KNOXVILLE, TN, Jan. 20, 2021 (GLOBE NEWSWIRE) -- Provectus (OTCQB: PVCT) today announced that H. Lee Moffitt Cancer Center (Moffitt) has released a manuscript preprint describing how investigational autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary small molecule rose bengal disodium (RBD), in combination with gemcitabine may enhance the chemotherapy’s efficacy against pancreatic tumors. Chemotherapy regimens that include gemcitabine are the standard of care for the treatment of pancreatic cancer.
The manuscript, entitled “Intralesional injection of Rose Bengal augments the efficacy of gemcitabine chemotherapy against pancreatic tumors,” is available at the following link: https://assets.researchsquare.com/files/rs-140621/v1/cb1df721-b58b-4f5d-9ba6-1b8b2880391d.pdf.
Moffitt co-authors/researchers Patrick Innamarato, Jennifer Morse, Amy Mackay, Sarah Asby, Matthew Beatty, Jamie Blauvelt, Scott Kidd, John Mullinax, Amod Sarnaik, and Shari Pilon-Thomas showed that:
- The injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation,
- The combination of PV-10 and systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of untreated distal tumors,
- The combination was markedly more successful in immunogenic tumors that express the neoantigen ovalbumin, suggesting PV-10 and gemcitabine enhanced the immune clearance of tumors, and
- The regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of myeloid-derived suppressor cells (MDSCs) and increases in damage associated molecular patterns (DAMPs) high-mobility group box 1 (HMGB1), S100A8, and interleukin-1α.
HMGB1, S100A8, and interleukin-1α are dual-function alarmins that have key intracellular and extracellular functions1 (alarmins are a subgroup of the larger set of DAMPs). PV-10 treatment-mediated DAMP-release has been demonstrated in three different tumor types: melanoma, colon cancer, and now pancreatic cancer.
Intralesional (IL) PV-10 treatment alone or in combination with gemcitabine was capable of inducing the complete regression of injected pancreatic tumors, while gemcitabine monotherapy failed to induce complete regressions. This suggested that increased pancreatic tumor burden, which diminished gemcitabine efficacy, was overcome when PV-10 was combined with gemcitabine.
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, “Moffitt’s preclinical data, which show PV-10 improves chemotherapy’s efficacy against pancreatic cancer, are consistent not only with preclinical data showing synergistic activity of PV-10 and either chemotherapy or radiation against relapsed and refractory neuroblastoma, but with clinical data that demonstrate PV-10 enhances the efficacy of immune checkpoint blockade in checkpoint-naïve and checkpoint-refractory metastatic melanoma and metastatic uveal melanoma, and of radiotherapy in in-transit and metastatic melanoma.”
Mr. Rodrigues added, “A strategic aim of Provectus’ drug development program is to show that PV-10 can be a universal contributor in a variety of different cancer combination therapies. Improving the efficacy of standard-of-care chemotherapy against pancreatic cancer is just one example of how Provectus and PV-10 can help make the biotechnology social contract a reality.”
About PV-10
Intralesional (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.2,3,4 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with CB.5 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver.
About Rose Bengal Disodium
RBD is 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. Provectus' current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company's quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus' RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.
An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers.
IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.6,7
A topical formulation of cGMP RBD drug substance, PH-10®, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.8
Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.9,10
Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.
Different formulations of cGMP RBD are also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.
Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis
Tumor Cell Lysosomes as the Seminal Cancer Drug Target
Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.
Building on the Discovery, Exploration, and Characterization of Lysosomes
Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.11 Cancer progression and metastasis are associated with lysosomal compartment changes12,13, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance14.
RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus2,15, external collaborators6, and other researchers16,17,18 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.
Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.6
Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.10
Orphan Drug Designations (ODDs)
ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.
Intellectual Property (IP)
Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.
The Company's IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942.
About Provectus
Provectus Biopharmaceuticals, Inc. (Provectus or the Company) is a clinical-stage biotechnology company developing immunotherapy medicines for different disease areas based on an entirely- and wholly-owned family of small molecules called halogenated xanthenes. Information about the Company’s clinical trials can be found at the National Institutes of Health (NIH) registry, www.clinicaltrials.gov. For additional information about Provectus, please visit the Company's website at www.provectusbio.com.
References
1. Bertheloot et al. HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cellular & Molecular Immunology 14(1):43-64, 2017.
2. Wachter et al. Functional Imaging of Photosensitizers using Multiphoton Microscopy. Proceedings of SPIE 4620, 143, 2002.
3. Liu et al. Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1. Oncotarget 7, 37893, 2016.
4. Qin et al. Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death. Cell Death and Disease 8, e2584, 2017.
5. Liu et al. T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model. PLoS One 13, e0196033, 2018.
6. Swift et al. Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory neuroblastoma. OncoTargets and Therapy 12, 1293, 2019.
7. Swift et al. In vitro and xenograft anti-tumor activity, target modulation and drug synergy studies of PV-10 against refractory pediatric solid tumors. 2018 ASCO Annual Meeting, J Clin Oncol 36, 2018 (suppl; abstr 10557).
8. Krueger et al. Immune Modulation by Topical PH-10 Aqueous Hydrogel (Rose Bengal Disodium) in Psoriasis Lesions. Psoriasis Gene to Clinic, 8th International Congress, Br J Dermatol 177.
9. Swift et al. In Vitro Activity and Target Modulation of PV-10 Against Relapsed and Refractory Pediatric Leukemia. 2018 ASH Annual Meeting, Blood 132, 2018 (suppl; abstr 5207).
10. Thakur et al. Association of heat shock proteins as chaperone for STING: A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10. 2020 AACR VAM II, (abstr 5393).
11. Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.
12. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.
13. Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.
14. Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.
15. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.
16. Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.
17. Zamani et al. Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Journal of Immunotoxicology, 11(4), 367, 2014.
18. Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.
Trademarks
PV-10® and PH-10® are registered trademarks of Provectus, Knoxville, Tennessee, U.S.A.
FORWARD-LOOKING STATEMENTS: The information in this press release may include “forward-looking statements,” within the meaning of U.S. securities legislation, relating to the business of Provectus and its affiliates, which are based on the opinions and estimates of Company management and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Forward-looking statements are often, but not always, identified by the use of words such as “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “project,” “predict,” “potential,” “targeting,” “intend,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook.
The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any particular revenue levels.
Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in this press release are made as of the date hereof or as of the date specifically specified herein, and Provectus undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement.
Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the SEC, including those described in Item 1A of the Company’s Annual Report on Form 10-K for the year ended December 31, 2019 and Provectus’ Quarterly Report on Form 10-Q for the quarter ended September 30, 2020.
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Contact:
Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer
Phone: (866) 594-5999