On November 18, 2022 Oncorus, Inc. (Nasdaq: ONCR), a viral immunotherapy company focused on driving innovation to transform outcomes for cancer patients, reported the presentation of preclinical data for ONCR-719 in a poster at the 2022 Society for Neuro-Oncology (SNO) Annual Meeting, taking place November 17-20, 2022 in Tampa, Florida (Press release, Oncorus, NOV 18, 2022, View Source [SID1234624242]).

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ONCR-719 is a novel, armed oncolytic HSV-1 vector engineered with targeted entry via EGFR/EGFRvIII and expresses four immunomodulatory payloads designed to reverse GBM’s immunosuppressive tumor microenvironment. In addition, ONCR-719 is derived from a potent HSV-1 isolate to drive oncolysis, is engineered with fusogenic mutations to enhance viral spread, and uses Oncorus’ clinically validated microRNA attenuation strategy to inhibit viral replication in healthy cells.

Highlights from the preclinical poster describing ONCR-719, previously known as ONCR-GBM, include:

Minimal expression of HSV-1 virus entry receptor, NECTIN-1, on human GBM samples suggests targeted oncolytic viruses are required to effectively treat human GBM tumors.
ONCR-719 has been engineered to enter tumor cells using either EGFR/EGFRvIII or NECTIN-1 as an entry receptor, thereby increasing virus tropism for GBM tumors.
EGFR-targeting and engineered fusogenic mutations in ONCR-719 enhance virus spread and tumor immunogenicity by driving syncytia formation in human GBM tumor cell lines.
ONCR-719 is engineered to include IL-12, an anti-PD-1 nanobody, 15-hydroxyprostaglandin dehydrogenase (HPGD), and a novel macrophage modulating-Fc enhanced antibody. These payloads confer enhanced T cell recruitment and activation and target the immune suppressive macrophages and myeloid cells in the tumor microenvironment. Multiple payloads or transgenes were screened using in vivo orthotopic GBM models to identify immune-modulatory payloads to target the GBM microenvironment.
Together, EGFR/EGFRvIII targeting, oncolytic potency, and incorporation of rationally designed payloads within ONCR-719 leads to enhanced anti-tumor efficacy and complete responses in preclinical orthotopic GBM models.
ONCR-719 is engineered for safety in the central nervous system using multiple CNS-specific microRNA targets, Oncorus’ clinically proven strategy to limit viral replication in healthy cells. When injected intracranially in an HSV-1 sensitive mouse, ONCR-719 demonstrates a greater than 50,000-fold tolerability window compared to the unattenuated strain.
"Oncolytic viruses are well-positioned to treat this aggressive form of brain cancer. We are excited to share ONCR-719 as a cutting-edge preclinical candidate that is engineered to improve outcomes and can stimulate a productive and durable anti-tumor immune response across multiple mouse models following a single intratumoral injection," said Theodore (Ted) Ashburn, M.D., Ph.D., President and Chief Executive Officer of Oncorus. "Most notably, we’ve enabled the virus to use EGFR for entry, which is expressed at high levels in GBM. Underscoring the importance of this advance is our data showing that the canonical entry receptor for HSV, NECTIN-1, is only minimally expressed in GBM cells, which arguably makes using EGFR for entry an essential capability for such an agent. By utilizing our clinically proven microRNA attenuation strategy, ONCR-719 is engineered to protect healthy brain tissue while replicating at its full potential in tumor cells."

"GBM is the most common type of primary brain tumor in adults; it’s a devastating disease that has a great unmet need with a 5-year overall survival of approximately 7 percent," said Tooba Cheema, Ph.D., Senior Director, Translational Medicine and ONCR-719 Program Leader at Oncorus. "We engineered ONCR-719 to overcome the common impediment that this treatment class faces, limited spread of virus in the highly immunosuppressive GBM tumor microenvironment. We are pleased with the results demonstrated in preclinical models and look forward to seeing how our innovations translate into improved outcomes for GBM patients."

