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T3 Pharma raises 25M CHF to advance bacterial cancer therapy through clinic

On July 22, 2020 T3 Pharmaceuticals AG ("T3 Pharma"), a Swiss biotech advancing immuno-oncology with its bacteria-based protein delivery platform, reported the closing of its third financing round, raising over 25M CHF (Press release, T3 Pharmaceuticals, JUL 22, 2020, View Source [SID1234562255]).

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The financing was co-led by existing investors, including the Boehringer Ingelheim Venture Fund (BIVF), Reference Capital SA, Wille Finance AG and private investors, who all participated in the round. This latest financing brings T3 Pharma’s total funding since the launch of the Company in 2015 to 40 million CHF.

T3 Pharma will use the funds primarily to progress its lead candidate, T3P-Y058-739, through clinical studies. The Phase 1/2 clinical study in solid tumors is planned to start in early 2021.

T3P-Y058-739 is the first therapeutic candidate developed using T3 Pharma’s proprietary protein delivery platform. The technology is built on the discovery that the bacterial type III secretion (T3S) system can be repurposed to deliver chosen proteins into eukaryotic cells.1 T3 Pharma’s live bacteria vehicles have been optimised to accumulate and grow selectively at solid tumors, where they produce and deliver the therapeutic protein.

Dr. Simon Ittig, T3 Pharma’s CEO, commented: "This significant financing round comes at a pivotal moment for our company as we leverage the full potential of our proprietary platform and enter the clinic with our lead candidate. We are grateful to our investors for their continued support."

"Our novel approach to deliver bioactive proteins selectively to cancerous cells using live bacteria has the potential to revolutionize treatment of solid tumors," added Dr. Olivier Valdenaire, Chairman of the Board.

Dr. Frank Kalkbrenner, Global Head of BIVF, commented: "Since I joined the Board last year, I have been impressed not only by the technology, but also by the team and the approach they have taken to building T3 Pharma’s innovative, differentiated platform and progressing its lead candidate. It is an endorsement of the quality of the science and the team that another financing round has been completed with an exceptional group of investors, which share our vision of improving the lives of cancer patients."

Cullinan Oncology Launches Cullinan Amber to Pioneer Next-Generation Cytokine Fusion Proteins for Cancer Therapy

On July 22, 2020 Cullinan Oncology, LLC reported the launch of Cullinan Amber, a company focused on developing a next generation immuno-oncology platform to enhance the therapeutic window of immune-stimulatory cytokine combinations for the treatment of cancer (Press release, Cullinan Oncology, JUL 22, 2020, View Source [SID1234562254]). Cullinan Amber has acquired an exclusive license from the Massachusetts Institute of Technology for technology based on the seminal work of K. Dane Wittrup, the C. P. Dubbs Professor in Chemical Engineering and Biological Engineering, to develop novel multifunctional constructs that are retained in the tumor microenvironment via collagen binding, which enables prolonged local activity of immunostimulatory cytokine combinations. Cullinan Amber’s lead program is a single agent comprised of two potent antitumor cytokines, interleukin-12 (IL-12) and interleukin-2 (IL-2), along with a collagen-binding domain. IND-enabling studies are expected to commence in 2H20.

"We are delighted to have the opportunity to work with Dane and his team," stated Patrick Baeuerle, Chief Scientific Officer, Biologics and co-founder of Cullinan Oncology. "The Wittrup lab has developed a pioneering approach that we believe has the potential to combine and finally enable pro-inflammatory cytokines to realize their full potential as effective, safe and well-controlled cancer therapeutics."

"Historically, numerous studies have shown that cytokine combinations, including IL-12 and IL-2, can synergistically enhance both innate and adaptive immunity, and mediate impressive antitumor activity across a range of preclinical tumor models," stated Jon Wigginton, Chief Medical Officer of Cullinan Oncology. "Clinically, however, many cytokines have been limited by systemic toxicity, and were developed without the benefit of key learnings regarding dosing, supportive care and patient selection that have emerged in the field of immuno-oncology."

To address this challenge, the Wittrup Lab, as described in a groundbreaking publication in the June 2019 issue of Science Translational Medicine (Momin et al., 26 June 2019), fused various cytokines to a collagen-binding protein and injected them directly into the tumor, which effectively retained the cytokines locally, minimized their systemic dissemination and toxicities, and prolonged their anti-tumor activity. Most importantly, non-injected tumors likewise shrank in response to therapy due to the induction of a systemic immune response.

First Patient Enrolled in Novocure’s EF-33 Phase 2 Pilot Trial of Tumor Treating Fields Delivered Utilizing High-Intensity Transducer Arrays

On July 22, 2020 Novocure (NASDAQ: NVCR) reported that the first patient has been enrolled in its EF-33 phase 2 pilot trial of Tumor Treating Fields delivered utilizing high-intensity arrays in patients with recurrent glioblastoma (GBM) (Press release, NovoCure, JUL 22, 2020, View Source [SID1234562253]). Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division.

