On June 23, 2020 Kadmon Holdings, Inc. (NYSE:KDMN) reported that the first patient has been dosed in a Phase 1 clinical trial evaluating KD033, an anti-PD-L1/IL-15 fusion protein, in patients with metastatic or locally advanced solid tumors (Press release, Kadmon, JUN 23, 2020, View Source [SID1234561410]). KD033 is a novel immunotherapy designed to stimulate innate and adaptive immune responses directed to the tumor microenvironment.

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"We are pleased to initiate clinical development of KD033, which has demonstrated encouraging efficacy and durability in a variety of tumor types in preclinical models," said Harlan W. Waksal, M.D., President and CEO of Kadmon. "By directing the anti-tumor activity of IL-15 to the tumor microenvironment, KD033 has the potential to stimulate patients’ immune responses to fight cancer while avoiding systemic toxicities. This study initiation represents an important milestone for Kadmon and our platform of IL-15-containing fusion proteins. We look forward to providing further updates on this trial as they become available."

Recombinant IL-15 (rIL-15) is an immunostimulatory cytokine that has demonstrated clinical activity in the treatment of several cancers. rIL-15 expands key tumor-fighting cell types, including natural killer (NK), natural killer T (NKT) cells and memory T cells, without expanding immunosuppressive Treg cells, allowing for robust and durable anti-tumor responses. Clinical use of rIL-15 has been limited by its short half-life and narrow therapeutic window. To address these challenges, Kadmon has developed KD033, which is designed to direct IL-15 activity to the tumor microenvironment of PD-L1-expressing tumors and to achieve a greater therapeutic window. KD033 is designed to promote long-lasting efficacy while reducing systemic exposure of IL-15 to potentially increase safety and tolerability.

In preclinical studies, a single dose of KD033 demonstrated robust in vivo pharmacological activity and inhibited tumor growth across multiple syngeneic mouse models. KD033 also induced T-cell memory, resulting in mice that remained tumor-free following several tumor re-challenges. KD033 demonstrated significant tumor inhibition in animal models that are resistant to approved immunotherapies such as PD-L1, PD-1 or CTLA-4 antibodies.

About the KD033-101 Clinical Trial

KD033-101 is a Phase 1, open-label, dose-escalation and dose-expansion study investigating the safety and efficacy of KD033 in patients with metastatic or locally advanced solid tumors. The dose-escalation phase of the study will evaluate the pharmacokinetics and pharmacodynamics and identify the maximum tolerated dose (MTD) of KD033. The dose-expansion phase of the study will enroll approximately 15 patients who have progressed or are refractory to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy to assess safety, efficacy and determine the recommended Phase 2 dose (RP2D) of KD033.

About KD033

KD033 is a novel immunotherapy developed in-house and is fully owned by Kadmon. KD033 combines an anti-PD-L1 antibody with IL-15, a cytokine that expands key tumor-fighting cell types, including natural killer (NK), natural killer T (NKT) and memory T cells, to potentially induce durable responses and inhibit tumor growth. The anti-PD-L1 antibody directs IL-15 activity to the tumor microenvironment, limiting systemic exposure of IL-15 to potentially increase safety and tolerability. KD033 was well tolerated in GLP toxicology studies at clinically relevant doses. KD033 process development and manufacturing was completed through a successful collaboration with Wuxi Biologics and exhibited desired manufacturability and stability criteria.

KD033 is the most advanced candidate from Kadmon’s IL-15 fusion protein platform. The Company is developing a portfolio of therapies combining IL-15 with select antibodies for the treatment of cancer.

On June 23, 2020 Cellaria reported it is presenting data on the value of modeling the metastatic niche, and the benefits of using patient-derived cancer cell models, mesenchymal stem cells (MSCs), and optimization of oxygen level and extracellular matrix (ECM) to study antitumor drug response, personalized therapy, and disease mechanisms (Press release, Cellaria, JUN 23, 2020, View Source [SID1234561395]). The data, featured in a poster at 2020 AACR (Free AACR Whitepaper) Annual Meeting II, results from Cellaria’s spheroid system using five cancer cell models (pancreatic, lung adenocarcinoma, colon adenocarcinoma, endometrioid ovarian and high-grade serous carcinoma). With this 3D system, Cellaria is addressing an unmet need to improve predictions of the safety and efficacy of new drugs in preclinical testing and clinical trials.

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By using patient-specific cell models, translational scientists are able to go beyond traditional cell lines, to address the complexity and individuality of the disease and identify treatments that better meet the needs of each patient. Specificity in cell models enables researchers to derive the answers they need earlier in the drug development life cycle and with a continuous, direct connection to the patient.

