December 8, 2016

Rose Bengal (PV-10) + Oncology + Pediatrics

Updated below: 12/8/16.

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.

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
Click to enlarge
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.

November 8, 2016

SITC 2016, ABSTRACT: Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer

Updated below: 11/8/16 {thrice}.

Source link

Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer

Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A Sarnaik H. Lee Moffitt Cancer Center, Tampa, FL, USA

Journal for ImmunoTherapy of Cancer 2016, 4(Suppl 1):P256

Rose Bengal is a xanthene dye that has been utilized for liver function studies and is currently used topically in ophthalmology. Intralesional (IL) Rose Bengal (PV-10) has been shown in murine models and melanoma clinical trials to induce regression of treated melanoma lesions and uninjected bystander lesions. This study was undertaken to measure whether IL PV-10 can induce systemic anti-tumor effects alone or in combination with gemcitabine (Gem) therapy in a murine model of pancreatic cancer.

C57BL/6 mice received Panc02 pancreatic tumor cells subcutaneously (SC) on one flank to establish a single tumor. On day 7, tumor was treated with IL PV-10. Control mice received IL phosphate
buffered saline (PBS). Tumor growth was measured. Splenic T cells were collected and co-cultured with Panc02 or irrelevant B16 cells. Supernatants were collected to measure Panc02-specific T cell responses by IFN-gamma ELISA. To measure the effect of IL PV-10 on the growth of an untreated, bystander tumor, mice received Panc02 cells in bilateral flanks. The resulting right tumor was injected IL with PV-10 or PBS. Tumor sizes were measured for both the right (treated) and left (untreated/bystander) tumors. To determine the efficacy of combination therapy with IL PV-10 and systemic Gem, mice bearing a single or bilateral Panc02 tumors were treated with PV-10 alone or in combination with Gem. Mice received 60 mg/kg Gem intraperitoneally (IP) twice per week.

C57BL/6 mice bearing Panc02 tumors treated with IL PV-10 had significantly smaller tumors than mice treated with PBS (p < 0.001). A significant increase in the IFN-gamma production in response to Panc02 was measured in the splenocytes of mice treated with PV-10 as compared to mice treated with PBS (p < 0.05). Mice with bilateral tumors had a significant regression of tumors injected IL with PV- 10 and there was a reduction in the untreated (bystander) flank Panc02 tumor (p < 0.01). Gem therapy in combination with IL PV-10 injection led to enhanced tumor regression (p < 0.05) compared to IL PV-10 or Gem alone in both a single tumor model and a bilateral tumor model.

Regression of untreated pancreatic tumors by IL injection of PV-10 in concomitant tumor supports the induction of a systemic anti-tumor response. Addition of Gem chemotherapy enhances the effects of IL PV-10 therapy. Given that patients with metastatic pancreatic cancer have a dismal prognosis, combination therapy of IL PV-10 combined with Gem may benefit patients with metastatic pancreatic cancer.

Updated (11/8/16).1: My underlined emphasis above. Note PV-10 use in the above murine model work as a monotherapy, and in combination with systemic chemotherapy.

Updated (11/8/16).2: H/t @bradpalm1:

Click to enlarge. Tweet image source
"Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer," Eriksson et al., Journal of Translational Medicine 2016 14:282
Gemcitabine regulates the immune system in patients with pancreatic cancer including MDSCs, Tregs and molecules such as TGFβ-1 but does not hamper the ability of effector lymphocytes to expand to stimuli. Hence, it may be of high interest to use gemcitabine as a conditioning strategy together with immunotherapy."
Updated (11/8/16).3: Unlike some, I do not read too much into Moffitt's abstract with respect to the additivity or synergism of PV-10 and gemcitabine (systemic chemotherapy) based on the cancer center's murine model work (i.e., p values of PV-10 alone, and in combination with chemo). And, I'd like to see the poster if Provectus facilitates its release (e.g., the company did not facilitate the release of Moffitt's AACR 2016 poster, which I believe may lead to a peer-reviewed publication).

