On July 7, 2016 PharmaCyte Biotech, Inc. (OTCQB: PMCB) reported that its signature live-cell encapsulation technology, Cell-in-a-Box, is being used in treatments for both cancer and diabetes (Press release, PharmaCyte Biotech, JUL 7, 2016, View Source [SID:1234513760]). For diabetes, the company’s therapy, which is made up of pinhead-sized, porous capsules filled with insulin producing cells, will create an "artificial pancreas" for type 1 diabetics and insulin-dependent type 2 diabetics that no longer produce their own insulin. Meanwhile, for cancer, the company’s therapy is made up of those same pinhead-sized, porous capsules; however, for advanced pancreatic cancer, they’re filled with genetically modified cells that act as a type of "artificial liver."

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First things first, PharmaCyte’s Cell-in-a-Box is not a drug delivery system. There are no drugs encapsulated inside the porous capsules for any of its treatments. Instead, for pancreatic cancer, which we will focus on today, the capsules are filled with about 10,000 live cells that are capable of converting an inactive chemotherapy drug (ifosfamide) into its active cancer-killing form — just as the enzyme system in a patient’s liver would normally do.

Keep in mind that because the chemotherapy drug ifosfamide is a prodrug or an inactive drug, it can travel all over the body and have no effect whatsoever until it is activated in the liver. Knowing that, PharmaCyte is, in a way, moving the "normal" conversion site (the patient’s liver) of that inactive drug closer to the cancerous tumor by using Cell-in-a-Box capsules and the live cells inside them to do the job of the patient’s liver or to act as an "artificial liver."

So how does the treatment work and why is it important to move the conversion site closer to the pancreatic tumor?

First, we will tackle how PharmaCyte’s therapy works.

The encapsulated live cells (Cell-in-a-Box capsules) are placed as close to the patient’s cancerous tumor as possible. Once implanted, ifosfamide, the aforementioned chemotherapy drug that needs to be activated in the body, is given to the patient intravenously at one-third the normal dose. The ifosfamide is then carried by the circulatory system to where the encapsulated cells have been placed. When the ifosfamide, which is normally activated in the liver, comes in contact with the encapsulated live cells in the Cell-in-a-Box capsules, the chemotherapy drug is activated into its cancer-killing form right at the site of the cancer.

This is "targeted chemotherapy" in the truest sense, and the company’s therapy has proven effective and safe to use in past clinical trials. This is how PharmaCyte will use its therapy in an upcoming Phase 2b clinical trial, so now let’s discuss why it’s important to move the drug activation site closer to the pancreatic tumor in the first place.

There are actually a number of reasons to move the activation site closer to the tumor. We’ll start with the chemotherapy drug itself. Ifosfamide, when activated, has a very short half-life (time before it decays and no longer offers any effect), so by using the cells inside the Cell-in-a-Box capsules to activate the drug at the site of the tumor, ifosfamide can immediately be the most effective when it’s the most potent before dying off minutes later.

Without a treatment like PharmaCyte’s, ifosfamide would be given to the patient intravenously and then activated "normally" in the liver, the activated drug would then affect tissues and organs other than the pancreas, and by the time it reached the pancreas, it undoubtedly would have lost much of its effectiveness. So, this, of course, means to be effective against a pancreatic tumor when the Cell-in-a-Box capsules are not used, a large dose of the drug has to be administered.

Using ifosfamide in such large doses has proven to be damaging for tissues and organs including the patient’s liver, and because the activated drug would come in contact with such other organs and good cells throughout the body on its way to the pancreas, the side effects would be intolerable; in fact, this is known to be the case.

By moving the conversion site as close to the tumor as possible, PharmaCyte is able to give a much smaller dose of the chemotherapy drug (one-third the normal dose), which patients are able to tolerate, and because of the smaller dose, the treatment can be administered without any side effects from the chemotherapy.

That’s right — chemotherapy without any side effects!

On July 7, 2016 Accurexa Inc. (the "Company") (ACXA), a biotechnology company focused on the development of novel neurological therapies to be directly delivered into the brain,reported that it filed a new patent application related to its proprietary formulation used in its ACX-31 program (Press release, Accurexa, JUL 7, 2016, View Source [SID1234516519]). Accurexa is developing its ACX-31 program for the local delivery of temozolomide as adjunctive therapy to BCNU, both chemotherapeutics, in the treatment of brain tumors.

