March 24, 2017

"Provectus Biopharmaceuticals Announces Terms Of Definitive Financing Commitment"

♢♢ Note: I and others entered into a securities transaction with Provectus in March 2017. Please see the Blog's Disclosures page and/or refer Provectus' Securities and Exchange Commission filings for further, future disclosures.

The source link of Provectus' March 23rd press release related to my and others' securities transaction and involvement with the Company (reproduced below) is here. Also see the Disclaimer to the right, and the blog's Disclosures page.

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KNOXVILLE, Tenn., March 23, 2017 /PRNewswire/ -- Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT, ("Provectus" or the "Company"), a clinical-stage oncology and dermatology biopharmaceutical company, today disclosed terms of the previously announced Definitive Financing Commitment Term Sheet (the "Definitive Financing") it entered into on March 19 with a group of the Company's stockholders, who are referred to in the Definitive Financing as "PRH Group" in a Form 8-K filed with the Securities and Exchange Commission.

The members of PRH Group include Edward Pershing (serving exclusively in an advisory capacity only); Dominic Rodrigues and Bruce Horowitz, who were previously named as special advisers to the Board of Directors of Provectus ("the Board") on February 23; and additional members as the PRH Group may determine at its sole discretion.

Under the Definitive Financing, PRH Group would undertake best efforts to arrange for a financing of a minimum of $10 million and a maximum of $20 million, which would be provided to Provectus in several tranches.  The structure of the Definitive Financing takes the form of a secured loan that would convert into a new series of preferred stock with a liquidation preference upon the sale, dissolution or liquidation of the Company, a conversion into common stock that prices one common share at approximately $0.29, and customary voting rights on an as-converted basis.

Within the next 30 days or sooner, a total of $5 million will be made available to the Company, comprised of the acceleration of the remainder of the $2.5 million from the previously announced promissory note issued to Eric Wachter, Ph.D., co-founder and Chief Technology Officer and an additional $2.5 million from PRH Group. Once funded, the $5 million will become secured convertible promissory notes from the Company to each Investor.

Three current members of the Board will resign simultaneously upon the PRH Group's funding of the $2.5 million tranche into escrow, and PRH Group will nominate three new directors for approval by and appointment to the Board.  Additionally, the Company has agreed that, as soon as practicable after the funding of the second tranche of the financing, in which PRH Group intends to raise an additional $5 million by June 30, 2017, the two remaining current Board members will resign and be replaced by two new directors appointed to and approved by the Board.

PRH Group is joining with the Company to expand its current search for additional executives with biotechnology and pharmaceutical industry experience, including but not limited to a new Chief Executive Officer.

Dominic Rodrigues said, "PRH Group believes the fundamentally strong value of Provectus' asset base and intellectual property has attracted the initial interest of highly qualified managerial talent.  As the Company reestablishes a sound financial foundation, PRH Group is confident that Provectus will be well positioned to hire talented and experienced executives and managers. We are delighted to be a part of Provectus' evolution as a biopharmaceutical company by guiding its advancement of clinical development programs to develop vitally needed new treatments to help cancer patients."

About Provectus

Provectus is a clinical-stage biopharmaceutical company developing new therapies for the treatment of solid tumor cancers and dermatologic diseases. Provectus' investigational oncology drug, PV-10, is an oncolytic immunotherapy currently enrolling patients in Phase 3 clinical trials for metastatic melanoma. The Company has received orphan drug designations from the FDA for its melanoma and hepatocellular carcinoma indications. PH-10, its topical investigational drug, has completed Phase 2 clinical trials as a treatment for atopic dermatitis and psoriasis. Information about these and the Company's other clinical trials can be found at the NIH registry, For additional information about Provectus, please visit the Company's website at or contact Allison + Partners.