I believe the point of this mousie work, which of course is beyond cell line (in vitro) work but behind clinical studies, is to demonstrate in principle that (a) intralesional (IL) PV-10 could be used to treat pancreatic cancer (i.e., tumor type, leading to a suitable cancer indication) via (i) ablation/destruction of an injected tumor and (ii) the subsequent triggering of the immune response to reduce or destroy an untreated one, and (b) IL PV-10 plus chemo sees enhanced untreated tumor reduction or destruction.

These principles of (x) ablation/destruction by injection and (y) immunologic signalling (immune system harnessing) already have been shown preclinically by Moffitt for PV-10 as a monotherapy in melanoma (also clinically) and breast cancer (AACR 2013), and in combination with checkpoint inhibition for melanoma (SITC 2014).

So, this continues Rose Bengal, PV-10 and Provectus' theme of (A) agnosticism (ablation, immunologic signalling), (B) synergism (in that one therapy enhances another; "induce and boost"), (C) orthogonality (although this would be better shown in clinical work to emphasize no greater toxicity, if not less to far less), and...

(D) PV-10 is an immunotherapy. See January 19, 2016 blog post PV-10 is an immunotherapy.

November 3, 2016

It will take more than just checkpoint inhibition to achieve the next step forward in oncology

Image source
Updated below: 11/3/16 {twice} and 11/5/16.

(alternative blog post title: Can Clever Chronological Combos Cure Cancer?)

Clinicians and medical researchers around the world are growing in their realization that current immuno-oncology is not mission accomplished. It will take more than just checkpoint inhibition to achieve the next step forward in oncology.

Even immunologist Dr. James Allison, PhD, whose work led to the development of anti-CTLA-4 drug ipilimumab (Yervoy), highlighted this "look forward" in Laura Panjwani's October 31st OncLive article entitled "James Allison Says Rational Combinations Key to Immunotherapy Success in "Cold" Tumors:"
"The success of immunotherapies in those cancers—which are likely seeing a better rate of response due to their high mutational burden—is now paving the way for what are known as “cold” tumors, those that don’t have a heavy mutational burden or significant T-cell infiltration. 
There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions. As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic."
Among various combinations of therapies and therapeutics with checkpoint inhibition, Dr. Allison discussed radiation, chemotherapy and targeted therapy in the OncLive article:
"Most of the activity now, at least that I know about, is in radiation...There is also some chemotherapy combination research going on... 
Relatively few targeted therapies are being investigated with immunotherapies, although that research is happening. One of the problems is that there are so many options for combinations; the temptation is there to just combine something from column A, something from column B, and something from column C, and see if it works. That is the way it used to be done back in the empirical days of chemotherapy, but we know enough now to not do that."
PV-10's (Rose Bengal's) clinical & pharmacoeconomic value proposition is clear, simple and straightforward:
Click to enlarge. Sample image source, Sidoti Fall 2016
Germane to this blog post is the value proposition PV-10 provides a combination partner: agnosticism, orthogonality, and synergism:
Click to enlarge. Same sample source as above.
PV-10's combinatorics drug development program/portfolio to date comprises chemotherapy, radiotherapy, and checkpoint inhibition in pancreatic cancer, melanoma, and liver cancer:
  • November 2016, SITC: preclinical (murine models), PV-10 + chemotherapy (gemcitabine/Gemzar®), pancreatic cancer, Moffitt Cancer Center,
  • November 2014, SITC: preclinical (murine models), PV-10 + co-inhibitory blockade [checkpoint inhibition] (anti-CTLA-4, anti-PD-1, anti-PD-L1), melanoma, Moffitt Cancer Center,
  • April 2013, AACR: preclinical (murine models), PV-10 + anti-CTLA-4 [checkpoint inhibition], melanoma, Provectus,
  • November 2012, SITC: preclinical (murine models), PV-10 + chemotherapy (5-fluorouracil/5-FU, Adrucil®), hepatocellular carcinoma (HCC), Provectus, and
* There is not yet sufficient information to suggest patients on a course sorafenib have been treated with PV-10 (see May 10, 2016 1Q16 business update conference call, pp 44-45).

