June 14, 2016

Proxy Vote

Provectus’ 2016 annual meeting of stockholders is scheduled for Thursday, June 16th at 4 pm EDT in New York, New York. Shareholders of record as of April 25th's close of business should have until the annual meeting to vote. Practically, however, votes probably should be received at least 48 hours ahead of the meeting (i.e., no later than Tuesday, June 14th at 4 pm EDT). This year Provectus asked shareholders to vote on three proposals:
  1. A slate of five directors to serve on the company's board for a one-year term,
  2. An advisory vote to approve Provectus' named executive officers’ compensation, and
  3. The selection of accounting firm Marcum LLP as the company's independent auditor for 2016.
You can read about my 2015 proxy vote and rationale in May 30, 2015 blog post Proxy Vote. I will vote all of our shares for/against as noted below in the sample/illustrative ballot. See Still [road] trippin' (June 13, 2016) on the blog's Current News page.

My Ballot
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In a world different than the one Provectus and its shareholders currently inhabit, things could or would be more better — sooner rather than later — for the company and its investigational oncology compound PV-10 (and dermatology compound PH-10):
  • The category of intralesional (IL)/intratumoral (IT)/local cancer agents would not have been abject failures for so long,
  • There would have been earlier regulatory agency comfort with IL/IT/local agents that could treat the systemic disease that is cancer,
  • Perhaps, what once may have been an industry (the pharmaceutical industry, that is) of regular, real innovation would not have become one of mostly me-toos and followers,
    • For example, former Provectus Chairman, CEO and a co-founder Dr. Craig Dees, PhD's belief (my assumption) that the pharmaceutical industry would immediately beat a path to the company's and his door because of how well Rose Bengal and PV-10 (and PH-10) worked therapeutically. How well, of course, was based on his contextual view of the "necessary amount" of preclinical and clinical data. Well, what happens (what was your plan and approach) if they (Big Pharma) did not do so, immediately?
    • And/or company CTO, board member and a co-founder Dr. Eric Wachter, PhD's belief (again, my assumption) that the FDA, a/the key regulatory agency, would immediately embrace (approve?) Rose Bengal and PV-10 for therapeutic use because of how well Rose Bengal and PV-10 (and PH-10) worked.  How well, of course, was based on Eric's contextual view of the "necessary amount" of preclinical and clinical data. Well, what happens (what was your plan and approach) if it (the Agency) did not do so, immediately?
  • There would have been real Provectus board members.
    • Both Craig and company President, board member and a co-founder Dr. Tim Scott, PhD had insufficient innate or learned ability to be Provectus board members. Founding a company is not a long-term reason or mandate for board membership.
    • In my view, Eric possesses/has had the ability to be a quality board member of this company if so developed, coached and immersed over time on/in a real, thoughtful, intelligent board and board culture.
    • Past and present independent/outside board members have not contributed enough leadership in principled and/or intelligent manners.
  • There would have been more effort and experience by company management and the board to surround themselves/associate with a higher quality of non-clinical advisors across several operational functions.
But the world in which Provectus and its shareholders currently live is all that it/they/we have until it changes for the better, and hopefully in a sustainably, much more positively manner.

If I had to sum up or more cogently articulate my sense of Provectus' singular, primary and key deficit, it would be, generally speaking, a lack or vacuum of quality leadership, at both company management and board levels. Prior and certain current company "leadership" created an unacceptable culture, potentially paradigm-shifting innovation notwithstanding. Independent/outside directors appear to have done little-to-nothing to change or improve this culture for the better.

Proposal #1, A slate of five directors to serve on the company's board for a one-year term

The rationale for my WITHHOLD vote for board member Dr. Scott, consistent with how I voted our shares in 2015 (a Withhold vote), includes his insufficient leadership at the board level and, at a minimum, his disqualification as a board member resulting from the Dees debacle (i.e., Provectus' March 16, 2016 press release Announces Results of Internal Investigation).

My FOR vote for board member Eric, who replaced Craig on the board, is based on my belief that he is capable of being a quality board member with the potential to display better leadership at the board level, and my thinking that his clinical development program experience (among other clinical operational roles and responsibilities) would be an important and necessary contribution to an eventual, hoped for, board level discussion of a company buyout in the future.

The rationale for my FOR votes for board Chairman Al Smith IV and board members Dr. Kelly McMasters, MD, PhD and Jan Koe includes my thinking that they should be in place at the present time for business continuity reasons (such as but not limited to the CEO search process). I acknowledge the potentially inconsistency of this vote given they have not acted like real board members (i.e., they have displayed insufficient leadership). I believe they should transition themselves off Provectus' board at the appropriate time and be replaced by board members committed to doing "it" properly.