FORWARD-LOOKING STATEMENTS: This release contains "forward-looking statements" as defined under U.S. federal securities laws. These statements reflect management's current knowledge, assumptions, beliefs, estimates, and expectations and express management's current views of future performance, results, and trends and may be identified by their use of terms such as "anticipate," "believe," "could," "estimate," "expect," "intend," "may," "plan," "predict," "project," "will," and other similar terms. Forward-looking statements are subject to a number of risks and uncertainties that could cause our actual results to materially differ from those described in the forward-looking statements. Readers should not place undue reliance on forward-looking statements. Such statements are made as of the date hereof, and we undertake no obligation to update such statements after this date.

Risks and uncertainties that could cause our actual results to materially differ from those described in forward-looking statements include those discussed in our filings with the Securities and Exchange Commission (including those described in Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2015, as supplemented by those described in Part II, Item 1A of our Quarterly Report on Form 10-Q for the quarter ended September 30, 2016) and the following:
  • Provectus' potential receipt of sales from PV-10 and PH-10, transaction fees, licensing and royalty payments; payments in connection with the Company's liquidation, dissolution or winding up, or any sale, lease, conveyance or other disposition of any intellectual property relating to PV-10 or PH-10;
  • our ability to raise additional capital if we determine to commercialize PV-10 and/or PH-10 on our own;
  • our ability to close on an equity financing from PRH; and
  • whether our securities remain listed on the NYSE MKT.

February 2, 2017

"Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death"

Article source link is here.
Click to enlarge.
Immunotherapeutic approaches to manage patients with advanced gastrointestinal malignancies are desired; however, mechanisms to incite tumor-specific immune responses remain to be elucidated. Rose bengal (RB) is toxic at low concentrations to malignant cells and may induce damage-associated molecular patterns; therefore, we investigated its potential as an immunomodulator in colon cancer. Murine and human colon cancer lines were treated with RB (10% in saline/PV-10) for cell cycle, cell death, and apoptosis assays. Damage-associated molecular patterns were assessed with western blot, ELISA, and flow cytometry. In an immunocompetent murine model of colon cancer, we demonstrate that tumors regress upon RB treatment, and that RB induces cell death in colon cancer cells through G2/M growth arrest and predominantly necrosis. RB-treated colon cancer cells expressed distinct hallmarks of immunogenic cell death (ICD), including enhanced expression of calreticulin and heat-shock protein 90 on the cell surface, a decrease in intracellular ATP, and the release of HMGB1. To confirm the ICD phenotype, we vaccinated immunocompetent animals with syngeneic colon cancer cells treated with RB. RB-treated tumors served as a vaccine against subsequent challenge with the same CT26 colon cancer tumor cells, and vaccination with in vitro RB-treated cells resulted in slower tumor growth following inoculation with colon cancer cells, but not with syngeneic non-CT26 cancer cells, suggesting a specific antitumor immune response. In conclusion, RB serves as an inducer of ICD that contributes to enhanced specific antitumor immunity in colorectal cancer."
...In the current study, we have provided several lines of evidence demonstrating that RB exhibited pronounced direct cytotoxicity in colorectal cancer cells both in vivo and in vitro. Our data also confirmed RB-induced prominent cell growth arrest at the G2/M phase and predominant necrotic cell death that was partially dependent on lysosome function. Furthermore, the findings from the current study identified that RB promoted expression of hallmarks related to ICD in colon cancer cell lines. Vaccination with RB-treated colon cancer cells and intralesional tumor injection resulted in retardation in tumor growth or prevention of subsequent tumor formation following challenge with the same tumor cells. These findings show that RB may serve as an inducer of ICD that contributes to enhanced specific antitumor immunity in colorectal cancer. Additional studies are warranted to elucidate the therapeutic potential of RB-induced ICD."