ONCR-719 is the company’s second candidate from its HSV Platform and is developed from a clinical isolate of HSV-1 selected for oncolytic potency across cancer cell lines. Further development of ONCR-719 is dependent on a strategic partnership or additional financing.

On November 18, 2022 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA) reported that its ongoing rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) for lifileucel is expected to be completed in the first quarter of 2023 (Press release, Iovance Biotherapeutics, NOV 18, 2022, View Source [SID1234624239]).

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As part of an amendment to the ongoing investigational new drug application (IND) submitted during the third quarter of 2022, Iovance received recent FDA feedback regarding supplemental assay validation information and comparability data for lifileucel. Iovance will address these FDA comments promptly and will now complete its rolling BLA submission during the first quarter of 2023.

Lifileucel is an investigational tumor infiltrating lymphocyte (TIL) therapy for patients with advanced (unresectable or metastatic) melanoma who progressed on or after prior anti-PD-1/L1 therapy, and targeted BRAF/MEK inhibitor therapy where appropriate. There are no FDA approved therapies in this treatment setting.

Frederick Vogt, Ph.D., J.D., Iovance’s Interim President and Chief Executive Officer stated, "We continue to make substantial progress with our ongoing BLA submission and remain close to the finish line. The FDA has provided recent valuable feedback to the IND application and remains supportive during the rolling BLA submission process. Iovance is fully committed to securing FDA approval as soon as possible to deliver the first individualized, one-time cell therapy for advanced melanoma patients, who have a significant unmet medical need."

As previously announced, Iovance held a successful pre-BLA meeting in July 2022, and the rolling BLA commenced in August 2022. A rolling BLA allows Iovance to submit portions of the BLA to the FDA on an ongoing basis, which enables the FDA to begin review as early as possible as documents are received. The rolling BLA submission and eligibility for priority review are benefits available under the FDA’s guidance on expedited programs for serious conditions. The FDA previously granted a regenerative medicine advanced therapy (RMAT) designation for lifileucel in advanced melanoma.

The BLA submission for lifileucel is supported by positive clinical data from the C-144-01 clinical trial in patients with advanced melanoma. The Phase 3 trial of lifileucel in combination with pembrolizumab in frontline advanced melanoma, on track to begin in late 2022, is intended to serve as a confirmatory study and is expected to be well underway at the time of a potential approval.

Investor Webcast on Friday, November 18, 8:00 a.m. ET

Iovance will host a webcast on Friday, November 18 at 8:00 a.m. ET to discuss this corporate update. To participate in the webcast, please register at https://register.vevent.com/register/BI99a18daf00f04087b70d9c6b45008d6f. The live webcast and replay can be accessed in the Investors section of the company’s website at IR.Iovance.com.

On November 18, 2022, Iovance Biotherapeutics reported that entered into a new Open Market Sale Agreement (the "Sales Agreement") with Jefferies LLC ("Jefferies") with respect to an at the market offering program, under which the Company may, from time to time in its sole discretion, issue and sell through Jefferies, acting as sales agent, up to $500.0 million of shares of the Company’s common stock, par value $0.000041666 per share (the "Common Shares") (Filing, 8-K, Iovance Biotherapeutics, NOV 18, 2022, View Source [SID1234624238]). The Prior Sales Agreement (as defined below) was terminated, and the Sales Agreement replaces the Prior Sales Agreement.

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The issuance and sale, if any, of the Common Shares by the Company under the Sales Agreement will be made pursuant to a prospectus supplement, dated November 18, 2022, to the Company’s registration statement on Form S-3ASR, originally filed with the Securities and Exchange Commission on May 27, 2020, which became effective immediately upon filing.

Pursuant to the Sales Agreement, Jefferies may sell the Common Shares by any method permitted by law deemed to be an "at the market" offering as defined in Rule 415 of the Securities Act of 1933, as amended (the "Securities Act"). Jefferies will use commercially reasonable efforts consistent with its normal trading and sales practices to sell the Common Shares from time to time, based upon instructions from the Company (including any price or size limits or other customary parameters or conditions the Company may impose).