While one might argue that good board leadership could include meaningful [to a board member in context and based on his or her individual circumstance] stock ownership, consistent with Provectus' proposed guidelines on corporate governance, section IV.l {badly numbered], it is not the only consideration. Nevertheless, consider that two independent/outside directors (Dr. McMasters, Mr. Smith) own no common stock despite having joined the board in 2008 and 2011, respectively. Consider also that Peter has acquired (purchased) all of his stock ownership, compared to Dr. Scott who purchased (for money) fractions of what Eric and Peter themselves have bought over time.

My FOR vote for Jan Koe in 2016 is different from my vote in 2015, which was Withhold. At the time I wrote:
"Jan Koe originally was added to Provectus' board of directors in May 2012 to facilitate the forming of an independent board to meet corporate governance requirements in advance of uplisting onto a major U.S. stock exchange (i.e., more independent members than insiders). Up until that point, company insiders/founders (i.e., Dees, Scott and Wachter ) outnumbered independent members. As a result, Provectus' Chief Technology Officer Dr. Eric Wachter, PhD stepped off the board. 
I met Mr. Koe for the first time briefly at a Provectus shareholder event during ASCO 2014. I recall he immediately sounded like he had no substantive technology (let alone life sciences) knowledge. A quick check of his background at the time of his board appointment revealed no biopharmaceutical industry experience (presumably save for his investment in Provectus). He struck me as someone who would not offer a principled, intelligent counterbalance to the company's insider directors (i.e., Craig and Dr. Scott). To be fair to Mr. Koe, Provectus' board has never struck me as an active or engaged entity, but more of a rubber stamping "authority." Board independence is not insignificant of course, but his contribution in this regard no longer is required. The time to upgrade this independent director position with someone with both substantial industry and board experience is overdue."
I have recently spoken to Jan on a couple of occasions in regards to the CEO search process — see CEO Search Committee (June 13, 2016) on the blog's Current News page — and believe his heart and intent is in the right place even though I do not believe he can fully/properly execute on his goals and this process.

I believe both COO and interim CEO Peter Culpepper and Eric are important to the current process of generating sufficient clinical trial data in context, and engaging prospective licensees/co-development partners/[eventual] acquirers. Neither of them, however, is a suitable CEO candidate. I do believe both of them would agree that a good-to-great candidate would be a medical doctor who has a proven track record of leading a successful biopharmaceutical company.

In regards to the CEO search process, I tried to convey not only the above to Jan, but also the following. First, the person the search committee and board may pick today might not be the person they would pick in, say, 6 months (round number) when more clinical data potentially were available. I do not believe a deal person with fundraising experience is necessary or an important qualification.

Second, the CEO search process might be a two-step or two-stage one, where the first step/stage would be the concurrent following of Eric’s process/path (together with Peter's non-clinical business/corporate development) efforts as data are generated in context and continuing of interviewing CEO candidates to get smarter about who the committee and board are looking for and why. The second step/stage is, assuming they do not find an A+ candidate during first step/stage, would be to determine whether the company is on a clear and present trajectory to be sold at a/the proper price as data in context becomes available, or whether the board would want to transition to a new board and CEO who could take the valuation level Eric and Peter may have helped build to a much higher amount.

Proposal #2, An advisory vote to approve Provectus' named executive officers’ compensation

The rationale for my AGAINST vote includes, repetitiously, the poor or lacking leadership of current independent/outside board members (i.e., those on the compensation committee, and of course on the full board), and the tone deafness of management to accept enhanced compensation at this point in time, irrespective of the company's compensation committee and its policies, reviews, deliberations, plans, etc.

I voted Abstain in 2015. At the time I wrote:
"As an advisory vote I'm inclined to believe the final decision carries little weight with management despite language to the contrary in the SEC filings (see for example, page 10 of the proxy statement). I do not believe historic share price performance and very significant share dilution has fully warranted historic levels of compensation. I also am of the opinion a negative vote is not commensurate with my net positive assessment of management's progress to date to achieve what I believe is a paradigm shift in the treatment of solid tumor cancer. Abstention in my opinion reflects a wait-and-see attitude for the next 12 months."
The board and management continued to fail to show leadership by granting and accepting compensation in 2015 based on commercial and operational performance milestones, peer company compensation data, and the achievement of specific scientific, medical and clinical milestones while not acknowledging poor share price (and market capitalization so as to address the notion of fully diluted) performance as a major component of their thinking.

I do not believe compensation committee members (or the full board) would be any more real or intelligent in 2016. Show me meaningful success on the share price and market capitalization fronts, and I would very much and very easily consider, in context, substantial enhanced compensation for Eric and Peter.

Proposal #3, The selection of accounting firm Marcum LLP as the company's independent auditor for 2016

My FOR vote for this proposal is pretty much a perfunctory one. At a basic level Provectus needs this, in context, to eliminate questions over being a going concern and all that might or could come from not being one or operating without such an opinion.

