On June 4, 2021 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported two trial in progress posters, on the Phase 1 INNATE clinical trial and the Phase 2 SELECT clinical trial, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting (Press release, Jounce Therapeutics, JUN 4, 2021, View Source [SID1234583507]). INNATE, a proof-of-concept (POC) trial, is evaluating Jounce’s lead macrophage program JTX-8064 (anti-LILRB2/ILT4 inhibitor) as a monotherapy and in combination with pimivalimab (anti-PD-1 inhibitor, formerly known as JTX-4014) in patients with a variety of advanced solid tumors. SELECT, Jounce’s second POC trial, is evaluating pimivalimab as a monotherapy and in combination with vopratelimab (ICOS agonist) in a novel biomarker selection paradigm in PD-(L)1 naïve non-small cell lung cancer patients.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Our INNATE trial is rapidly progressing through dose escalation and we are on-track to begin indication-specific, POC, monotherapy and pimivalimab combination expansion cohorts in the second half of this year," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "Furthermore, we are excited to announce the expansion cohort indications for INNATE, which were selected using our translational data-driven approach, linking JTX-8064’s mechanism to tumor types in three groups of patients including: PD-(L)1 inhibitor experienced and resistant, PD-(L)1 inhibitor naïve and historically resistant, and PD-(L)1 inhibitor and historically more sensitive. JTX-8064 is one of only two clinical-stage LILRB2 programs in development and we expect it to be the first program to initiate expansion cohorts in four of our chosen tumor types. We are also pleased to see TISvopra positivity rates tracking with expectations in our biomarker selection trial, SELECT, and we remain on-track to report data next year."

Poster Presentation Details:

Poster Title: Phase 1, First-in-Human trial of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody, as monotherapy and in combination with anti-PD-1 in adult patients with advanced solid (INNATE)
Presenter: Kyriakos P. Papadopoulos, MD, South Texas Accelerated Research Therapeutics (START), San Antonio, TX
Session Title: Developmental Therapeutics – Immunotherapy
Abstract Number: TPS2672
Date and Time: Friday, June 4, 2021; 9:00am ET
Highlights from the trial in progress poster include the selection criteria for expansion cohorts in the ongoing Phase 1 INNATE trial and an outline the future biomarker plan:

Expansion cohort selection was informed using human histoculture and gene signature analysis from Jounce’s Translational Science Platform and includes PD-(L)1 naïve and experienced patients as well as PD-(L)1 sensitive and resistant tumor types.
The INNATE trial is divided into 4 stages with indication-specific expansion cohorts intended to establish proof-of-concept for JTX-8064:
JTX-8064 monotherapy dose escalation in relapsed / refractory solid tumors
JTX-8064 plus pimivalimab dose escalation in relapsed / refractory solid tumors
JTX-8064 monotherapy expansion in PD-(L)1i naïve platinum resistant ovarian cancer
JTX-8064 plus pimivalimab expansions in:
PD-(L)1i naïve platinum resistant ovarian cancer
PD-(L)1i naïve head and neck squamous cell carcinoma (HNSCC)
PD-(L)1i naïve undifferentiated pleomorphic sarcoma (UPS) and liposarcoma (LPS)
PD-(L)1i experienced non-small cell lung cancer (NSCLC)
PD-(L)1i experienced clear cell renal cell carcinoma (ccRCC)
PD-(L)1i experienced triple negative breast cancer (TNBC)
PD-(L)1i experienced cutaneous squamous cell carcinoma (cSCC).
The dose for expansion cohorts will be selected based on safety, pharmacokinetic and receptor occupancy data from the monotherapy dose escalation stage of INNATE.
Archival and pre-treatment tumor biopsies as well as pre- and post-treatment blood samples will be collected to evaluate a number of potential predictive and pharmacodynamic biomarkers using Jounce’s Translational Science Platform.
Poster Title: Phase 2 Study of PD-1 Inhibitor JTX-4014 (Pimivalimab) Alone and in Combination with Vopratelimab, an ICOS Agonist, in Biomarker-selected Subjects with Metastatic NSCLC After One Prior Platinum-containing Regimen (SELECT)
Presenter: Oleh Kobziev, MD, Regional Center of Oncology, Kharkiv, 61070, Ukraine
Session Title: Lung Cancer – Non-Small Cell Metastatic
Abstract Number: TPS9137
Date and Time: Friday, June 4, 2021; 9:00am ET

