RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupts these lysosomes, and causes the cells to die. Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumors can yield immunogenic cell death and induce tumor-specific reactivity in circulating T cells.1-3
The abstract accepted for poster presentation at SITC 2020 is entitled “Intralesional injection of rose bengal augments the efficacy of gemcitabine chemotherapy against pancreatic tumors” (Abstract ID: 585; Category: Immune-stimulants and immune modulators). Moffitt co-authors include
This pancreatic cancer work was led by
- “Intralesional injection of rose bengal induces a systemic tumor-specific immune response in murine models of melanoma and breast cancer” (Toomey et al., PLoS One 2013),
- “Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1” (Liu et al., Oncotarget 2016), and
- “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” (Liu et al., PLoS One 2018).
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.1-3 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
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 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
Orphan Drug Designations (ODDs)
ODD status has been granted to RBD by the
Intellectual Property (IP)
Provectus’ IP includes a family of US and international (a number of countries in
The Company's IP also includes a family of US and international (a number of countries in
About Provectus
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 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
8. 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).
9. Thakur et al. Association of heat shock proteins as chaperone for
10. Piao et al. Targeting the lysosome in cancer. Annals of the
11. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells.
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.
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.
16. Zamani et al.
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,
FORWARD-LOOKING STATEMENTS: The information in this press release may include “forward-looking statements,” within the meaning of
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
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