Accounting professionals (and those who dig into this due diligence topic) may assess firm and individual account leadership (and team) reputations. Recent rankings, primarily revenue-based, would place Marcum as a Top 20 accounting firm. See, for example, below.
Click to enlarge. The 2015 Inside Public Accounting (IPA) 100 Firms
Click to enlarge. The 2014 accountingTODAY Top 100 Firms
Relating this proposal to the blog post's theme of a vacuum/lack of leadership, Provectus' former independent auditor BDO USA LLP (like the company's internal auditor vendor that was terminated earlier this year) clearly displayed insufficient leadership by not identifying Craig's potentially or purported inappropriate actions and activities sooner.

Image source
Road trippin': I would have got this post out sooner, but I was dealing with car troubles in cheese country.

June 1, 2016

Intralesional PV-10 for In-Transit Melanoma—A Single-Center Experience

Article: Lippey et al., "Intralesional PV-10 for in-transit melanoma-A single-center experience," J Surg Oncol, 2016 May 30.

H/t a shareholder and regular hatter for access to the above paper. Bolding-in-paragraph and underlined emphasis below is mine.

[From the end of the paper] "Synopsis: This paper reviews a single metropolitan cancer hospitals experience with PV-10 for the treatment of in-transit melanoma. Over a 4-year period, we have treated 19 patients with PV-10 for melanoma and achieved disease control in 68% of patients. We find it a helpful tool in our armory for local control of this often-difficult clinical scenario."
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"Toxicity: The majority of treatments (73%, 24/33) were well tolerated without any reported side effects. Edema, pain and erythema were the most common side effects, although these were minor in severity, limited in duration, and easily managed by simple analgesia. Five patients required opiate analgesia for pain associated with PV-10 injection.

One patient was readmitted to hospital 1 week following treatment with lower limb cellulitis requiring intravenous antibiotics for 2 days. This patient was obese and elderly and the cellulitis arose in the area of recent injection."

"Treatment Response: After a median follow up of 11.7 months, disease control was achieved in 63% of patients. Five patients (26%) achieved a complete response, another five (26%) patients achieved a partial response, and two patients had stable disease (11%) at the time of last follow-up. Seventy-four percent (14/19) of patients had a clinical response at time of first follow-up (median time 21 days); range 8–91 days. Younger patients and those with smaller lesions were more likely to respond to treatment (Table III). The number of injected lesions and the time from primary diagnosis to treatment were not predictive of response.
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Ten patients did not have all lesions injected, primarily due to the number of lesions present. A bystander response was noted in un-injected lesions in 50% of patients who did not have all their lesions directly injected (Table II). After a median follow up of 11.7 months, eight patients had died
from metastatic melanoma."

"DISCUSSION: This single-center retrospective review demonstrates that intralesional PV-10 is an effective, safe, and well-tolerated treatment option for patients with ITMs and loco-regional recurrence of melanoma. Treatment was delivered to a group of patients who were elderly (median age 82 years) and in many cases considered inappropriate for more aggressive and potentially toxic therapies such as ipilimumab or isolated limb infusion.

There have been several previous reports of success with intratumoral injection of PV-10, providing local control in this group of patients with an acceptable toxicity profile. There is still a lack of data about durability of PV-10 as well as a lack of long-term survival data. The largest published study assessing the use of PV-10 in the setting of refractory melanoma published in 2014 analyzed 80 patients from seven international sites. In this study, a 52% overall response rate and 26% complete response rate were described which is comparable to the overall response rate of 63% and complete response rate of 26% in the current series as well as in another previously published single-center series (Table IV).

The effective treatment options for metastatic and locoregional inoperable disease melanoma have rapidly improved over the last 5 years. With the introduction of novel systemic agents targeting immune checkpoints (ipilimumab, pembrolizumab, nivolumab), and mutations in the MAP kinase
pathway (dabrafenib and trametinib), the treatment options for patients with unresectable metastases have increased and the prognosis for these patients has significantly improved. However, these agents may be associated with significant toxicity and in the case of PD-1 targeted therapy require frequent hospital visits for infusions. Intralesional PV-10 compares favorably with other
intralesional therapies including talimogene laherparepvec (T-VEC) which in the recently published OPTiM study demonstrated on overall response rate of 26.1%. It is important to note that the
patient population in the OPTiM study had more advanced disease than the population in the current study, and the response rate for patients with all lesions injected lesions with T-VEC was 33%. For an
elderly patient with ITM, a simple and effective local therapy with minimal side effects is an attractive option. In our center, the use of ILI has steeply decreased with the availability of PV-10.