Tumor Treating Fields survival benefit has shown a positive correlation with electric field intensity. The Optune system currently delivers Tumor Treating Fields therapy for the treatment of GBM using four transducer arrays with nine ceramic discs each. To increase field intensity, Novocure designed high-intensity arrays with 14 ceramic discs each for use in the EF-33 study. Increasing the surface area of the array is expected to enable delivery of higher field intensities while maintaining the treatment’s safety profile.

"Building upon a foundation of compelling preclinical and clinical evidence, we continue to expand our product development programs to support our mission to extend survival in some of the most aggressive forms of cancer," said William Doyle, Novocure’s Executive Chairman. "We believe we have a considerable opportunity to improve Tumor Treating Fields delivery systems through product innovation and are very pleased to bring the first high-intensity arrays to the clinic. We look forward to sharing data from these programs in future quarters."

EF-33 is an open-label, single-arm clinical trial to study if Optune delivered at 200 kHz to the brain using high-intensity arrays in the treatment of recurrent GBM significantly improves the clinical outcomes of patients compared to using standard transducer arrays. The study will enroll 25 patients with a minimum follow-up of six months. Patients will remain on Optune until disease progression. The primary endpoint of EF-33 is progression free survival. Secondary endpoints include overall survival, progression free survival rate at six months, overall survival rate at one year and two years, overall radiological response, and severity and frequency of adverse events. All comparisons will be made against historical control data from Novocure’s EF-11 study. Final data from the study is expected in 2022, at which point Novocure will determine the appropriate regulatory pathway for potential commercial use.

About Optune

Optune is a noninvasive, antimitotic cancer treatment for GBM. Optune delivers Tumor Treating Fields to the region of the tumor.

Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division. Tumor Treating Fields does not stimulate or heat tissue and targets dividing cancer cells of a specific size. Tumor Treating Fields causes minimal damage to healthy cells. Mild to moderate skin irritation is the most common side effect reported. Tumor Treating Fields is approved in certain countries for the treatment of adults with GBM and in the U.S. for MPM, two of the most difficult cancer types to treat. The therapy shows promise in multiple solid tumor types – including some of the most aggressive forms of cancer.

Approved Indications (U.S.)

Optune is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM).

Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy.

For the treatment of recurrent GBM, Optune is indicated following histologically- or radiologically-confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

Important Safety Information

Contraindications

Do not use Optune in patients with GBM with an implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective.

Use of Optune for GBM together with implanted electronic devices has not been tested and may lead to malfunctioning of the implanted device.

Do not use Optune for GBM in patients known to be sensitive to conductive hydrogels. Skin contact with the gel used with Optune may commonly cause increased redness and itching, and may rarely lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions

Optune can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure.

The most common (≥10%) adverse events involving Optune in combination with chemotherapy in patients with GBM were thrombocytopenia, nausea, constipation, vomiting, fatigue, convulsions, and depression.

The most common (≥10%) adverse events related to Optune treatment alone in patients with GBM were medical device site reaction and headache. Other less common adverse reactions were malaise, muscle twitching, and falls related to carrying the device.

If the patient has an underlying serious skin condition on the treated area, evaluate whether this may prevent or temporarily interfere with Optune treatment.

Do not prescribe Optune for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune in these populations have not been established.

Transgene Reports Results from Clinical Study of TG4001 in Combination with Avelumab in Advanced HPV-Positive Cancers

On July 22, 2020 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that performed a pooled analysis of the data from the Phase 1b/2 trial combining TG4001, a HPV16 targeted therapeutic vaccine, with avelumab (BAVENCIO), a human anti-PD-L1 antibody, in HPV16-positive recurrent and/or metastatic malignancies (Press release, Transgene, JUL 22, 2020, View Source [SID1234562252]). This analysis confirms that TG4001 can be safely combined with an immune checkpoint inhibitor and shows clinical activity of this combination regimen. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer.

The purpose of this exploratory Phase 1b/2 trial was to evaluate the safety and efficacy of the combination of TG4001 and an immune checkpoint inhibitor in a heterogeneous group of patients with aggressive, recurrent and/or metastatic HPV16-positive cancer. Clinical activity was observed in the overall study population (34 evaluable patients with oropharyngeal, anal, cervical, or other HPV16-positive cancers). In addition, Transgene has identified a selection criterion corresponding to patients showing particularly promising clinical activity in this trial. For more than 50% of these patients, the disease had not progressed at 12 weeks, compared to an expected median progression-free survival (PFS) of 8 weeks for this population with current treatment regimens [*].

Consistent with data presented at ESMO (Free ESMO Whitepaper) 2019 [1], durable responses have been observed in most of the responder patients. Transgene is currently completing translational analyses. Patient follow-up is still ongoing. Complete data will be presented at an upcoming scientific conference.

