scientific Officer of Macrophage Therapeutics. "Based on the role tumor associated macrophages are thought to play in the progression of cancer, there exists a strong rationale that targeting CD206 represents a therapeutic pathway that is highly likely to exist across tumor types, and which reverses the immunosuppressive effects of cancer cells."

"In my experience, the impressive loss of TAMs demonstrated in these Manocept studies is unique and potentially extremely relevant clinically," said Dr. McGrath. "The results from data in primary human KS tissue, which provides the closest experimental model to human patients, showed not only selective killing of only CD206+ KS tumor cells and macrophages, but demonstrated through a biomarker that the Manocept conjugate induced programmed cell death in tumor cells and exhibited unprecedented anti-HIV activity which could eventually address a broad unmet need for patients with Kaposi’s sarcoma and other tumor types."

The preclinical studies included use of Human peripheral blood mononuclear cells (PBMCs) to measure the time course of Manocept uptake in CD206+ macrophages. Flow cytometry studies identifying CD206+ cells allowed quantitation of the amount of Cy3-Manocept bound to and internalized into the CD206+ cells and also verified Cy3-Manocept-doxorubicin internalization. Confocal microscopy was used with KS biopsies that were cultured overnight with Cy3-Manocept or Cy3-Manocept-doxorubicin and showed that all cells within the KS tissue including macrophages and spindle cells were CD206+ and incorporated the Cy3-Manocept with and without doxorubicin. In KS organ cultures, immunofluorescence assays for the detection of antibodies against latent nuclear antigen (IFA-LANA) and Annexin V were performed. Inhibition studies showed Cy3-Manocept-doxorubicin exhibited anti-HIV activity in HIV infected macrophage culture. In summary, the data presented include evidence that:

KS tissue based cells take up Cy3-Manocept or Cy3-Manocept-doxorubicin into both KS tumor cells and TAMs.

Manocept conjugate uptake is dose and time dependent in CD206+ macrophages

Cy3-Manocept and Cy3-Manocept-doxorubicin bind to CD206 positive macrophages equivalently indicating that the linkage of a drug conjugate did not lessen the CD206 binding ability

Manocept-doxorubicin killed CD206 expressing macrophages. After 24 hours, Cy3-Manocept-doxorubicin killed 70% of CD206 positive macrophages in tissue cultures. Doxorubicin alone showed no toxicity.

KS organ culture treated with Manocept-doxorubicin resulted in the loss of macrophages and induced programmed tumor cell death and apoptosis in KS HHV8+ spindle cells, and showed anti-HIV activity in HIV infected macrophage cultures.

"We are very encouraged that our Manocept platform, with its unique ability to seek out activated macrophages, may selectively deliver a therapeutic that can kill tumor cells, tumor support cells and virus contained in the macrophage. This activity was seen with a therapeutic that without our delivery system would not be effective on the tumor, the TAM’s or either of the viruses. This data suggests that targeting the activated macrophage is a viable strategy for attacking cancers that have TAM’s. It is well established that depleting TAM’s makes the tumor more susceptible to chemotherapy, radiation therapy and many of the new and emerging immune therapy drugs. In addition the effect of this agent with no known anti-viral properties on killing both HIV and HHV8 suggests a novel anti-viral strategy that will not require development of specific tailored drugs to a given virus," said Michael M. Goldberg, M.D., CEO of Macrophage Therapeutics and Director of Navidea. "We look forward to advancing development of our broad therapeutic platform through animal testing this summer in a number of solid tumor models as well as explore the potential of our technology in CNS diseases, viral diseases and animal models of auto-immune disease. Our goal is to seek strategic collaborations with industry leaders to enable rapid development. Finally, we will host an investor day at the end of the summer where we will review the accumulated data being generated."

Navidea and Macrophage Therapeutics plan a webcast to provide investors with a complete look at the data being presented at the International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents conference on July 7, 2015 at 1:00 pm EDT. Webcast details will be available on the Navidea website.

About Manocept CD206 Targeting Platform for Therapeutics Development

Manocept CD206 Targeting Platform is a proprietary mannose-containing, receptor-directed technology platform designed to engineer novel, synthetic receptor targeted imaging agents and therapeutics for cancer and other diseases. Manocept’s unique structural and molecular properties enable the design of novel immuno-constructs that selectively target and bind to CD206 (mannose receptor) and other C-type Lectins found on activated, disease-associated macrophages and tumor associated macrophages (TAMs). The Manocept CD206 Targeting Platform provides a novel and valuable approach to the design of drug molecules targeting CD206 disease-associated macrophages for therapeutic purposes.