In the modern era of effective systemic therapies, patient selection for intralesional therapy is critical. Previously described factors predictive of response include the presence of ulceration, blistering, eschar, or pain following injection. In the current study, lesion size was also found to be predictive. Of the five patients who achieved a complete response, the average lesion diameter was 3 mm compared to the cohort average size of 6.3 mm. We did not specifically collect data on eschar formation but anecdotally have seen significant ulceration and eschar in most responders which may represent a brisk immune response to treatment or a direct toxic
effect.

Aside from the local toxicity of pain and edema and an isolated report of photosensitivity, PV-10 remains a very safe treatment option. As compared to radiotherapy, PV-10 has the advantages of allowing a wider field of treatment which may be repeated if necessary. A successful combination of radiotherapy and intralesional PV-10 has been reported and may warrant further
investigation.

The limitations to this study are the retrospective nature and the variable treatment regimens which were tailored to patients according to social, geographic, and oncological factors. As our cohort consisted of elderly and comorbid patients, we often limited their required visits to hospital which is reflected in the short follow-up intervals.

There are a growing number of options for the treatment of unresectable in-transit disease and choice depends on many factors including availability of treatment, patient suitability, and disease factors. Intralesional PV-10 compares favorably in that it is well tolerated especially in an elderly patient or one with significant comorbidities.

May 25, 2016

Checkpoint Inhibition Differentiation or Death: Proprietary Combinations with Protectable Agents

Updated below.

From this project's Twitter feed: Dr. Sally Church, PhD, ‏@MaverickNY
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How would Big Pharma distinguish each of its immune checkpoint inhibitors (CIs) from another? Efficacy? Tolerability? Cancer indication? Cost? Within groups (e.g., PD-1s, PD-L1s, etc.), efficacy and safety should equivalent. Different antibodies — for example, with the PD-1s, like nivolumab/Opdivo and pembrolizumab/Keytruda — function in almost identical fashion and differ only by means of manufacture and corporate decisions made with regards to clinical development (e.g., dose schedule, target indication). Magically, there is parity in pricing.

Based on drug sales to date and sales projections thus far, captured in part by @grhyasen's tweet graphic above, Bristol-Myers (nivolumab/Opdivo) and Merck & Co. (pembrolizumab/Keytruda) may be in no serious rush to differentiate their CIs beyond their current, respective corporate strategies. But Roche (atezolizumab/Tecentriq), AstraZeneca (durvalumab) and Merck KGaA/Pfizer (avelumab), all with "late to market" CIs, surely must be thinking about ways to differentiate their respective compounds.

Does meaningful, sustainable and profitable differentiation come in the form of combination, and thus in the form of a partner compound for a CI? In other words, could combination create branded differentiation — ultimately based on efficacy, tolerability, indication and cost of the combination. Proprietary combinations with protectable agents.

Novartis, one Big Pharma without a "lead CI" but having PD-1, TIM-3, LAG-3 and PD-L1 CIs within its pipeline, seems to have begun its brand differentiation by expanding its strategic thinking to include or focus on first-in-class combinations. See Pharmaceuticals and Oncology Business Units, Meet Novartis Management, May 24-25, 2016:
Click to enlarge. Fuzzy orange rectangle is mine
Click to enlarge. Fuzzy orange rectangle is mine
PV-10's, and thus Provectus', value proposition to the likes of Roche, AstraZeneca, Merck KGaA, Novartis, etc. might be to (a) combine their CI with PV-10 and (b) use Provectus' combo patent* to defend the unique combination thus formed — a proprietary combination with a protected agent.

* United States Patent No. 9,107,887, Eagle et al., August 18, 2015, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer

Updated (6/11/16): Deena Beasley, Reuters, June 11th, Regulator says too many drugmakers chasing same cancer strategy:
"A new type of cancer drug that takes the brakes off the body's immune system has given drugmakers some remarkable wins against the deadly disease, but a top U.S. regulator says too many companies are focused on the same approach. 
Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology products, was referring to therapies designed to disable the PD-1 protein that tumors use to evade the immune system...  
"People should ask themselves ... would we be better off spending those resources into looking at more novel drugs?" Pazdur told Reuters during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago this week.... 
"As with everything in drug development, it is about reduction of risk," he said. But the number of similar drugs in development at the same time is a first in the oncology field, and latecomers to the PD-1 market will likely be relegated to "niche" indications, he added. 
Drug company executives disputed Pazdur's critique. In interviews with Reuters, they argued that the science around cancer is advancing rapidly, with a focus on how to best combine therapies to attack multiple mechanisms of the disease, determine which patients are most likely to respond to them and how long patients will need to be treated."
Blumenthal and Pazdur, Response Rate as an Approval End Point in OncologyJAMA Oncol. 2016;2(6):780-781.
"Overall response rate (ORR) as a surrogate end point in oncology drug approval has a long history. In the 1970s, the US Food and Drug Administration (FDA) usually approved drugs on the basis of ORR. In the 1980s, after discussions with the Oncologic Drug Advisory Committee, the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvements in overall survival (OS), tumor-related symptoms, or physical function.1 In the past decade, due to an improved understanding of the genomic underpinnings of cancer, better molecular characterization of tumors, and more precisely targeted agents, unprecedented rates of response have radically altered the therapeutic landscape in a number of malignant neoplasms. Therefore, ORR and duration of response as assessed in single-arm trials has served as the basis of accelerated approval and at times regular approval in a number of refractory malignant neoplasms, including non–small-cell lung cancer (NSCLC), lymphoma, melanoma, and myeloma."
This presumably works [very well] only for systemic drugs using standard RECIST. Provectus' pivotal melanoma Phase 3 is employing [standard] RECIST 1.1.