Updated (11/3/16).2: A table of the bullet points above is below.
Click to enlarge
Updated (11/5/16).3: Speaking of old oncology therapeutics and therapies ("In cancer, it’s back to the future as old treatments make cutting-edge ones more effective," Stat, Sharon Begley, August 4th):
"New cancer drugs that unleash the immune system on tumors are all the rage, getting credit for curing former President Jimmy Carter’s advanced melanoma and inspiring tech billionaire Sean Parker to pledge $250 million to cancer research. Behind the excitement, however, is the hard truth that these therapies work in only a minority of patients. 
Now scientists are finding hints of a solution in an unexpected place: Older, out-of-favor cancer treatments such as chemotherapy and radiation may make the cutting-edge immune-based drugs effective against more cancers — even hard-to-treat ovarian and pancreatic tumors... 
One answer: through chemotherapy or radiation. When these old-line treatments begin to kill tumor cells, those cells release molecules that can attract T cells to join in the attack. “They have the potential to prime the pump for immunotherapies,” said Dr. Gary Gilliland, president of the Fred Hutchinson Cancer Research Center in Seattle... 
Radiation, which was first used against cancer at the turn of the 20th century, can also turn cold tumors hot. In a study published in June, scientists led by radiation oncologist Dr. Ralph Weichselbaum of the University of Chicago Medical Center found exactly that in mice with pancreatic cancer, which is notorious for being nearly untreatable, as well as for not attracting tumor-destroying T cells. (The only immunotherapy having any effect on pancreatic cancer in people slowed tumor growth in a mere 8 percent of them.) 
“We think radiation turned a cold tumor into one that attracts T cells, while the immunotherapy kept the T cells from being disabled,” Weichselbaum said. “I think some cancers that aren’t now treated with radiation might be,” as long as immunotherapy follows." {my underlined emphasis} 
Dr. Weichselbaum's paper is here: "Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance," Oncotarget, Zheng et al., June 7, 2016.
The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy."
In Moffitt Cancer Center's upcoming SITC 2016 poster presentation of its PV-10-related work, "Intralesional injection with rose bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer," (Provectus press release) (a) Rose Bengal more than likely was administer before chemotherapy (not after, like in Weichselbaum's murine model work of radiation plus checkpoint inhibition), and (b) PV-10 plus chemotherapy induced, elicited, generated, etc. anti-tumor immunity, unlike Weichselbaum's work.

October 19, 2016

Turning [more anti-PD-1] non-responders into responders

Image source
Updated below: 10/19/16.

What is PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®), among other Big Pharma in the oncology space? In no particular order, is it, among other things:
  • As a primer, front-end, turner-on-of-the-engine, stepper-on-the-gas pedal, [insert your favorite over-, weakly- or wrongly-used analogy or metaphor],
  • Synergism, where from an efficacy perspective 1 + 1 >> 2,
  • Agnosticism to tumor type/cancer indication,
  • Safety profile, and/or
  • Turning cold tumors hot, and hot tumors hotter?
Industry discussion appears to recognize immune checkpoint inhibitors work — when/where they do work — in a portion of cancer patients. Is the summary clinical value proposition of PV-10 in combination with Keytruda/Opdivo to make the latter (i.e., these anti-PD-1 drugs) work better when and where they work? Or is PV-10's proposition, the more powerful one, to show it can make Keytruda/Opdivo work better where they do not work?

PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®) is that it (PV-10) can turn more anti-PD-1 non-responders into responders than any other partner drug or investigational compound.

For this blog post, consider, among other things, two combinations with pembrolizumab (for advanced melanoma):
  • Intralesional* agent electroporation with plasmid interleukin-12 (epIL-12) (ImmunoPulse, OncoSec), the combination of a medical device and an investigational agent, and
  • Intratumoral* agent toll-like receptor 9 (TLR9) agonist SD-101 (Dynavax), an investigational agent too.
* Intralesional = intratumoral

OncoSec. OncoSec announced in November 2014 it would combine ImmunoPulse and pembrolizumab, UC San Francisco and OncoSec Medical Collaborate to Evaluate Investigational Combination of ImmunoPulse and Anti-PD-1 Treatment. Data from this investigator-initiated study were presented at AACR 2016 (April), "Positive Melanoma Clinical Data at American Association for Cancer Research (AACR) Annual Meeting 2016," where patients initially were treated with ImmunoPulse and, then, some went to receive systemic anti-PD-1/PD-L1 therapy. Notably, however, OncoSec announced this month data from the same study would be presented at SITC 2016 (November), "Acceptance of Late Breaking Abstract at Upcoming Society for Immunotherapy of Cancer (SITC) Annual Meeting 2016," where the focus would be on [clinical data from] patients with a low likelihood of response to an anti-PD-1 alone (i.e., anti-PD-1 failures).