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"We are proud that we as an emerging company have the intellectual capability in-house to create new technologies for our brain cancer program. This is our first patent application that we believe has the potential to further protect our brain cancer program in addition to the patent that we licensed from Prof. Brem and his co-inventors at Johns Hopkins University last year. This is our first step of adding internally created technologies to our model of in-licensing of assets and growing our company’s capabilities and assets," said Dr. George Yu, Accurexa’s President & CEO.

On July 6, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on treatment of primary and metastatic liver cancers, reported that data from a large single hospital experience conducted at Southampton University Hospital in the United Kingdom were presented in an oral presentation at the 6th European Post-Chicago Melanoma/Skin Cancer Meeting held in Munich, Germany from June 30 – July 1, 2016 (Press release, Delcath Systems, JUL 6, 2016, View Source;p=RssLanding&cat=news&id=2182241 [SID:1234513737]).

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The abstract, Chemosaturation Via Percutaneous Hepatic Perfusion – An Update On A Single Centre Experience Of Treating Metastatic Uveal Melanoma, Southampton University (United Kingdom) was presented by lead author, Ioannis Karydis, M.D, of Southampton University Hospital. Researchers conducted a retrospective evaluation of 27 metastatic uveal melanoma patients treated with CHEMOSAT over four years, analyzing survival, tumor response, time to progression and treatment related adverse events. Two patients could not be treated and were excluded from analysis; 25 patients received 43 treatments. Results showed that 14 patients remained alive after a median 290 days. Of 24 evaluable patients, one patient had a complete response (4%), five patients had partial responses (21%), and 12 patients had stable disease for greater than 90 days (50%). Progression free survival for patients who had progressed was 181 days at the time of data cut off, and 11 patients were alive for greater than one year following their first treatment with a projected media overall survival of 511 days. Eleven deaths from disease progression occurred at a median of 264 days following first treatment, and there were no treatment related deaths. Treatment overall was well tolerated, and non-hematological adverse events (6) were relatively rare. Most common adverse events were transient, mild

Researchers concluded that "PHP can be used safely by an experienced team to deliver liver-directed therapy in selected uveal melanoma patients, and achieves unprecedented progression free and overall survival."

"The progression free and overall survival benefits observed in this study are dramatic, especially given the limited treatment options for patients suffering with these life-threatening cancers. Importantly, these supportive data provide us with considerable confidence that similar results may be formally validated by our FOCUS Phase 3 Trial in hepatic dominant ocular melanoma that is currently underway in the U.S. and Europe to secure marketing authorization in the U.S.," said Jennifer K. Simpson, Ph.D., MSN, CRNP, President and CEO of Delcath Systems. "The quality and pace of global research being presented and published continues to strongly support CHEMOSAT as a therapy for metastatic liver cancer. We look forward to building on this momentum to further advance the commercial and clinical adoption of CHEMOSAT in Europe, the U.S. and around the world."

On July 5, 2016 CEL-SCI Corporation (NYSE MKT: CVM) ("CEL SCI" or the "Company") reported that during the month of June it has enrolled 32 patients in its ongoing Phase 3 trial of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) in patients with advanced primary head and neck cancer (Press release, Cel-Sci, JUL 5, 2016, View Source [SID:1234513719]). Total patient enrollment for the trial is now 848 as of June 30, 2016.

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About the Multikine Phase 3 Study

The Multikine Phase 3 study is enrolling patients with advanced primary (not yet treated) 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.

About Multikine

Multikine 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, and at University of California, San Francisco (UCSF), as a potential treatment for peri-anal warts in HIV/HPV co-infected men and women. Dr. Joel Palefsky, a world-renowned scientist and Key Opinion Leader (KOL) in human papilloma virus (HPV) research and the prevention of anal cancer, is the Principal Investigator at UCSF, which was added to the study in July 2015.