Road tripping:
My proxy vote should be posted by June 14th.

May 21, 2016

Could PV-10 (Rose Bengal) be implicated in different kinds of cell death?

Image source
Reference article: Garg et al., Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translationCell Death and Differentiation (2016) 23, 938–951.

N.B. There is no reference to Rose Bengal (generic name) or PV-10 (proprietary name) in the February 2015 Garg et al. article.
Article Abstract: Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of ‘eat me’ signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.
Provectus says PV-10/Rose Bengal:
  • Does not rely on a single pathway to work [I assume 'signalling pathway'],
  • Does not focus on a single receptor to work [I assume 'cell receptor'], and
  • Has no known resistance [I assume little no cancer drug resistance].
A highly specific compound in its targeting of only diseased (cancerous) tumors/lesions, tissue and cells, sparing healthy ones in the process, might the veracity of PV-10/Rose Bengal's "multiplicity" be based in its lack of "specificity" in regards to cell death?

That is, might Provectus' investigational compound's apparent implication in different kinds of cell death help explain why PV-10/Rose Bengal does not rely on a single pathway or focus on a single receptor to work, and has no known resistance?

Of note in Garg et al.'s article are (a) a table describing "major cell death pathways and their immunobiological" profiles and (b) a figure illustrating "therapeutic exploitation of phagocytosis of dying cancer cells for T-cell-mediated cancer cell elimination."

The table of major cell death pathways includes (i) apoptosis, (ii) autophagy (autophagic cell death) and (iii) immunogenic cell death.
Click to enlarge. Image source
The illustration appears to draw three paths to anti-tumor immunity; one that is direct (e.g., DAMPs like HMGB1), and two that additionally employ co-stimulatory signals such as TLR agonists or co-inhibitory signals such as immune checkpoint therapy.
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A sampling of Provectus and independent medical researcher work implicates PV-10 in apoptosis, autophagy, necrosis, and immunogenic cell death:
Garg et al. observe "The mechanisms of cancer cell death elicited by anticancer therapy and the type of phagocytes (e.g., tumour-resident versus therapy-recruited) interacting with dying cells are decisive factors in making a difference between anti-inflammatory or pro-inflammatory responses."

Some cell death via PV-10 occurs in the injected lesion or tumor (i.e., tumor-resident), which is the upstream trigger of subsequent cell death via a tumor-specific immune response (i.e., therapy-recruited).

May 18, 2016

Rose Bengal (PV-10) at ASCO 2016

[Colored emphasis below is mine.]

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.

Author(s): Matthew C Foote, Bryan H Burmeister, Janine Thomas, Tavis Read, Bernard Mark Smithers; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Princess Alexandra Hospital, Brisbane, Australia

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% (CR 33%, PR 53%) with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months. Size of metastases ( < 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Intralesional rose bengal for treatment of melanoma.

Author(s): Sanjiv S. Agarwala, Robert Hans Ingemar Andtbacka, Kristen N. Rice, Merrick I. Ross, Charles Raben Scoggins, Bernard Mark Smithers, Eric D. Whitman, Eric Andrew Wachter; St. Luke's Hospital and Health Network and Temple University, Bethlehem, PA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Medcl Onc Assoc of San Diego, San Diego, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Louisville, Louisville, KY; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Atlantic Melanoma Ctr, Morristown, NJ; Provectus Biopharmaceuticals, Inc, Knoxville, TN

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 (NCT02288897) is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

May 12, 2016

Moffitt: IL RB in melanoma elicits tumor immunity via activation of DCs by the release of HMGB1

Updated below, again.