January 1, 2017

Rose Bengal (PV-10); The Glocalization of Cancer Treatment: "Act Locally, Think Globally"

Wikipedia's glocalization page notes:
"Glocalization (a portmanteau of globalization and localization) is the adaptation of international products around the particularities of a local culture in which they are sold. The process allows integration of local markets into world markets. 
The term first appeared in a late 1980s publication of the Harvard Business Review. At a 1997 conference on "Globalization and Indigenous Culture", sociologist Roland Robertson stated that glocalization “means the simultaneity – the co-presence – of both universalizing and particularizing tendencies.”"
An intellectually honest treatment of intralesional or intratumoral delivery of immunotherapy frames the work of more than 100 years ago of Dr. William Coley, MD, "now considered the “Father of Cancer Immunotherapy”" in terms of both route of delivery (intralesional or intratumoral, as opposed to orally or intravenously), and what is delivered (dead bacteria).

See Do Dr. Jedd Wolchok/Sloan Kettering Understand Immunotherapy's History? (July 12, 2016) on the blog's Archived News VI page.

It would appear that Memorial Sloan Kettering Cancer Center (MSKCC) recently (i.e., that is 2015, perhaps earlier) embraced the history of the medical institution's involvement with harnessing the immune system to fight and treat cancer by describing the work of Dr. William Coley, MD, "now considered the “Father of Cancer Immunotherapy,”" on its website. See MSKCC webpage "Immunotherapy: Revolutionizing Cancer Treatment since 1891." Dr. Coley began his career as a bone surgeon at New York Cancer Hospital, which later became part of MSKCC.

When writing about immunotherapy, and usually pointing to Bristol-Myers' anti-CTLA-4 drug ipilimumab (Yervoy) and/or anti-PD-1 drugs pembrolizumab (Merck & Co., Keytruda) and nivolumab (Bristol-Myers, Opdivo), many mainstream media and medical writers and journalists often include in their introduction descriptions of Dr. Coley's work. I think it makes for a good story, as the writers endeavor to link history, and descriptions and lessons from the past, to the present day, and potentially our future.

MSKCC says Dr. Coley's work "paved the way for the modern immunotherapies that are helping patients today."

Route of delivery matters. Dr. Coley's work, and his approach to treatment, comprise two key feature, one of which nearly all who write about him (but not everyone) routinely ignore, conflating his discoveries, observations and conclusions with drugs incapable of delivering what he experimented with in order to seek better patient outcomes.

Coley's approach to the treatment of cancer was composed of (a) a "drug compound," the heated-killed bacteria known as Coley’s toxins whose actions following treatment somehow engaged the immune system (e.g., fever), and (b) the route of administration by injection of the dead bacteria into the patient's tumors.

The key feature of Coley's work that is ignored, conflated, confused or misunderstood: the manner in which the drug, drug compound, biologic or small molecule is delivered. Yervoy, Keytruda and Opdivo are immunotherapies that are intravenously administered to patients; they are not injected into patient tumors.

Google "Wolchok" and "Coley," and thousands of results are returned. MSKCC's Dr. Jeff Wolchok, a medical oncologist, apparently uses Coley's story when he (Dr. Wolchok) explains immunotherapy. Dr. Wolchok, holder of MSKCC's Lloyd J. Old Chair for Clinical Investigation, was a student of Dr. Lloyd Old, MD, who (according to Memorial Sloan Kettering):
"...did some of the first modern research on immunotherapy, with a substance called BCG, now an FDA-approved treatment for bladder cancer. BCG is made from a weakened version of the bacterium that causes tuberculosis. Experts think Coley’s toxins may have worked in a similar manner to BCG — jumpstarting an immune response to cancer by provoking one against the bacteria."
This work of Dr. Old appears to be during the 1950s. For example, see "Effect of Bacillus Calmette-Guérin Infection on Transplanted Tumours in the Mouse." Who am I to say or write this, but perhaps Dr. Old was focused on one of the two key features, the use of a biologic (i.e., the "drug compound") to engage the immune system. He may have ignored Coley's work's other feature, route of delivery.

The administration of BCG (aka Bacillus Calmette-Guérin) for bladder cancer is intravesical, which means it is "put directly into the bladder through a catheter, instead of being injected into a vein or swallowed." See the illustration below.
Image source
Intravesical, like intravenous is not injection into the tumor (i.e., intralesional, intratumoral).