Dynavax. Dynavax and Merck & Co. announced a collaboration in June 2015, Investigating the Combination of Immuno-Oncology Therapies. Initial clinical data of the combination of SD-101 and pembrolizumab in patients with metastatic melanoma was presented at ESMO 2016, "Phase 1b/2, Open-Label, Multicenter, Dose-Escalation and Expansion Trial of Intratumoral SD-101 in Combination With Pembrolizumab in Patients with Metastatic Melanoma." Preclinical work on SD-101 was presented at AACR 2016 by Dynavax observed, "These data provide a strong rationale for the clinical assessment of SD-101 in combination with agents blocking the PD-1/PD-L1 pathway in patients unresponsive to PD-1 blockade alone." Dynavax and Merck jointly observed on their ESMO 2016 poster, "Preclinical studies suggest that the immunostimulatory effects of SD-101 might also boost the activity of PD-1 checkpoint inhibitor therapy. In mouse models, SD-101 converted anti-PD-1 non-responders into responders by increasing the quantity and quality of tumor-specific T cells." {my underlined emphasis}

In order for Provectus CTO Dr. Eric Wachter, PhD to put Provectus in a position to garner a collaboration with a Big Pharma and its immune checkpoint inhibitor, he has to provide a compelling demonstration of the features of PV-10 in combination with an anti-PD-1 drug like pembrolizumab (e.g., clinical trial PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma). The features of this demonstration would include (a) preliminary safety and efficacy results, (b) immune biomarkers to facilitate appropriate patient selection if and when the combination is approved, and, presumably, (c) the ability of PV-10 to better turn anti-PD-1 non-responders into responders.

Contesting anti-PD-1 non-responders into responders should be a big deal for Merck and Bristol-Myers because such contestation is all about eating more of the rest of the pie, much more so than fighting over the same sliver of it.

Updated (10/19/16): OncoSec. ref. "OncoSec (ONCS) Q4 2016 Earnings Call Transcript," Seeking Alpha

I referenced epIL-12 (and OncoSec) above because of the useful information regarding anti-PD-1 failures or non-responders. The oncology playing field continues to evolve, and combination therapy approaches clearly are evolving as well across multiple dimensions, like (i) determining which patients when and how [immune biomarkers], and (ii) expanding the addressable market from responders to non-responders.

Among other aspects of an analysis of epIL-12 (and OncoSec), which historically has been mentioned together with Amgen's T-Vec and Provectus' PV-10, like at ASCO 2014 (see "Expert Point of View: Axel Hauschild, MD," The ASCO Post, Caroline Helwick, July 25, 2014), (a) there does not appear to be an initial pathway to approval yet (if at all) for epIL-12 as a monotherapy and (b) the investigator-initiated study was neither designed nor powered to transition to a pivotal trial as a combination therapy. OncoSec hopes to secure agreement with (acquiescence by) the FDA on a pivotal/registration trial design by the end of the year. Initial pathways to approval, like what Provectus has with PV-10 as a monotherapy for locally advanced cutaneous melanoma, as with valuable beachfront property, is valuable drug treatment "real estate." Nevertheless, it is a good strategy for OncoSec to focus on PD-1 failures; using emerging biomarker data to select "likely" PD-1 failures, however, is likely to prove somewhat more challenging. It will be interesting to see how this plays out.

Dynavax. This is a true treatment combination and company collaboration (compared to the OncoSec treatment combination, for which the clinical trial protocol is here). The results are interesting, if not very preliminary (e.g., efficacy from 5 patients, measurement [for purposes of the ESMO 2016 abstract] was made after only 12 weeks). One would have hoped they could have provided a few more details (e.g, the number of injections of SD-101 [presumably 11 in total], more details on patient stage [particularly Stage IV, like M1a, M1b and/or M1c], what the grade 4 SAE was, etc.).