Article link: Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1

H. Lee Moffitt Cancer Center and Research Institute departments & facilities: Immunology, Flow Cytometry, Translational Science, Cutaneous Oncology, Pathology, and Cutaneous Data Management

Click to enlarge.
Takeaways:

These data/results:
  • "...support the role of IL [intralesional] RB to activate dendritic cells at the site of tumor necrosis for the induction of a systemic anti-tumor immune response,"
  • "...suggest that IL PV-10 can induce tumor-specific T cells with memory characteristics in M05 melanoma-bearing mice,"
  • "...show that CD8+ T cells are crucial for the tumor-specific immune response induced by IL injection of PV-10,"
  • "...support that IL injection of PV-10 can boost T cell infiltration in tumors,"
  • "...support a role for IL PV-10 to induce DCs [dendritic cells] to take up antigens at the tumor site, infiltrate into the DLN [draining lymph node], and become functionally mature,"
  • "...suggest that PV-10-treated tumors may release factors that activate DCs,"
  • "...suggest that PV-10 can kill tumor cells at a dose that is not toxic to non-tumor cells,"
  • "...support the role of IL PV-10 treatment to induce a systemic anti-tumor immune response in patients with metastatic melanoma," and
  • "...support the design of additional clinical studies to measure anti-tumor immune responses after IL injection of PV-10 in patients with melanoma."
The Cancer Immunity Cycle & PV-10
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ABSTRACT

Intralesional (IL) therapy is under investigation to treat dermal and subcutaneous metastatic cancer. Rose Bengal (RB) is a staining agent that was originally used by ophthalmologists and in liver function studies. IL injection of RB has been shown to induce regression of injected and uninjected tumors in murine models and clinical trials. In this study, we have shown a mechanism of tumor-specific immune response induced by IL RB. In melanoma-bearing mice, IL RB induced regression of injected tumor and inhibited the growth of bystander lesions mediated by CD8+ T cells. IL RB resulted in necrosis of tumor cells and the release of High Mobility Group Box 1 (HMGB1), with increased dendritic cell (DC) infiltration into draining lymph nodes and the activation of tumor-specific T cells. Treatment of DC with tumor supernatants increased the ability of DCs to stimulate T cell proliferation, and blockade of HMGB1 in the supernatants suppressed DC activity. Additionally, increased HMGB1 levels were measured in the sera of melanoma patients treated with IL RB. These results support the role of IL RB to activate dendritic cells at the site of tumor necrosis for the induction of a systemic anti-tumor immune response.

RESULTS, summary of article subtitles
  • IL PV-10 elicits a tumor-specific immune response
  • IL PV-10 leads to DC activation
  • PV-10 treatment increases DC activation via HMGB1
  • IL PV-10 leads to HMGB1 increase in the sera of melanoma patients
DISCUSSION

Melanoma incidence rates have increased rapidly in the United States over the past 30 years and is the fifth most common cancer in men and the seventh most common cancer in women [38]. IL therapy is a promising treatment modality for patients with dermal and/or subcutaneous metastatic melanoma. Importantly, it may induce not only local tumor regression but also a systemic anti-tumor immune response. In a recent clinical trial in metastatic melanoma patients, IL PV-10 led to a
50% objective response rate with mild to moderate side effects [17]. In treated patients, 8% had no evidence of disease after 52 weeks and 26% experienced complete regression in bystander lesions. However, the mechanism by which IL PV-10 leads to systemic anti-tumor immunity is unknown.

In this study, we showed that IL PV-10 led to the necrosis of melanoma cells and the release of HMGB1. These data are consistent with the observation that HMGB1 was passively released from photosensitized HeLa cells treated with a Rose Bengal analog [39]. Pretreatment with Rose Bengal acetate led to apoptosis and autophagy and the secretion of HSP70, HSP90 and HMGB1. In contrast, our results showed that PV-10 treatment induced necrosis in melanoma cells and the secretion of HMGB1, but not HSP70, while the amount of HSP90 was unchanged. This discrepancy may be explained by differences in response to RB and its acetate analog, dose of test article, differences in the cell lines used, or mechanisms of ablative and photodynamic therapies. Moreover, HMGB1 levels in the sera of patients were increased after IL PV-10. This is in line with another study that showed increased HMGB1 levels in the serum of cancer patients after chemoradiation; notably, HMGB1
levels were increased in patients with antigen-specific T cell responses and higher expression of HMGB1 in resected tumor samples was correlated with better survival [40].

Maturation of DCs is crucial for priming CD8+ T cells [41]. HMGB1 has been shown to be important for activation of myeloid and plasmacytoid DCs [25, 31, 42–46]. In our model, DC maturation with up-regulation of CD40, CD80 and CD86 was measured in tumor draining LN after IL PV-10. Furthermore, our study showed that HMGB1 in the supernatant of tumor cells treated with PV-10 was responsible for the up-regulation of CD40 expression on BM-derived DCs and for the increased ability of DC to stimulate T cell activation. It has been shown that short-term CD40 signaling augments DC migration to tumor-draining LNs and induced protective immunity. Moreover, HMGB1 has been shown to enhance DC responses to CCL9 and CXCL12 [47]. Interactions between HMGB1 and RAGE can induce the migration of s.c. injected DCs into DLNs [48]. In our study, IL PV-10
increased the number of DCs migrating from the tumor site into the draining LNs.