Ironically, the second aspect of Coley's work, route of delivery, was explored in the 1970s with BCG (or BCG immunotherapy) in metastatic melanoma when the drug was it was directly injected into metastatic melanoma lesions limited to the skin; see, for example, "BCG Immunotherapy of Malignant Melanoma: Summary of a Seven-year Experience." Unfortunately, the immunotherapy failed a Phase 3 trial; see 2004 paper "Mature results of a phase III randomized trial of bacillus Calmette–Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I–III melanoma (E1673):"
"In what to our knowledge is the largest ever trial to test the role of BCG as adjuvant therapy for melanoma, no benefit for BCG was observed for patients with AJCC Stage I–III disease. The mature results of the current trial projected to 30 years confirmed the negative results of previous smaller studies utilizing this agent."
What does Dr. Coley's work tell us about how to treat cancer via immunotherapy? Is it about the drug compound? Is it about the route of administration? Or, as I believe (because of Rose Bengal), is it both?

Consider April 2016's "Germ of an Idea: William Coley's Cancer-Killing Toxins", which more appropriately places Dr. Coley's work into context:
"That was all Coley needed to proceed directly to human trials, and Zola would become his first test subject. Coley filled a syringe with living Streptococcus pyogenes, known to induce erysipelas attacks, and injected the solution directly into Zola’s tumor. It took awhile — in fact, it took repeated injections over five months — but finally, an hour after one particular injection in October, Zola broke out into sweaty chills, and his body temperature soared to 105 degrees... 
“Coley injected his first patient a century ago, and what he saw was almost identical to what we saw in our first patient,” says Saurabh Saha, a partner with Atlas Venture, former BioMed Valley researcher and senior author of the study...” 
C. novyi is really a two-pronged weapon against cancer: It germinates in tumors and releases cancer-killing enzymes, and it may also trigger an immune response similar to Coley’s Toxin. Since C. novyi survives only in oxygen-poor environments — tumors can be notoriously void of oxygen — the bacteria die when they reach healthy, oxygen-rich tissues, sparing collateral damage. Essentially, the injections perform highly precise biosurgery from the inside out."
Updated (7/31/16): Does The New York Times understand cancer immunotherapy's history? The NYT's Denise Grady wrote "Harnessing the Immune System to Fight Cancer" on July 30th. In it she references Dr. Coley's name 18 times, and presumably uses his work as a vehicle to discuss Dr. James Allison's immune checkpoint inhibitor work. Interestingly, this author, while invoking Coley's biologic material he injected into patients, does not mention the route of delivery Coley used. She uses the verb "inject," but does not say where:
"Dr. Coley began to inject terminally ill cancer patients with Streptococcal bacteria in the 1890s. His first patient, a drug addict with an advanced sarcoma, was expected to die within weeks, but the disease went into remission and he lived eight years. 
Dr. Coley treated other patients, with mixed results. Some tumors regressed, but sometimes the bacteria caused infections that went out of control. Dr. Coley developed an extract of heat-killed bacteria that came to be called Coley’s mixed toxins, and he treated hundreds of patients over several decades. Many became quite ill, with shaking chills and raging fevers. But some were cured."
Ironically, she references radiation, which is making a resurgence because of the growing understanding/belief that local treatments to/on tumors may unlock the gateway to the immune system's reaction around the body:
"Early in the 20th century, radiation treatment came into use. Its results were more predictable, and the cancer establishment began turning away from Coley’s toxins. Dr. Coley’s own institution, Memorial Hospital (now Memorial Sloan Kettering Cancer Center) instituted a policy in 1915 stating that inpatients had to be given radiation, not the toxins. Some other hospitals continued using them, but interest gradually waned. Dr. Coley died in 1936."
See, for example, June 2015's "June Podcast: The Abscopal Effect with Sandra Demaria."