The SELECT trial is currently enrolling approximately 75 immunotherapy naïve NSCLC patients who have been pre-selected with the TISvopra predictive biomarker

TISvopra may serve as a unique biomarker for potential increased benefit for both pimivalimab monotherapy as well as pimivalimab in combination with vopratelimab.
Data from Jounce and a third-party ICOS agonist program support an ICOS-focused biomarker selection strategy to identify patients that may benefit from ICOS agonism.
Early screening data from SELECT support Jounce’s estimate that approximately 20% of PD-(L)1i naïve non-small cell lung cancer patients tested for TISvopra in the study would meet the TISvopra positivity threshold.
SELECT is on-track to report clinical data in 2022.
Both posters will be available on the "Our Pipeline" section of the Jounce Therapeutics website under "Publications" at www.jouncetx.com.

About JTX-8064

JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1 clinical trial named INNATE (NCT04669899) of JTX-8064 as a monotherapy and in combination with Jounce’s internal anti-PD-1 inhibitor, pimivalimab (formerly JTX-4014) is currently enrolling patients with advanced solid tumors.

About Pimivalimab

Pimivalimab (formerly JTX-4014) is a well-characterized fully human IgG4 monoclonal antibody designed to block binding to PD-L1 and PD-L2. Pimivalimab demonstrated a 17% durable overall response rate in a Phase 1 trial of 18 heavily pre-treated PD-(L)1 inhibitor naïve patients, which excluded all tumor types for which PD-(L)1 inhibitors were approved. In this Phase 1 trial, pimivalimab was shown to have an acceptable safety profile. Pimivalimab is currently being assessed in the INNATE Phase 1 trial (NCT04669899) in combination with JTX-8064, a LILRB2 (ILT4) inhibitor. Pimivalimab is also being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with vopratelimab, a clinical-stage monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO-Stimulator, a protein on the surface of certain T cells commonly found in many solid tumors.

About Vopratelimab

Vopratelimab is a clinical-stage monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO-Stimulator, a protein on the surface of certain T cells commonly found in many solid tumors. Vopratelimab is currently being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with Jounce’s internal investigational PD-1 inhibitor, pimivalimab (formerly JTX-4014), compared to pimivalimab alone. The SELECT trial is currently enrolling approximately 75 immunotherapy naïve NSCLC patients who have been pre-selected with the TISvopra predictive biomarker, an 18 gene RNA tumor inflammation signature which predicted the emergence of ICOS hi CD4 T cells and clinical benefit in the ICONIC trial of vopratelimab alone and in combination with a PD-1 inhibitor. SELECT is powered to demonstrate the statistical superiority of the combination of vopratelimab plus pimivalimab compared to pimivalimab.

On June 4, 2021 Glycotope GmbH, a biotechnology company developing antibodies against proteins carrying tumor-specific carbohydrate structures, reported it is presenting two posters at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held virtually this year due to COVID-19 (Press release, Glycotope, JUN 4, 2021, View Source [SID1234583526]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Henner Kollenberg, Managing Director of Glycotope GmbH commented: "The data presented at ASCO (Free ASCO Whitepaper) highlight our ability to draw on our long-standing expertise in glyco-biology to generate novel biopharmaceuticals targeting cancer indications. The data showed that a Glycotope-developed anti-TA-MUC1 antibody combined with the anti-EGFR Tomuzotuximab or Panitumumab in patients with refractory solid tumors is safe and feasible and exhibited interesting anti-tumour activity."