In this study, we have shown a mechanism of tumor-specific immune response induced by IL PV-10.
In melanoma-bearing mice, IL PV-10 induced necrosis of tumor cells leading to the release of HMGB1, which is crucial for DC activation. This resulted in DC maturation and infiltration into draining LNs for the activation of tumor-specific T cells. Additionally, increased HMGB1 levels measured in sera of patients treated with IL PV10 suggests that HMGB1 may be involved in eliciting a systemic immune response in patients. We have shown that circulating T cell populations and tumor-specific CD8+ T cells are increased in melanoma patients after IL PV-10 therapy. Together these results support the design of additional clinical studies to measure anti-tumor immune responses after IL injection of PV-10 in patients with melanoma.

MATERIALS AND METHODS, Incl. Human subjects

Fifteen patients with dermal and/or subcutaneous metastatic melanoma were enrolled in a pilot study
(NCT01760499). Peripheral blood and serum were collected prior to biopsy, 7-14 days after IL PV-10 injection into a single melanoma tumor, and 21-28 days after IL PV-10 injection. PBMCs were isolated by Ficoll–Paque Plus (GE healthcare). Blood samples were sent for HLA typing to determinate HLA-matched tumor and HLA mismatched tumor for each patient. Serum was prepared by collecting the supernatant after incubation of blood at room temperature for 1 hour and centrifugation at 1,000 g. Two tumor lesions in each patient were sampled by biopsy pre-treatment; one of the two lesions was injected with IL PV-10 7 days after biopsy, then both residual sites were completely excised 7-14 days later. Biopsy specimens were fixed in formalin and embed in paraffin. The specimens were stained with hematoxylin and eosin stains for determination of pathologic complete response. Immunohistochemistry for melanin A (mel A) was performed. Flow cytometry was performed to detect CD3, CD4, CD8, and CD56 staining on PBMC.

ACKNOWLEDGMENTS

We thank Dr. Dmitry Gabrilovich for valuable comments during the preparation of this manuscript. This work was supported in part by the Flow Cytometry, Analytic Microscopy, and Tissue Core Facilities at the Moffitt Cancer Center, and in part by the Cancer Center Support Grant P30 CA076292 from the National Cancer Institute. This work was also supported by NCI-5K23CA178083-02 (AAS). PV-10 was provided by Provectus Biopharmaceuticals.

Updated (5/13/16): Provectus issued a press release and made an associated 8-K filing today related to Moffitt's PV-10 mechanism of action paper, "Announces Publication of Article in Oncotarget Detailing PV-10's Immuno-Ablative Mechanism of Action" -- with the company's CTO Dr. Eric Wachter, PhD calling the paper's publication "a a watershed event in the development of PV-10."

I really liked the press release, which is rare praise for an aspect of the company — corporate communications — that has been woeful and woefully lacking dating back to when I began due diligence on Provectus. I found the PR crisp, cogent, insightful and nuanced.

Key takeaway: In my view, the upshot of the release, and more importantly the Oncotarget paper, stemming from Moffitt's initial mouse work first presented at AACR in April 2013 — "Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma" — is that PV-10 is an immunotherapy, or an immuno-ablative as Provectus has labelled its lead, advanced, investigational oncology drug that should focus attention on PV-10's physical chemistry properties (i.e., ablative, and e.g., ablation, chemoablation, etc.) rather than the biological chemistry properties of immune checkpoint inhibitors, oncolytic viruses, and certain other classes of immunotherapies. Keep in mind that folks more recently are wondering about the potential immunotherapeutic properties of chemotherapy and radiotherapy, which are "non-biologics."