About Kaposi’s Sarcoma

Kaposi sarcoma (KS) is a cancer that develops from the cells that line lymph nodes or blood vessels. It usually appears as tumors on the skin or on mucosal surfaces such as inside the mouth, but tumors can also develop in other parts of the body, such as in the lymph nodes (bean-sized collections of immune cells throughout the body), the lungs, or digestive tract. The abnormal cells of KS form purple, red, or brown blotches or tumors on the skin. These affected areas are called lesions. The skin lesions of KS most often appear on the extremities, trunk and face. AIDS-related KS is the most common type of KS in the United States which develops in people who are infected with HIV, the virus that causes AIDS. KS can also develop in people whose immune systems have been suppressed after an organ transplant and is called transplant-related KS.1

On July 2, 2015 Navidea Biopharmaceuticals and its subsidiary, Macrophage Therapeutics reported that imaging results from the Manocept clinical trial in Kaposi’s Sarcoma (KS) and other preclinical studies were presented at the 18th International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents in Hollywood, Florida (Press release, Navidea Biopharmaceuticals, JUL 2, 2015, View Source;p=RssLanding&cat=news&id=2064415 [SID:1234506023]). The clinical imaging study, using Tc 99m tilmanocept, a Manocept platform product, in both HIV+ and HIV- patients suggests that KS tumor lesions, both cutaneous and suspected extra-cutaneous sites, can be easily visualized and mapped, demonstrating that this technique may potentially provide a means for routine patient assessment. The results also show that use of Manocept represents a potential therapeutic pathway for targeting tumor associated macrophages (TAMs). Manocept agents are designed to target CD206, which is highly expressed on TAMs and the KS tumor itself. As a potential therapeutic, Manocept could be used as a precision vehicle to deliver payloads to tumor sites throughout the body.

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"These pre-clinical and clinical studies support using Kaposi’s sarcoma as a model tumor system for evaluating therapeutic approaches for the Manocept platform in other forms of solid tumors," commented Michael Tomblyn, M.D., Navidea’s Chief Medical Officer. "They provide evidence that Manocept agents can target CD206 and are internalized into tumor associated macrophages and tumor cells. This along with clinical observations that demonstrate tilmanocept can be used to image KS tumors both externally and internally indicates excellent potential for immunotherapeutic utility."

"Using a targeted imaging agent like tilmanocept in this group of HHV8+patients represents an elegant approach to potentially detect internal KS lesions that would previously be difficult or impossible to non-invasively locate," commented Toby Maurer, M.D., FAAD, Professor of Dermatology at the University of California, San Francisco (UCSF), and Chief of Dermatology at San Francisco General Hospital and Trauma Center, who co-led the clinical study at UCSF with Michael S. McGrath, M.D., PhD. "Further, the specificity and the ability to quantify tumor burden could enable regular patient evaluations and monitoring of therapeutic effectiveness addressing important unmet patient needs."

Five Human Herpes Virus8 positive (HHV8+) patients (4 HIV+, 1HIV-) were enrolled in the NAV03-12 study. Patients received a single subcutaneous injection of Technetium Tc 99m tilmanocept in the region of a cutaneous KS lesion and imaging was performed at 1, 4 and 24-hours post-injection to visualize localization of tilmanocept. Results represented by whole body Single-Photon Emission Computed Tomography (SPECT/CT) imaging scans from study patients were presented. Collectively, the scans show localization of tilmanocept and detected multiple cutaneous lesions in the extremities, face and genitalia, as well as extra-cutaneous localization found in the nasopharynx, lymph nodes and brain. Results also indicate that KS lesions are anatomically linked in chains by and within the lymph ducts. The study concludes that both HIV+ and HIV- patients have pan-tumor expression of CD206, strongly suggests tilmanocept crosses the blood brain barrier and that a Manocept-drug conjugate may have the potential as a therapeutic with high target effect and low off-target concerns.

The data from these studies also suggest a novel theory on the genesis of KS in which KS arises from an HHV8 infected macrophage type cell and its interaction with the lymphatic system. This interaction provides the means for access of the KS through CD206 receptor for diagnosis, evaluation, and potential therapy using the Manocept platform.

Navidea and Macrophage Therapeutics plan a webcast to provide investors with a complete look at the data being presented at the International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents conference on July 7, 2015 at 1:00 pm EDT. Webcast details will be available on the Navidea website.

About the Manocept CD206-targeting platform

The Manocept platform is predicated on the ability to specifically target the CD206 mannose receptor expressed on macrophages. Macrophages play important roles in many disease states and are an emerging target in many disorders. This flexible and versatile platform acts as an engine for purpose-built molecules that may enhance diagnostic accuracy, clinical decision-making, targeted treatments and ultimately patient care. As a diagnostic tool, the Manocept technology has the potential to utilize a breadth of imaging modalities, including SPECT, PET, intra-operative and/or optical-fluorescence detection. By adding a therapeutic agent on the Manocept molecular backbone, there is the potential to develop novel, targeted immunotherapies specifically designed to selectively deliver an agent that can kill or alter disease-associated macrophages. Navidea’s FDA-approved precision diagnostic imaging agent, Lymphoseek (technetium 99m tilmanocept) injection, is representative of the platform’s ability to successfully exploit this mechanism and offer the potential for development of new CD206-targeted diagnostic agents and therapeutics.