"This data demonstrates the power of using patient specific cell models in a 3D format to model the tumor microenvironment and gain more actionable information from drug screening studies" comments David Deems, CEO, Cellaria Inc. "By using specific model patient populations that maintain their heterogeneity and individuality, users can test targets on our highly characterized cell models and select the mutation profile that is most important to their research."

On June 22, 2020 Ascendis Pharma A/S (Nasdaq: ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to address unmet medical needs, reported the presentation of preclinical data for TransCon IL-2 β/γ, an oncology product candidate designed to provide sustained systemic release of a receptor-biased IL-2 (IL-2 β/γ), at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II from June 22 to June 24, 2020 (Press release, Ascendis Pharma, JUN 22, 2020, View Source [SID1234561294]).

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"Our preclinical results have demonstrated that TransCon IL-2 β/γ selectively binds and activates the IL-2 β/γ receptor and provides sustained and long-lasting exposure. By applying our TransCon technology to this clinically validated cytokine, we have overcome the two most significant limitations of IL-2 therapy, improving both the receptor-binding properties and the pharmacokinetic profile," said Juha Punnonen, M.D., Ph.D., Ascendis Pharma’s Senior Vice President and Head of Oncology. "Based on the promising preclinical results we’ve seen with our TransCon IL-2 β/γ and TransCon TLR7/8 Agonist product candidates, we believe our TransCon technologies – which enable systemic and long-acting intratumoral administration – have the potential to improve treatment outcomes in cancer patients. We look forward to our first Investigational New Drug application, or similar, in oncology later this year for TransCon TLR7/8 Agonist, followed by a planned filing for TransCon IL-2 β/γ in 2021."

TransCon IL-2 β/γ is a novel long-acting prodrug of IL-2 β/γ designed to address limitations of alternative IL-2 treatments, including aldesleukin, which has been available since the 1990’s as a treatment for advanced kidney cancer and advanced melanoma. TransCon IL-2 β/γ is designed with a parent drug that selectively binds and activates the IL-2Rβ/γ. By applying the innovative TransCon technology platform, preclinical data also showed that TransCon IL-2 β/γ demonstrated a long in vivo half-life of approximately 32 hours, expected to support potential dosing of every three weeks in patients. Preclinical results show a single dose of TransCon IL-2 β/γ selectively expanded lymphocyte counts (CD8+ T cells and NK cells) in non-human primates, with minimal signs of systemic inflammation (IL-5 and IL-6 markers) or endothelial cell damage (E-Selectin and VCAM-1 markers) and no dose-limiting toxicities.

Presentation Details

American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II

Title Date/Time
P4507: TransCon IL-2 β/γ: a novel long-acting prodrug of receptor-biased IL-2 designed for improved pharmocokinetics and optimal activation of T cells for the treatment of cancer Monday, June 22, 2020

8:45 a.m. Eastern

The poster is available on the company’s website under Selected Publications in the Pipeline section:

View Source

About TransCon Oncology Programs

Ascendis Pharma is developing potentially best-in-class oncology therapies by applying its TransCon technologies for systemic and intratumoral administration to clinically validated pathways in order to improve efficacy and reduce systemic toxicity. Multiple oncology programs are currently in preclinical evaluation.

About TransCon Technology

TransCon refers to "transient conjugation." The proprietary TransCon platform is an innovative technology to create new therapies that are designed to potentially optimize therapeutic effect, including efficacy, safety and dosing frequency. TransCon molecules have three components: an unmodified parent drug, an inert carrier that protects it, and a linker that temporarily binds the two. When bound, the carrier inactivates and shields the parent drug from clearance. When injected into the body, physiologic conditions (e.g., pH and temperature) initiate the release of the active, unmodified parent drug in a predictable manner. Because the parent drug is unmodified, its original mode of action is expected to be maintained. TransCon technology can be applied broadly to a protein, peptide or small molecule in multiple therapeutic areas, and can be used systemically or locally.

On June 22, 2020, Cue Biopharma, Inc. (the "Company") reported that it entered into an At-The-Market Equity Offering Sales Agreement (the "Sales Agreement") with Stifel, Nicolaus & Company, Incorporated, as agent ("Stifel"), pursuant to which the Company may offer and sell, from time to time through Stifel, shares of its common stock, par value $0.001 per share (the "Common Stock"), for aggregate gross proceeds of up to $40.0 million (the "Shares") (Filing, 8-K, Cue Biopharma, JUN 22, 2020, View Source [SID1234561313]). The offer and sale of the Shares will be made pursuant to a shelf registration statement on Form S-3 and the related prospectus (File No. 333-239357) that became effective on June 22, 2020, as supplemented by a prospectus supplement dated June 22, 2020 and filed with the Securities and Exchange Commission pursuant to Rule 424(b) under the Securities Act of 1933, as amended (the "Securities Act").