Mouse-to-man-to-mouse: I'd venture, in my limited experience as a biotechnology or pharmaceutical industry investor, that Moffitt's work might be the epitome of a translational study, going from mouse to human, and back to mice before returning to human, as the cancer center team confirmed and/or discovered new things in their work. As Eric said in the PR {underlined emphasis below is mine}:
"The Moffitt researchers have systematically documented each of the key steps in the immuno-oncology cycle described by Chen and Mellman in their landmark review article (Oncology Meets Immunology: the Cancer-Immunity Cycle. Immunity 2013; 39: 1-10). In an exemplary demonstration of translational medicine, this team identified important immunologic markers in model systems and verified key facets of these in clinical trial participants, and similarly identified other markers in clinical trial participants and substantiated these in mouse models. While a number of their main observations were previously reported at scientific meetings, these are presented here in detailed, integrated fashion for the first time."
Moffitt team leader Dr. Shari Pilon-Thomas also broached this mouse-to-man-to mouse approach:
"Concordance of tumor-specific T cells in peripheral blood of clinical trial participants and mice led us to look for triggers of T cell activation. Working back from these observations, we found that HMGB1 release was common in mouse and man after tumor ablation with PV-10. These results support PV-10 ablation and the resulting tumor necrosis as the upstream trigger for systemic anti-tumor response." {concordance = agreement}
PV-10 is an immunotherapy: With Moffitt's work, presentation as Eric noted in a "detailed, integrated fashion for the first time," I'm hard pressed to understand anyone saying, in an intellectually honest fashion of course, that PV-10 is anything but an immunotherapy. As Eric further noted:
"This paper is a watershed event in the development of PV-10, walking the reader through all the steps of immune activation after PV-10 injection, from immunogenic cell death and signaling via release of HMGB1, dendritic cell recruitment and infiltration into draining lymph nodes, activation of tumor-specific T cells, and killing of uninjected tumors upon infiltration by these T cells."
Additionally, Eric underscored the immunotherapeutic role PV-10 plays as a single agent or monotherapy, and in combination with other therapies and therapeutics {bolded emphasis is mine, too}:
"This mechanism of action informed the design of the two active PV-10 clinical trials: NCT02288897 in patients with locally advanced cutaneous melanoma (melanoma limited to the skin) to test the hypothesis that PV-10 alone can produce a systemic immune response that translates to longer progression free survival (PFS); and NCT02557321 in patients with later stage melanoma to test whether combination of PV-10 with the recently approved systemic immunotherapy, pembrolizumab, can 'induce and boost' an immune response against melanoma."
Updated (5/13/16): I discussed choice of medical journal with Eric. He said New England Journal of Medicine (NEJM), Journal of Clinical Oncology (JCO) and the like focus on relatively large clinical trials. Moffitt's topic and study were not a good match for NEJM, JCO, etc. Oncotarget is a high-impact journal specializing in oncology mechanism and therapeutics (i.e., translational medicine), having a 2014 impact factor of 6.4. For comparison*, for example:
  • NEJM's 2014 impact factor was 55.9,
  • Lancet, 45.2,
  • JCO, 18.4,
  • Cancer Research 9.3,
  • Clinical Cancer Research, 8.7,
  • Oncotarget, 6.4,
  • Cancer, 4.9,
  • Journal of Immunotherapy, 4.0
  • Immunology 3.8, and
  • Melanoma Research, 2.2.

The NEJM and the Lancet cover all diseases, while Melanoma Research only covers melanoma. As such, readership naturally is very different, as are resulting citations.

* The information above can be downloaded from this file.

May 5, 2016

Advancing from “occasional cures” to “routine cures”

On the blog's Current News today I compared an article in The Australian from last month, April 2016, "Melanoma drug Keytruda denied full listing on PBS," to one in The ABC from June 2015, about a year later, "'Revolutionary' melanoma drug worth $150,000 a year listed on PBS, saving Australian patients thousands."

Last year, Australian patients with advanced melanoma gained access to Merck & Co.'s anti-PD-1 or immune checkpoint inhibitor drug pembrolizumab (Keytruda) following its initial, "partial" listing on the country's Pharmaceutical Benefits Scheme (PBS). This year Keytruda was denied full listing on the PBS because there was insufficient evidence of clinical benefit to justify its cost — with The Australian calling Keytruda "a much-hyped melanoma drug."

The above dialog from Australia is one part of an ongoing, maturing, global discussion with respect to this topic: whether current “revolutionary” drugs are truly revolutionary, and ultimately worth the requested price. A paragraph from The Australian's article goes to the very heart of this topic:
"The knock-back comes less than a year after the PBAC flagged concerns about a “substantial mismatch” between the public’s expectations for the so-called “breakthrough drug” and the supporting scientific data." [PBAC is Australia's Pharmaceutical Benefits Advisory Committee]
Keytruda (aka lambrolizumab) received the FDA's breakthrough therapy designation (BTD) for advanced melanoma in 2013.

Since the beginning of 2016 there has been an increasing realization that declaring “mission accomplished” in the fight against cancer might be premature. At the Vatican's recent 2016 healthcare conference, Cellular Horizons: How Science, Technology, Information and Communication will Impact Society, it was noted that the current immuno-oncology (I-O) drugs lead to “occasional cures,” but that this outcome is not good enough. Part-and-parcel with this view is the realization that combinations — combinations of different cancer treatments, whether therapies or therapeutics — likely will be paramount to advancing from occasional cures to routine cures.

The global oncology community is actually now talking about cures, realizes the immune system is crucial for this (as was first noted by the Society for Immunotherapy of Cancer in 2013), and is looking at cancer with a markedly increased sophistication in the search for necessary treatment algorithms for various tumors and tumor subtypes.

As with the rest of the oncology community, Provectus has challenges ahead, but PV-10 appears to be congruent with the mainstream more and more daily.
Click to enlarge. Image source