On November 16, 2020 Provectus (OTCQB: PVCT) reported that H. Lee Moffitt Cancer Center (Moffitt) presented non-clinical data from ongoing research on investigational autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary small molecule rose bengal disodium (RBD), as a single-agent and in combination with gemcitabine chemotherapy for the treatment of pancreatic cancer at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 35th Anniversary Annual Meeting & Pre-Conference Programs (SITC 2020), held online from November 9-14, 2020 (Press release, Provectus Biopharmaceuticals, NOV 16, 2020, View Source [SID1234571154]).
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RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupts these lysosomes, and causes the cancer cells to die. Intralesional (IL) (aka intratumoral) administration of PV-10 causes acute destruction of injected tumors, resulting in the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens. These signaling factors may initiate an immunologic cascade, where the innate immune system response may facilitate systemic anti-tumor immunity by the adaptive immune system. PV-10-mediated DAMP release may activate CD8+ T cells, CD4+ T cells, and NKT cells.
Moffitt’s poster presentation, authored by Innamarato et al. and entitled "Intralesional injection of rose bengal augments the efficacy of gemcitabine chemotherapy against pancreatic tumors," concluded:
PV-10 kills human and murine pancreatic tumor cells in vitro,
The combination therapy of PV-10 and gemcitabine reduces the growth rate of murine Panc02 tumors in vivo,
Immunogenic Panc02OVA tumors are more sensitive in vivo to single-agent PV-10,
The combination therapy reduces the growth of non-injected bystander Panc02OVA tumors in vivo, and
Reduced tumor growth after PV-10 treatment is associated with the release of DAMPs.
PV-10-mediated DAMP-release has been demonstrated in three different cancers, varying from immunologically "cold" to "hot" tumor types:
Pancreatic cancer: Innamarato et al., SITC (Free SITC Whitepaper) 2020 (Moffitt; non-clinical)
Colon cancer: Qin et al., Cell Death and Disease 2017 (University of Illinois at Chicago; non-clinical), and
Melanoma: Liu et al., Oncotarget 2016 (Moffitt; clinical and non-clinical).
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "We are grateful to the leadership and researchers of the Pilon-Thomas Lab at Moffitt Cancer Center for their translational investigation of cancer immunotherapy PV-10 in melanoma, breast cancer, and now pancreatic cancer. The non-clinical results presented at this year’s annual meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) demonstrate that intralesional administration of PV-10 can enhance the efficacy of gemcitabine chemotherapy against pancreatic tumors."
Mr. Rodrigues added, "A key aspect of our drug development strategy for intralesional administration of PV-10 in solid tumor cancers is targeting disease indications where there is high unmet need among patients, limited activity from approved therapies, and the opportunity to display the contribution of PV-10’s functional immune response to successful patient treatment outcomes. Pancreatic cancer is a deadly disease for which PV-10 could enhance standard of care chemotherapy."
A copy of the poster presentation is available on Provectus’ website at View Source
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. The Company manufactures cGMP RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients.
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. By targeting tumor cell lysosomes, RBD treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1,2,3 Adaptive immunity can be enhanced by combining immune checkpoint blockade (CB) with RBD.4 IL PV-10 is undergoing clinical study for relapsed and refractory adult solid tumor cancers, such skin and liver 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.5,6
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.7
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.8,9
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.
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.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.
RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,14, external collaborators5, and other researchers15,16,17 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.5
Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of 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.9
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. Wachter et al. Functional Imaging of Photosensitizers using Multiphoton Microscopy. Proceedings of SPIE 4620, 143, 2002.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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 (Free ASCO Whitepaper) Annual Meeting, J Clin Oncol 36, 2018 (suppl; abstr 10557).
7. 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.
8. Swift et al. In Vitro Activity and Target Modulation of PV-10 Against Relapsed and Refractory Pediatric Leukemia. 2018 ASH (Free ASH Whitepaper) Annual Meeting, Blood 132, 2018 (suppl; abstr 5207).
9. 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 (Free AACR Whitepaper) VAM II, (abstr 5393).
10. Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.
11. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.
12. Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.
13. Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.
14. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.
15. Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.
16. 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.
17. 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.