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Pursuant to the Sales Agreement, Stifel may sell the Shares in sales deemed to be "at-the-market" equity offerings as defined in Rule 415 promulgated under the Securities Act, including sales made directly on or through the Nasdaq Capital Market. If agreed to in a transaction notice, the Company may sell Shares to Stifel as principal, at a purchase price agreed upon by Stifel and the Company. Stifel may also sell Shares in negotiated transactions with the Company’s prior approval. The offer and sale of the Shares pursuant to the Sales Agreement will terminate upon the earlier of (a) the issuance and sale of all of the Shares subject to the Sales Agreement or (b) the termination of the Sales Agreement by Stifel or the Company pursuant to the terms thereof.

The Company has agreed to pay Stifel a commission of up to 3.0% of the aggregate gross proceeds from any Shares sold by Stifel and to provide Stifel with customary indemnification and contribution rights, including for liabilities under the Securities Act. The Company also will reimburse Stifel for certain specified expenses in connection with entering into the Sales Agreement. The Sales Agreement contains customary representations and warranties and conditions to the placements of the Shares pursuant thereto.

A copy of the Sales Agreement is filed as Exhibit 1.1 to this Current Report, and the description of the terms of the Sales Agreement is qualified in its entirety by reference to such exhibit. A copy of the opinion of K&L Gates LLP relating to the legality of the issuance and sale of the Shares is attached as Exhibit 5.1 hereto.

This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy the Shares, nor shall there be any offer, solicitation, or sale of the Company’s Common Stock in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state.

On June 22, 2020 OncoSec Medical Incorporated (the "Company" or "OncoSec") (Nasdaq: ONCS), a company developing late-stage intratumoral cancer immunotherapies, reported that new data further demonstrating the power of OncoSec’s next-generation interleukin-12 (IL-12) plasmid (TAVOPLUS) therapeutic when combined with a T cell stimulator (TAVOPLUS-CD3) or an enhanced chemokine gradient (TAVOPLUS-CXCL9) (Press release, OncoSec Medical, JUN 22, 2020, View Source [SID1234561329]). These product candidates, coupled with the new low-voltage electroporation gene delivery system, represent a promising approach for treating patients with a variety of solid tumors. The data were presented today during two late-breaking poster presentations at the American Association for Cancer (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II being held from June 22-24, 2020.

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"Multiple studies have used intratumoral plasmid IL-12 (TAVO) to treat solid tumor indications with a demonstrable clinical benefit due to this cytokine’s ability to drive deep and durable immune responses," said Christopher Twitty, Ph.D., OncoSec’s Chief Science Officer. "The new preclinical data exhibited in both AACR (Free AACR Whitepaper) presentations highlights the evolution of OncoSec’s IL-12-based platform. Incorporation of a chemokine gradient and a polyclonal T cell stimulator with the enhanced IL-12 backbone of TAVOPLUS holds significant potential in the treatment of solid tumors. We believe these data provide a strong rationale for filing an Investigational New Drug application and we are excited to advance TAVOPLUS into clinical development."

The following posters were presented during the session titled, "Late-Breaking Research: Immunology 2":

Title: "Intratumoral electroporation of plasmid-encoded IL-12 and membrane-bound anti-CD3 increases tumor immunogenicity and augments the function of T cell subsets"
Poster Number: 14
Abstract Number: LB-390

Study Highlights:

Compared to IT-tavo-EP, TAVO+-αCD3 enhances T cells engagement with tumor cells and augments T cell killing function in preclinical cancer models by:

Increasing expressor memory T cells, which may extend anti-tumor response from treatment.
Increasing activated T cells in peripheral blood, which may enhance anti-tumor response throughout the body.
Increasing antigen specific T cells anti-tumor activity, which leads to enhanced cancer cell recognition by T cells.
Restoring the exhausted, non-active T cells’ anti-tumor activity, which leads to re-energized cancer cell killing activity.
Title: "Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of CXCL9 synergizes with IL-12 gene therapy (TAVO) to elicit robust anti-tumor immunity"
Poster Number: 20
Abstract Number: LB-396

Study Highlights:

Data demonstrated that IL-12, in concert with CXCL9 (a potent chemokine), leads to brisk infiltration of T cells and efficient remodeling of the tumor microenvironment, making tumors more susceptible to treatment.
This new product candidate thus builds upon OncoSec’s plasmid based immunotherapeutic platform by augmenting the effects of IL-12 with the inclusion of CXCL9.
Study showed that combining intratumoral TAVO with a DNA-encoded, locally secreted CXCL9, significantly improves anti-PD1 response, thus providing an approach to extend the benefit of PD-1 blockade to more patients.
The full abstracts presented at the AACR (Free AACR Whitepaper) Virtual Meeting II are available online at www.aacr.org and the posters are available on OncoSec’s website at www.oncosec.com.