Finally, it is interesting to note that Allison, Wolchok and others submitted a patent application (published in 2014) for the use of an oncolytic virus with immune checkpoint inhibitors via the injection of the virus into tumors.

Which brings us back to glocalization in cancer treatment...

H/t @bradpalm1:
Tweet image source
Click to enlarge.
Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell–mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes. The Journal of Immunology, 2017, 198: 31–39.
"Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally," Aznar et al., J Immunol. 2017 Jan 1;198(1):31-39.

The article does not mention or reference PV-10. Nevertheless, the notion of concept of local delivery of immunotherapy is important, and the authors do reference oncolytic virus (OV) immunotherapy or oncolytic immunotherapy T-Vec -- "Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma."

The introduction of the article frames Coley's work in context:
"More than 100 years ago, the surgeon William Coley found that in some cases of soft tissue sarcoma there were regressions following erysipelas. Facing similar cases in his practice, he proceeded to cause such risky infections on purpose, observing some successful responses. To make it safer he went on to use bacterial-derived material (Coley’s toxins) to locally inject tumor masses. Since then, we have learned that the results obtained by Coley were related to a systemic antitumor immune response following local delivery of the ill-defined microorganisms and bacterial toxins."
Provectus CTO Dr. Eric Wachter, PhD noted the interest in the field of intralesionally delivered cancer medicines in his November 14th slide presentation:
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The challenge or opportunity for intralesional or intratumoral delivery, however, is the beneficial power -- both breadth and depth -- of the immunological signalling generated subsequent to tumor injection with the compound in question.

Aznar et al. note as much:
"There are a number of immune mechanisms to be exploited by local delivery that would mimic infection by a pathogen (Fig. 1). The key aspect is that local intervention needs to exert systemic effects against distant metastases based on lymphocyte recirculation. The difficulty in achieving systemic effects would depend on factors such as proximity, similar lymphatic drainage, vascularization or truly anatomical distance. In tumor vaccination, it has been observed that the site of priming imprints recirculation patterns to T cells. This cellular behavior is dependent on chemokine and tissue homing receptors. Interestingly, DCs in each territory imprint the pattern of recirculation receptors to the T cells that they prime by cognate Ag presentation."
Click to enlarge. Part 1 of 2 of full image. Figure 1, Aznar et al.
Click to enlarge. Part 2 of 2 of full image. Figure 1, Aznar et al.

December 22, 2016

Rose Bengal (PV-10): HCC, Colorectal liver mets

Provectus issued a press release today regarding its clinical liver cancer work, "Announces Two Poster Presentations on PV-10 for Liver Tumors." As of this writing no associated 8-K was filed.

The press release highlighted two abstracts and upcoming [poster, presumably] presentations of results from the company's ongoing liver Phase 1 trial, which has evolved into (a) a "basket study" treating patients with and collecting data on a range of tumor types affecting the liver, and (b) a study of hepatocellular carcinoma (HCC) (primary liver cancer).

Results from patients with colorectal cancer that has metastasized to the liver, and treated with PV-10 (Rose Bengal) will be presented at the 2017 Symposium on Clinical Interventional Oncology (CIO) (CIO) on February 4-5 in Hollywood, Florida. These data should comprise results from at least 5 patients (see the slide from Provectus' November 14th 3Q16 business update call below). The title of the abstract is "Percutaneous Rose Bengal as an Ablative Immunotherapy for Hepatic Metastases," with my underlined emphasis.

Results from patients with HCC, and treated with PV-10 (Rose Bengal), the original goal or initial phase of the liver Phase 1 study, will be presented at the 26th Conference of the Asian Pacific Association for the Study of the Liver (APASL) on February 15-19 in Shanghai, China. These data should comprise results from the original/initial patients (see the slide below). The title of the abstract is "Intralesional Rose Bengal as an Ablative Immunotherapy for Hepatic Tumors," with my underlined emphasis.
Click to enlarge.
Initial liver data was presented in Barcelona, Spain and Osaka, Japan in July 2015, "Phase 1 Study of PV-10 for Chemoablation of Hepatocellular Cancer and Cancer Metastatic to the Liver." Note the absence of the word "immunotherapy" in the abstract/poster's title.

