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:
Click to enlarge
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
    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.