On July 1, 2015 CEL-SCI Corporation (NYSE MKT: CVM)("CEL SCI" or the "Company") reported that in June it has enrolled 25 patients in its ongoing Phase 3 trial of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) in just diagnosed, not yet treated patients with head and neck cancer (Press release, Cel-Sci, JUL 1, 2015, View Source [SID:1234506541]). Total patient enrollment is now 488 as of June 30, 2015 in the world’s largest Phase 3 study in head and neck cancer.

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A total of 880 patients are expected to be enrolled, through approximately 100 clinical centers in about 25 countries by the end of March 2016.

About the Multikine Phase 3 Study

The Multikine Phase 3 study is enrolling just diagnosed, not yet treated patients with advanced primary squamous cell carcinoma of the head and neck. The objective of the study is to demonstrate a statistically significant improvement in the overall survival of enrolled patients who are treated with the Multikine treatment regimen plus standard of care ("SOC") vs. subjects who are treated with SOC only. Standard of Care for these patients consists of the surgical removal of the tumor and any locally involved lymph nodes, followed by radiotherapy or concurrent radiochemotherapy.

About Multikine

Multikine (Leukocyte Interleukin, Injection) is an investigational immunotherapeutic agent that is being tested in an open-label, randomized, controlled, global pivotal Phase 3 clinical trial as a potential first-line treatment for advanced primary squamous cell carcinoma of the head and neck. Multikine is designed to be a different type of therapy in the fight against cancer: one that appears to have the potential to work with the body’s natural immune system in the fight against tumors.

Multikine is also being tested in a Phase 1 study under a Cooperative Research and Development Agreement ("CRADA") with the U.S. Naval Medical Center, San Diego, as a potential treatment for peri-anal warts in HIV/HPV co-infected men and women. CEL-SCI has also entered into two co-development agreements with Ergomed Clinical Research Limited to further the development of Multikine for cervical dysplasia/neoplasia in women who are co-infected with HIV and HPV and for peri-anal warts in men and women who are co-infected with HIV and HPV.

On July 1, 2015 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, reported that the company has managed to further strengthen its patent portfolio for its lead clinical anti-cancer programme resminostat (Press release, 4SC, JUL 1, 2015, View Source [SID:1234506542]).

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For the epigenetic agent resminostat, an HADC inhibitor targeting in particular HDAC 1, 2, 3 and 6, the US Patent Office has granted the patent for the medical use in cancer indications. The patent relates to the so-called method of treatment claims, and covers medical application of resminostat in mono- and/or combination therapy for cancer indications.

In addition, the Canadian patent authority has granted the composition of matter patent for resminostat. Thus resminostat has now composition of matter protection in all major markets including the US, Europe, Japan, China, South Korea, Russia, India, and now Canada.

The granting of the two patents constitutes an additional protection against potential competitors and thus further strengthens the protection of 4SC’s intellectual property assets, including the composition of matter, mesylate salt and manufacturing patents of resminostat, for which up to date patents have been granted in 58 countries, including the major markets.

Enno Spillner, Chief Executive Officer of 4SC, said: "We are pleased to announce the recent additions to our patent portfolio. The two patents will further strengthen not only the wide strategic position of our resminostat programme but also of 4SC as an important player in the field of epigenetic cancer therapies." Enno Spillner continued: "Especially, the resminostat medical application patent shows the broad possibilities of future use of our lead drug candidate. This is in particular evident in the light of the recently announced additional clinical use by our partner Yakult Honsha in pancreatic and biliary tract cancer as well as our own planned European Phase II trial in the indication of CTCL."

About Resminostat
Resminostat (4SC-201) is an oral histone-deacetylase (HDAC) inhibitor, targeting in particular HDAC 1, 2, 3 and 6, with an innovative epigenetic mechanism of action that potentially enables the compound to be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, both in monotherapy and, in particular, in combination with other cancer drugs. Like other epigenetic therapies, resminostat modifies transcription of genes in cancer cells and, thereby, reprograms the phenotypes of such cancer cells. Additionally, resminostat has immunotherapeutic effects by activating NK cells, restoring MHCI and MHCII proteins and suppression of unspecific immunosuppression. Resminostat is assumed to be able to halt tumour progression and induce tumour regression. Furthermore, due to its epigenetic mode of action resminostat is supposed to 2 develop additional synergetic effects when combined with classical cancer therapies and to counteract the development of tumour cell resistance.

Resminostat – by 4SC and its Japanese partner Yakult – has been investigated or is currently being investigated in a broad clinical campaign comprising liver cancer (HCC), Hodgkin’s Lymphoma (HL), colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), pancreatic and biliary tract cancer. Resminostat is partnered with Yakult Honsha for Japan and with Menarini AP in the Asia Pacific (APAC) region excluding Japan. 4SC is currently in preparations of a randomised, controlled Phase II trial in the indication of advanced cutaneous T-cell lymphoma (CTCL) in Europe.