Poster details are as follows:

Poster 2524

Title: Safety and tolerability results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody Gatipotuzumab with the anti-EGFR Tomuzotuximab or Panitumumab in patients with refractory solid tumors
Session: Poster Session: Developmental Therapeutics—Immunotherapy
Abstract ID: 332635

Download: View Source

Poster 2522
Title: Activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody Gatipotuzumab with the anti-EGFR Tomuzotuximab or Panitumumab in patients with refractory solid tumors

Session: Poster Session: Developmental Therapeutics—Immunotherapy
Abstract ID: 329709

On June 4, 2021 Notable Labs Inc., a leader in technology-powered life science with a proprietary platform for predicting patient outcomes and accelerating precision drug development, reported top-line results from its clinical response prediction technology platform in a pediatric acute myeloid leukemia (AML) study to be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held June 4th-8th (Press release, Notable Labs, JUN 4, 2021, View Source [SID1234583542]). The data will be presented by Dr. Alexandra Stevens at Texas Children’s Cancer Center and highlights the correlation of functional drug sensitivity screening using Notable’s predictive technology platform with clinical outcomes of pediatric patients.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In the exploratory study, blood or bone marrow samples from 22 de novo pediatric AML patients prior to receiving pre-induction chemotherapy were processed using Notable’s predictive technology platform. Chemosensitivity profiles across a broad spectrum of ex vivo conditions were analyzed and integrated into a predictive measure for individual patients. This measure of ex vivo drug sensitivity correlated with the patients’ clinical results of minimal residual disease and one year relapse-free survival.

"Our collaboration with one of the leading pediatric medical centers further demonstrates the potential of Notable’s prediction technology in identifying and fast-tracking combination therapies in a real-world situation." said Dr. Thomas Bock, CEO of Notable. Dr. Stevens added, "These results are a critical step forward towards our vision of precision medicine where treatments are focused on those patients who will clinically respond, especially for hard-to-treat patient populations."

Details of the presentation are as follows:

Poster Presentation

Title: Ex Vivo Drug Sensitivity Assay Correlates with Clinical Response in Pediatric AML
Session Name: Poster Session: Pediatric Oncology
Abstract Number: 10032
Presentation Time: Available beginning June 4th, 2021

On June 4, 2021 Surface Oncology (Nasdaq: SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported a clinical trial collaboration with Roche to evaluate SRF388, Surface’s investigational anti-IL-27 antibody, in combination with Roche’s atezolizumab and bevacizumab in patients with treatment-naïve hepatocellular carcinoma (HCC) (Press release, Surface Oncology, JUN 4, 2021, View Source [SID1234583559]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Atezolizumab plus bevacizumab has been shown to significantly improve overall survival and, as reflected in many global clinical practice guidelines, is the new standard of care for unresectable or metastatic HCC. Evolving preclinical and epidemiologic data suggest a significant role for the immunosuppressive cytokine IL-27 in HCC and in resistance to PD-1 pathway blockade. Therefore, the addition of SRF388 to the proven efficacy of the atezolizumab/bevacizumab regimen has the potential to further improve outcomes in this challenging disease.

"At Surface, we are committed to identifying and accelerating the delivery to patients of life-changing treatments, whether as a single agent or in scientifically and clinically appropriate combinations," said Alison O’Neill, M.D., chief medical officer at Surface Oncology. "This collaboration leverages Roche’s deep experience in hepatocellular carcinoma and Surface’s commitment to rationally and rapidly develop SRF388, a first-in-class antibody against IL-27, to provide meaningful benefit to patients with liver cancer."

About SRF388:
SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine. Surface Oncology has identified particular tumor types, including liver and kidney cancer, where IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors. SRF388 targets the rate-limiting p28 subunit of IL-27, and preclinical studies have shown that treatment with SRF388 blocks the immunosuppressive biologic effects of IL-27, resulting in immune cell activation in combination with other cancer therapies including anti-PD-1 therapy, as well as potent anti-tumor effects as a monotherapy. Furthermore, Surface Oncology has identified a potential biomarker associated with IL-27 that may be useful in helping to identify patients most likely to respond to SRF388. In November 2020, Surface announced that SRF388 was granted Orphan Drug designation and Fast Track designation for the treatment of hepatocellular carcinoma from the FDA.