A 25% serious adverse event (SAE) rate seems a bit high, and this is kind of an odd way to report safety data; usually this is reported as CTCAE Grade 3 or higher events since this includes both severe AEs and the subset of those that qualify as SAEs. Robert et al. reported 10.1-13.3% rate of Grade 3 or higher AEs for pembrolizumab alone (NEJM 2015;372:26).

Notably, investigators/clinical sites on the poster included Agarwala/St. Luke's. The trial itself also is recruiting at Huntsman Cancer Institute (Andtbacka).

Since this is a collaboration with Merck, it would appear the Big Pharma is not requiring rigorous safety testing before the project moves to Phase 2 (a Merck staffer is a co-author on the ESMO 2016 poster). The poster's Methods section notes the trial is a dose-escalation and dose expansion study. It shows data from dose-escalation (i.e., 2 mg, 4 mg, 8 mg), but does appear to refer to the dose expansion portion, which normally would be additional patients at the highest tolerated dose. The N = 6 at 8 mg is dose expansion but, again, if Merck wants to green light this work to a Phase 2 trial, [as a Big Pharma] they probably are not going to get significant push-back from the FDA or institutional review boards (IRBs). If a small biotechnology company has a major player backing it, it is possible to do things that are not plausible for outsiders (i.e., the golden rule). Finally, this study might give Amgen pause, since SD-101 appears to function similarly to T-Vec, may produce a more robust effect than T-Vec and, most importantly, is not a live virus.

October 4, 2016


Edited (by me) image above; original image source
Let us take as given, finally in and by 2016, that PV-10 (chemical small [but heavy] molecule and halogenated xanthene Rose Bengal) is an immunotherapy

That is, the investigational compound is potentially capable of inducing the human body's immune system to mount a possibly worthy defense against solid tumor cancer after first being injected into lesions and tumors of said cancer.

That PV-10 has been independently shown to be that immunotherapy, at arms length from Provectus separately by both Moffitt Cancer Center (Moffitt) and the University of Illinois at Chicago (UIC) — reproducibility, the hallmark of Western Science— should make the claims about and data on PV-10 that much more veracious. See footnotes 1-5 below.

But let's now examine the notion, and growing preclinical and clinical evidence, that PV-10 treatment — singularly or in combination — potentially may lead to something greater and more profound than just the inducement or generation of an immune response....immunity.

AACR 2016 (April), Moffitt: T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model

2016 (May) peer-reviewed publication, Moffitt: Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1

SITC 2016 (November), Moffitt: Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer

Footnotes of non-Provectus biomedical research for "PV-10 is an immunotherapy:"
  1. SSO 2012, Moffitt: Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma In a Murine Model,
  2. 2013 peer-reviewed publication, Moffitt: Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer,
  3. SSO 2015, UIC: Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer,
  4. 2015 peer-reviewed publication, UIC: The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses, and
  5. ASO 2016, UIC: PV-10 Induces Potent Immunogenic Apoptosis in Colon Cancer Cells,

April 2016: Grant McArthur Discusses the Memory of Our Immune System

September 26, 2016

SITC 2016: Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer

Updated below: 9/26/16 {twice}, 9/28/16 and 9/30/16.

Click to enlarge
Updated (9/26/16): According to the Pancreatic Cancer Action Network, there are three chemotherapy drugs approved by the United States Food and Drug Administration (FDA) for the treatment of pancreatic cancer: albumin-bound paclitaxel (ABRAXANE®), gemcitabine (Gemzar®) and fluorouracil (5-FU).
"Gemcitabine (Gemzar®) was approved in 1996 for the treatment of unresectable pancreatic cancer. Studies have also shown that there is a benefit to using gemcitabine after surgery for pancreatic cancer. Prior to gemcitabine, fluorouracil (5-FU) was used as the standard treatment for unresectable pancreatic cancer. Both of these drugs are still used today. 
Most recently, in September 2013, albumin-bound paclitaxel (ABRAXANE®) was approved to be used in combination with gemcitabine (Gemzar®) as first-line treatment for metastatic pancreatic adenocarcinoma, the most common type of pancreatic cancer. 
In addition to the three FDA-approved drugs, FOLFIRINOX, a combination of three chemotherapy drugs (5-FU/leucovorin, irinotecan, and oxaliplatin) is commonly used in the treatment of metastatic pancreatic adenocarcinoma. In 2010, a Phase III clinical trial showed positive results for patients treated with FOLFIRINOX. Due to the results of this study, FOLFIRINOX is also considered a standard treatment option for patients with metastatic pancreatic cancer. However, patients treated with FOLFIRINOX may experience more severe side effects than those treated with gemcitabine alone, so this combination is usually given to patients who are healthy enough to tolerate the potential side effects."
Abraxane is made by Celgene. Gemzar is made by Eli Lilly. Provectus previously showed the combination of 5-FU and PV-10 for hepatocellular carcinoma in murine model work (SITC 2012).