The Company will pay Jefferies a commission of up to 3.0% of the gross sales proceeds of any Common Shares sold through Jefferies under the Sales Agreement.

The Company is not obligated to make any sales of Common Shares under the Sales Agreement. The offering of Common Shares pursuant to the Sales Agreement will terminate upon the earlier to occur of (i) the issuance and sale, through Jefferies, of all Common Shares subject to the Sales Agreement and (ii) termination of the Sales Agreement in accordance with its terms.

The Sales Agreement contains representations, warranties and covenants that are customary for transactions of this type. In addition, the Company has agreed to indemnify Jefferies against certain liabilities, including liabilities under the Securities Act and the Securities Exchange Act of 1934, as amended.

The foregoing description of the Sales Agreement is not complete and is qualified in its entirety by reference to the full text of the Sales Agreement, a copy of which is filed herewith as Exhibit 1.1 to this Current Report on Form 8-K and is incorporated herein by reference.

The legal opinion of DLA Piper LLP (US) as to the legality of the Common Shares is being filed as Exhibit 5.1 to this Current Report on Form 8-K.

This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy the securities discussed herein, nor shall there be any offer, solicitation or sale of the securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction.

On November 18, 2022 Intensity Therapeutics, Inc. ("Intensity"), a clinical-stage biotechnology company focused on the discovery and development of proprietary immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that data from its open-label phase 1/2 study of novel lead asset, INT230-6, as a monotherapy or in combination with ipilimumab in adult subjects with metastatic sarcomas, will be presented in an oral podium presentation, at the Connective Tissue Oncology Society Annual Meeting (CTOS) being held at the Vancouver Convention Center in Vancouver, BC, Canada from November 16 -19, 2022 (Press release, Intensity Therapeutics, NOV 18, 2022, View Source [SID1234624236]).

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"Preliminary data suggests that INT230-6, as a monotherapy or in combination with the immune checkpoint blocker ipilimumab, demonstrates direct tumor killing in soft tissue sarcoma (STS) and elicits an anti-cancer immune response within the injected tumor," stated Matthew Ingham, M.D., assistant professor of medicine in the Division of Hematology and Oncology, Columbia University Vagelos College of Physicians and Surgeons, and a principal investigator for the trial. "To date, INT230-6 treatment related adverse events are mostly low grade and the drug is well-tolerated either as a monotherapy or in combination with ipilimumab. Additionally, in patients who had 40% or more of their tumor burden treated with INT230-6, an exploratory analysis showed that overall survival was improved when compared to historical benchmarks for this patient population."

Lewis H. Bender, President and Chief Executive Officer of Intensity Therapeutics, added, "The compelling safety and efficacy results from use of our drug in treating such a deadly and hard-to-treat cancer as soft tissue sarcomas underscore the potential of this treatment. The promising data supports our belief that INT230-6 could show clinical benefit with lower levels of off-target side effects compared to standard chemotherapies. We have designed a randomized phase 3 trial protocol to evaluate INT230-6 versus standard of care in patients with advanced soft tissue sarcomas and look forward to initiation of the study."

Abstract ID: 1301741
Title: Intratumoral INT230-6 (Cisplatin, Vinblastine, Shao) Alone or with Ipilimumab Prolonged Survival with Favorable Safety in Adults with Refractory Sarcomas (NCT03058289)
Session: Session 9: Immunology & Immunotherapy
Session Date Friday, November 18, 2022
Time: 3:30 PM – 5:00 PM PST
First Author: Matthew Ingham, M.D.
Presenter: Christian Meyer, M.D.
The presentation will be accessible on the "Publications, Papers and Posters" section of Intensity’s website at: View Source

The data presented included results from 29 patients with different metastatic sarcomas treated with INT230-6 either as a monotherapy (n=15), or in combination with ipilimumab (n=14). The enrolled patients’ cancer progressed following a median of three prior lines of therapy (range 0 to 9) including all approved, appropriate therapies for a subject’s particular cancer. Demographics were similar in subjects enrolled in monotherapy and checkpoint inhibitor combination arms. Pharmacokinetic data shows that >95% of the active agents remain in the tumor. Immunohistochemistry shows that there is an increase in the immune cell infiltration pre and post dose.