On June 4, 2021 Provectus (OTCQB: PVCT) reported that preliminary full study data from the Company’s Phase 1 clinical trial of investigational cancer immunotherapy PV-10 (rose bengal disodium) for the treatment of neuroendocrine tumors (NET) metastatic to the liver (mNET) refractory to somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) (NCT02693067) is be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting, held June 4-8 online (Press release, Provectus Biopharmaceuticals, JUN 4, 2021, View Source [SID1234583575]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Highlights from the mNET Presentation at ASCO (Free ASCO Whitepaper) 2021:

Baseline and disease characteristics
12 patients; 50% male; median age of 66 years (range 47-79)
Primary tumor sites: 7 small bowel (58%), 2 pancreas (17%), 1 caecal (8%), and 2 unknown (17%)
NET grades: 5 Grade 1 (42%) and 7 Grade 2 (58%)
Refractory to SSA and PRRT; symptomatic progressive disease
PV-10 treatment summary
Median of 1 hepatic NET lesion injected (range 1-4); median of 1 injection cycle (range 1-4); 8 patients (75%) received 1 PV-10 treatment
Safety
Mild-to-moderate post-procedure pain reported by most patients
Grade 3 photosensitivity reaction in 1 patient, Grade 3 elevation of hepatic enzymes in 1 patient, and carcinoid flare in 2 patients
Injected lesion efficacy (RECIST 1.1)
42% partial response (PR) and 42% objective response rate (ORR)
Patient-level efficacy (RECIST 1.1)
83%a disease control rate (DCR)
Progression-free survival (PFS): median 9.2 months (range 1.0-41.8)
Overall survival (OS): median 22.5 months (range 5.5-41.8); 6 patients (50%) undergoing response follow-up at the data cut-off of April 30, 2021
Immune response
Upregulation of NK cells and activated CD4+ T cells was observed in peripheral blood collected 7 and 28 days post-PV-10 injection
Biomarkers and quality of life (QOL)
Chromogranin A levels remained stable in 10 patients (83%)
QOL assessments showed stable or improved carcinoid symptoms and global health status in most patients
a Typographical error on the poster

A copy of the poster is available on Provectus’ website at View Source

This clinical trial, a single-center study at The Queen Elizabeth Hospital (TQEH) in Adelaide, Australia that completed enrollment in 2020, is led by Tim Price, MBBS, DHlthSc (Medicine), FRACP, Head of Clinical Oncology Research and Chair of the combined Hematology and Medical Oncology Unit at TQEH and Clinical Professor in the Faculty of Medicine at the University of Adelaide. The primary endpoint of the trial is safety. Secondary endpoints include ORR of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Disease response assessments are conducted by independent review using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the six-person second cohort can receive PV-10 injections of multiple lesions per cycle.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "The vast majority of patients with neuroendocrine cancer present with liver metastases, and their prognosis is poor. PV-10 treatment of these hepatic tumors in heavily pre-treated patients resulted in durable systemic clinical benefit and evidence of immunotherapeutic activity in an otherwise immunologically cold tumor type."

Mr. Rodrigues added, "Provectus’ PV-10 development program for visceral hepatic tumors, led by more recent clinical study of neuroendocrine cancer and uveal melanoma, has not elicited any safety concerns and provided encouraging evidence of local and systemic response and disease control in refractory patient populations. Numerous liver metastases of defined tumor types have been treated in this program, including hepatoma, colorectal, lung, pancreatic, ovarian, cutaneous melanoma, breast, neuroendocrine, and uveal melanoma."

About PV-10

Intralesional (IL) 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.1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB).4 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. Systemic administration of PV-10 is also undergoing preclinical study as prophylactic and therapeutic treatments for refractory and high-risk adult solid tumor cancers, and as a treatment for relapsed and refractory blood cancers.

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.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.

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.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. Provectus2,14, 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 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

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 (i.e., 16/678,133), which has been allowed.