December 8, 2016

Rose Bengal (PV-10) + Oncology + Pediatrics

Updated below: 12/8/16 and 12/15/16.

Provectus issued a press release and filed an associated 8-K today regarding a collaboration (currently, an "agreement to establish a framework for collaborative pre-clinical research projects") to explore the use of Rose Bengal/PV-10 in pediatric cancer, Announces Agreement with POETIC (Pediatric Oncology Experimental Therapeutics Investigators Consortium) to Study Potential of PV-10 for Pediatric Cancer.

Image source
POETIC's website is here. POETIC co-founder Dr. Tanya Trippett, MD (Memorial Sloan Kettering Cancer Centerattended April healthcare conference at the Vatican, where Australia's Peter MacCallum Cancer Centre's Dr. Grant McArthur discussed PV-10.

See Infantile (July 26, 2016) on the blog's Archived News VI page:
"There also is a robust library of biomedical literature experimenting on/with, describing and discussing Rose Bengal's diagnostic applications in adults, and notably in children. See, for example October 15, 2015 blog post Still Standing, or Rose Bengal in children (hepatoblastoma, radiopharmaceutical) (May 6, 2016) on the blog's Archived News V page. In medicine, children are not small adults when it comes to safety, efficacy, dosing, etc. Most of the pediatric literature related to Rose Bengal refers to the API as liver function diagnostic 131I-Rose Bengal. From a safety and PK perspective, it is interesting, available for review, and dates back to at least the 1960s."
See also October 15, 2015 blog post Still Standing:
"Rose Bengal’s medical properties have been established in the clinic, adults and children[5], and the literature, as well as with the FDA. The compound was noted as a stain for visualizing corneal ulcers in 1919[6] and a marker for impaired liver function in 1923[7]. Currently there are more than 3,800 Rose Bengal references in the U.S. National Institutes of Health's National Library of Medicine’s PubMed Central database.[8] The compound has [non-therapeutic] FDA safety profiles as an intravenous hepatic diagnostic called Robengatope® and a topical ophthalmic diagnostic called Rosettes® or Minims®."
Updated (12/8/16).1: Additional Information & Takeaways
  • I'm led to believe MSKCC (Memorial Sloan Kettering Cancer Center) [on the pediatric oncology side] began using reagent grade Rose Bengal (i.e., drug substance, or the active pharmaceutical ingredient [API] in PV-10; e.g., available from Sigma-Aldrich) -- presumably in in vitro models -- in the spring (following the above mentioned Vatican healthcare conference). Apparently, PV-10 (i.e., pharmaceutical grade drug product) was shipped to MSKCC and other POETIC partners (specifically, I would imagine to Alberta Children's Hospital, which will lead the pre-clinical development of another POETIC collaboration; see CorMedix below).
  • I also imagine POETIC and others' treatment approach to pediatric cancer patients may mirror the approach being taken with adult cancer patients in the current"age," "era" or time of immuno-oncology; that is, combination of PV-10 with checkpoint inhibition.
Updated (12/15/16).2: "Copyright infringement?" Yuck, yuck...
Click to enlarge. Tweet image source
Provectus' attendance link is here:

    November 23, 2016


    Source of tweet image below: Paul D. Rennert (@PDRennert).
    Click to enlarge
    On the SITC slide above, I imagine PV-10 (in combination with a/the PD/PDL1 "backbone") would fall under "oncolytic" in the pembrolizumab column (second from the left). The slide clearly illustrates an amazing amount of work underway to augment this fundamental concept of combination therapy or treatment in cancer.