Updated (9/26/16): I believe the systemic chemotherapy used in Moffitt's work is gemcitabine (Gemzar®), which by now is produced by generics manufacturers.

Some recent information on the competitive landscape for pancreatic cancer:
  • "Eli Lilly's chemotherapy drug Gemzar (gemcitabine) is widely considered the standard of care for pancreatic cancer. Generic gemcitabine is available from numerous companies" {January 2014 source},
  • "In the past, companies have combined various targeted treatments with gemcitabine in an attempt to increase their survival benefit. These efforts include Bristol-Myers Squibb/Eli Lilly's Erbitux, Roche's Avastin, Pfizer's Inlyta, and Amgen/Bayer's Nexavar, among others. Unfortunately, none of these drugs has shown a significant survival benefit when combined with gemcitabine" {above source},
    • "Frontline therapies for patients with metastatic pancreatic cancer have advanced in the past 5 years, with the FDA approval of nab-paclitaxel (Abraxane) plus gemcitabine (Gemzar). These advancements branch off the established treatment paradigm of gemcitabine monotherapy, which showed a significant extension in overall survival (OS) compared with 5-FU alone in a phase III study."
  • "Pancreatic cancer is a particularly tough cancer to treat and a number of other companies have failed in their efforts to develop an effective treatment. In February, Incyte halted trials of its drug Jakafi in solid tumors, after a Phase 3 study in pancreatic cancer failed to show efficacy. And this past May saw pancreatic cancer immunotherapies from NewLink Genetics and Aduro Biotech fall short of goal in Phase 3 and Phase 2b trials, respectively" {September 2016 source}, and
  • Momenta Pharmaceuticals has decided to end development of necuparanib, an experimental drug for advanced pancreatic cancer and the biotech's lead clinical candidate, according to a regulatory filing submitted Thursday. Enrollment in a Phase 2 trial testing necuparanib in combination with Celgene's Abraxane was halted earlier this month after an independent data safety monitoring board concluded treatment didn't demonstrate a sufficient level of efficacy {above source}.
Updated (9/28/16): In 2011 co-founder and former Chairman and CEO Dr. Craig Dees, PhD presented Provectus' murine model work examining PV-10's "immunologic potential in treating melanoma and other cancer indications including liver, pancreatic and colorectal cancer." See several pertinent slides below.
Click to enlarge
Click to enlarge
Click to enlarge
Updated (9/30/16): H/t @bradpalm1: Vitamin D + immunotherapy + chemotherapy..."Physicians and Physicists Join Forces to Fight Pancreatic Cancer," The Wall Street Journal, September 25th, Ron Winslow
"The team is planning a clinical trial soon in which patients who are candidates for pancreatic-cancer surgery first will be treated with synthetic vitamin D, chemotherapy and Bristol-Myers Squibb Co.’s cancer immunotherapy Opdivo. Opdivo is one of the new so-called checkpoint inhibitors that are transforming treatment of cancers such as melanoma and lung cancer. The drugs work by releasing brakes on immune-system T cells, enabling them to pursue tumor cells." 
Bristol-Myers also is combining Opdivo with several other companies and drugs to treat pancreatic cancer, such as Celgene (Abraxane/Paclitaxel protein-bound) and Aduro Biotech (CRS-207 and GVAX)*. Opdivo combination trials for pancreatic cancer on include at least eight studies.

* CRS-207 and GVAX failed as a regimen for pancreatic cancer.