CEL-SCI has also entered into two additional co-development agreements for up to $3 million each 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 5, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the publication of preclinical research in the journal Nature Medicine by the Company’s researchers and scientific collaborators (Press release, Verastem, JUL 5, 2016, View Source;p=RssLanding&cat=news&id=2181887 [SID:1234513711]). The research, which was led by David G. DeNardo, PhD, Assistant Professor of Medicine, Division of Oncology, Department of Immunology, Washington University School of Medicine in St. Louis, and co-author of the paper, demonstrated that focal adhesion kinase (FAK) inhibition decreases fibrosis and immunosuppressive cell populations in pancreatic ductal adenocarcinoma (PDAC), rendering previously unresponsive tumors sensitive to chemo- and immunotherapy.

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"The application of immunotherapy holds great promise to improve outcomes for patients with pancreatic cancer, as it has for melanoma and lung cancer patients," said Dr. DeNardo. "To date, however, attempts at immunotherapy in PDAC have achieved limited clinical benefit when deployed as single agents. This is likely due in part to the presence of a uniquely immunosuppressive tumor microenvironment which is dominant in most human cases of PDAC. Major drivers of this pro-tumorigenic microenvironment include a highly fibrotic stroma and extensive infiltration by immunosuppressive cell populations. Thus, agents that can potentially overcome excessive fibrosis while altering immune suppression would be particularly attractive targets for PDAC."

The paper, titled "Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy," (Jiang, et al., advanced online publication, July 4, 2016 (doi:10.1038/nm.4123) describes the therapeutic targeting of FAK in in vivo murine PDAC models. Prior research has demonstrated that hyperactivated FAK activity is a significant regulator of the fibrotic and immunosuppressive tumor microenvironment (TME) in PDAC tumor cells.

In this study, researchers show that FAK signaling is a key driver of fibrosis, immunosuppression and PDAC progression. It was then demonstrated that single-agent treatment with Verastem’s FAK inhibitor VS-4718 significantly limited tumor progression, resulting in a doubling of survival in an in vivo model of human PDAC. This slowing of tumor progression was associated with dramatically reduced tumor fibrosis, and a reduced number of tumor-infiltrating immunosuppressive cells. Given these findings, it was then hypothesized that the resulting effects of FAK inhibition on the TME may render PDAC tumors more sensitive to immunotherapy. Study results then demonstrated that FAK inhibition rendered previously unresponsive in vivo models responsive to T cell therapy and anti-PD1 antagonists. These data strongly support the ongoing clinical evaluation of FAK inhibitors in combination with checkpoint immunotherapy in patients with pancreatic cancer.

"FAK signaling has been shown to be important in several carcinomas, including pancreatic tumors, but its compelling role in creating an immunosuppressive tumor microenvironment is just emerging," said Jonathan Pachter, PhD, Chief Scientific Officer of Verastem, and co-author of the paper. "Another study, recently published in Cell, found that FAK inhibition can modulate certain immune cell populations, namely CD8+ T cells and Tregs, enabling an immune response that destroys tumors. Similarly, in the current study, we found that FAK inhibition alters tumor cell production of pro-inflammatory and immunosuppressive cytokines and reduces the tumor’s ability to avoid immune surveillance. Together these findings provide important support and rationale for the ongoing Phase 1 dose-escalation clinical study evaluating Verastem’s FAK inhibitor VS-6063 in combination with pembrolizumab and gemcitabine in patients with pancreatic cancer."

In early 2016, Verastem launched a new clinical development program focused on advancing its FAK inhibitors in combination with immuno-oncology agents and other current and emerging standard of care treatments. The Company’s lead FAK inhibitor, VS-6063 is currently being evaluated in a Phase 1 dose-escalation study at the Washington University in Saint Louis in combination with Merck & Co.’s PD-1 inhibitor pembrolizumab and gemcitabine in patients with pancreatic cancer. VS-6063 is also the subject of an additional clinical collaboration between Merck KGaA, Pfizer and Verastem where it will be evaluated in a Phase 1/1b study in combination with avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, in patients with advanced ovarian cancer. This collaboration trial is expected to begin during the second half of 2016.

About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. VS-6063 (defactinib) and VS-4718 are orally available compounds that are potent inhibitors of FAK. VS-6063 and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. VS-6063 and VS-4718 are currently being studied in multiple clinical trials for patients with cancer.