Study IT-01 is a single arm study; however, published clinical phase 1/2 basket trials in sarcoma report mOS, ranging from 230 to 290 days (Jones et. al., Cassier et. al., Subbiah et. al.). Using the Subbiah study data a synthetic control group Kaplan Meier (KM) survival curve was generated. The overall survival of the control, all INT230-6 patients and those receiving a cumulative dose of greater than 40% of their total tumor burden (TTB), are shown in the below table. Subjects receiving combination with ipilimumab have not yet reached median survival with 345 days median follow-up. There have been only 2 deaths reported in the combination group as of data cut-off. Sarcoma subtypes may differ between groups and data is still early.

Sarcoma phase 1/2 studies Control (Subbiah) INT230-6 all INT230-6 >40% TTB INT230-6 + IPI
Median OS 205 days 649 days 715 days Not yet reached*
Confidence Interval – (195, 1352) (649, 1352)
Sample size 56 15 11 14
About INT230-6

INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor resulting in a favorable safety profile. In addition to local disease control, direct killing of the tumor by INT230-6 releases a bolus of neoantigens specific to the patient’s malignancy, leading to engagement of the immune system and systemic anti-tumor effects. Importantly, these effects are mediated without the immunosuppression of concomitant systemic chemotherapy.

INT230-6 is currently being evaluated in several phase 2 cohorts (NCT03058289) in patients with various advanced solid tumors as part of Study IT-01. In 2019, the Company signed a clinical collaboration agreement with Merck Sharpe & Dohme (Merck) to evaluate the combination of INT230-6 and KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, in patients with advanced pancreatic, colon, squamous cell and bile duct malignancies. In 2020, the Company executed a clinical collaboration agreement with Bristol-Myers Squibb Company to evaluate the combination of INT230-6 with Bristol-Myers Squibb’s anti-CTLA-4 antibody, ipilimumab, in patients with advanced liver, breast and sarcoma cancers. In 2021, the Company executed agreements with the Ottawa Hospital Research Institute and the Ontario Institute of Cancer Research to study INT230-6 in a randomized controlled neoadjuvant phase 2 study in women with early stage breast cancer (the INVINCIBLE study) (NCT04781725).

On November 18, 2022 HiFiBiO Therapeutics, a multinational clinical-stage biotherapeutics company, reported a second clinical trial supply agreement with Novartis to evaluate HiFiBiO’s HFB200603, a novel anti-BLTA monoclonal antibody in combination with tislelizumab, Novartis anti-PD-1 immune checkpoint inhibitor, for the treatment of advanced solid tumor indications preselected by HiFiBiO’s proprietary Drug Intelligence Science (DIS) platform (Press release, HiFiBiO Therapeutics, NOV 18, 2022, View Source [SID1234624235]).

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"The continuation of our collaboration with Novartis bring us a step closer to realize our vision to provide potentially curative immunotherapies for each and every patient using our Drug Intelligence Science (DISTM) approach for novel drug discovery and development" said Liang Schweizer, Ph.D., Founder, Chairperson and CEO at HiFiBiO Therapeutics.

Under the terms of the agreement, HiFiBiO Therapeutics will maintain control of the HFB200603 program, including global R&D and commercial rights. Novartis has agreed to supply tislelizumab for use in combination with HFB200603.

HFB200603

HFB200603 was identified using HiFiBiO single cell platform as a single-digit nanomolar binder to human and cynomolgus BTLA, capable of blocking BTLA interaction with its ligand HVEM, reversing HVEM-mediated immune suppressive effects, and inducing the production of inflammatory cytokines in the tumor microenvironment of different human tumor types. HFB200603 synergizes with anti-PD-1 to enhance IFN-γ production and demonstrates favorable developability, pharmacokinetic and safety profiles.

Tislelizumab
Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.