Transgene has stopped the trial in its current design. The Company intends to continue the clinical development of TG4001 in a larger, controlled confirmatory study.

All patients enrolled in the trial had an aggressive, recurrent and/or metastatic HPV16+ cancer that had progressed after one to three lines of chemotherapy. As previously reported [1], no new safety signals were observed.

Commenting on this novel immunotherapy regimen, Prof. Christophe Le Tourneau, MD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, and Principal Investigator of the trial, added: "The first results from this exploratory Phase 1b/2 trial are clearly encouraging. I believe that the response rate and the clinical outcomes of the combination compare favorably with existing standards of care and the historical data reported with immune checkpoint inhibitors alone."

"Patients with HPV16-induced cancers still do not have access to approved treatments designed to address the viral origin of their disease. We believe these data establish the clinical proof-of-concept of combining TG4001 with an immune checkpoint inhibitor. Based on these promising findings, Transgene intends to continue the clinical development of TG4001 in a larger, controlled confirmatory study and provide a better treatment option to this patient population," added Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene.

About the trial

This multi-center, open-label trial is assessing the safety and efficacy of this immunotherapy combination regimen (TG4001 + avelumab) in patients with HPV16 positive cancers who have disease progression on at least one line of systemic treatment for recurrent/metastatic disease (NCT03260023). Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, and a world expert in drug development and head and neck cancers, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, a leading science and technology company which in the US and Canada operates its biopharmaceutical business as EMD Serono, and Pfizer Inc (NYSE: PFE).

Patients received TG4001 at the dose of 5×107 pfu, SC, weekly for 6 weeks, every 2 weeks up to M6, and every 12 weeks thereafter, in combination with avelumab at 10 mg/kg, IV every two weeks, until disease progression.

The primary endpoint of the Phase 2 part is the overall response rate (ORR, using RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, disease control rate and other immunological parameters.

Provectus Biopharmaceuticals Announces Acceptance of Two PV-10® Melanoma Cancer Abstracts at European Society for Medical Oncology (ESMO) Virtual Congress 2020

On July 22, 2020 Provectus (OTCQB: PVCT) reported that data from an ongoing clinical trial of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) in combination with immune checkpoint blockade for the treatment of advanced cutaneous melanoma (NCT02557321) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress, to be held online from September 19-21, 2020 (Press release, Provectus Biopharmaceuticals, JUL 22, 2020, View Source [SID1234562251]).

The abstracts accepted for electronic poster presentations are entitled:

"A phase 1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma: results in patients naïve to immune checkpoint blockade" (#4281), and

"A phase 1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma: initial results in patients refractory to checkpoint blockade" (#4397).
Presentation details will be announced closer to the ESMO (Free ESMO Whitepaper) Virtual Congress 2020.

An injectable pharmaceutical product, PV-10 is a proprietary formulation of the Company’s current Good Manufacturing Practice (cGMP) rose bengal disodium (RB). This pharmaceutical-grade RB is produced by Provectus’ multi-step, quality-by-design (QbD) manufacturing process to exacting, modern regulatory standards that avoids the formation of previously unknown impurities present in commercial-grade rose bengal in uncontrolled amounts. The Company’s RB manufacturing process is protected by composition of matter and manufacturing patents as well as trade secrets.

About PV-10

By targeting tumor cell lysosomes, investigational new drug PV-10 treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells and a T cell mediated immune response against treatment refractory and immunologically cold tumors.1-3 Adaptive immunity can be enhanced by combining checkpoint blockade (CB) with PV-10.4

PV-10 is undergoing clinical study for adult solid tumor cancers, such as relapsed and refractory cancers metastatic to the liver and metastatic melanoma. PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers (e.g., neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma)5,6 and relapsed and refractory pediatric blood cancers (such as acute lymphocytic leukemia and acute myelomonocytic leukemia)7,8.

Tumor Cell Lysosomes as the Seminal 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.9 Cancer progression and metastasis are associated with lysosomal compartment changes10,11, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance12.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,13, external collaborators6, and other researchers14,15,16 have independently shown that PV-10 (RB) triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via PV-10: PV-10 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 event (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; the event has a duration of approximately one hour). Exposure to PV-10 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; this event has 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 PV-10.5

Tumor Autolytic Death via PV-10: PV-10 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 immunity8.

Orphan Drug Designations (ODDs)

ODD status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Investigational Drug Product

RB is 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium, a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. The Company manufactures RB using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients (cGMP). PV-10 drug product is an injectable formulation of 10% w/v cGMP RB in 0.9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and administered without dilution to solid tumors via intratumoral injection.

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 GMP RB and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial grade RB 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 PV-10 and systemic immunomodulatory therapy (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.