    The slide reinforces an important theme of Provectus' Dr. Eric Wachter, PhD's November 14th presentation (as part of the 3Q16 business update call): there is considerable interest and clinical activity in melanoma, and while he believes there is no doubt about the relevance of PV-10, cutting through the crowd to the front of the pack will require continued effort on Provectus' part. See, for example, the slides below from his presentation:
    Click to enlarge
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    Under Additive: 1 + 1 < 2. Synergistic: 1 + 1 > 2 (best case, >> 2) (June 25, 2016) on the blog's Archived News VI page I co-opted a slide from MD Anderson's Dr. Merrick Ross, MD's presentation -- see ASCO 2016: "The Role of Immunotherapy in the Medical Management of Melanoma: An Overview for the Oncologist" (June 22, 2016) -- that provided results from various combination therapy studies for advanced or metastaic melanoma slide in order illustratively model the difference between additivity and synergism:
    Click to enlarge
    The table above was updated to include recent combination therapy data of oncolytic virus CVA21 (Coxsackievirus A21, a cold virus) and anti-PD-1 drug pembrolizumab (Keytruda) presented at SITC 2016: "According to the preliminary data from the first 10 patients evaluable for best overall tumour response assessment, a disease control rate (DCR) of 100 percent (10/10 patients) was demonstrated, including seven patients (70 percent) with an objective tumour response and three patients (30 percent) with stable disease" {Viralytics’ CAVATAK™ in Combination with KEYTRUDA® Provides Promising Results in Advanced Melanoma from the CAPRA 1b study}.

    Interestingly, however, Viralytics' combination therapy above yielded no complete responses in its Best irRC Overall Response (see the SITC poster here), and did not use RECIST 1.1 in its tumor response measurement. Median doses of CVA21 and pembrolizumab (for the ten patients noted above) were 8 (range 6-11) and 6 (3-11), respectively. CVA21, like T-Vec, has to be delivered often for its effect to manifest, weak or weaker (than PV-10's immunologic signalling) as it is.

    Viralytics previously established a collaboration with Merck & Co. in November 2015 to combine CVA21 and pembro in either advanced stage non-small cell lung cancer (NSCLC) or metastatic bladder cancer. In June 2016 the parties initiated a Phase 1b study, one-site (Australia) program for NSCLC where CVA21 would be delivered intravenously (three different dosing levels of CVA21), and not intralesionally or intratumorally.

    In his November 21st article "Viralytics' anticancer virus aces checkpoint inhibitor combo trials," FierceBiotech's Phil Taylor provides or references several examples of funded or acquired oncolytic virus companies:

    • 2011: Amgen's acquisition of BioVex (U.S.), and thus T-Vec (Imlygic) (formerly OncoVEX) ($1 billion: $425 million upfront and a $575 million earn out), which was approved in 2015,
    Edison Investment Research's Dennis Hulme and Lala Gregorek's November 21st equity research note on Viralytics entitled "Cavatak data continue to impress" presents the valuation rationale below:
    Click to enlarge.
    "Notable changes in immune cell infiltrates and expression of PD-L1 within the CVA21-treated NMIBC tissue were also observed. Increased urinary levels of the chemokine, HMGB1, was observed in six of eleven patients following exposure to CVA21."
    Moffitt Cancer Center noted increased HMGB1 levels in sera of melanoma patients after intralesional PV-10 treatment.
    Click to enlarge. Image source
    Moffitt did not report the number of patients with elevation, but rather the change in mean. Inspection of Figure 6 in Liu et al. suggests most patients (n = 14) exhibited increased HMGB1.

    Oncolytic, as a label or category, can be somewhat deceiving.

    Intralesional (IL) oncolytic virus (e.g., T-Vec, CVA21, HF10, etc.) is different than IL chemical small molecule (i.e., PV-10), both of which might be referred to as oncolytic immunotherapy.

    Oncolytic virus immunotherapy however delivered (e.g., intralesionally/intratumorally, intravenously) is different from ablative immunotherapy (i.e., PV-10).

    Takeaway: There's a real opportunity for Provectus and PV-10. There is no doubt about the relevance of PV-10, but cutting through the crowd to the front of the pack will require continued effort on the company's part.