On June 22, 2020 Shasqi, a leader in chemistry based locally-activated cancer drugs, reported data showing that the company’s lead candidate SQ3370 produced robust anti-tumor responses both at the target site and at distal lesions in a preclinical cancer model (Press release, Shasqi, JUN 22, 2020, View Source [SID1234561411]). The study, titled "SQ3370, a Local Activation Therapy of Cytotoxic Agents, Produces Sustained Responses in Target and Distal Lesions via Immune Activation," was presented in a poster with audio at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II.

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Shasqi’s SQ3370 is a novel investigational drug product that uses bioorthogonal "click" chemistry reactions to capture and activate an attenuated anthracycline prodrug at the target tumor site enabling higher doses of the cancer drug while reducing side effects commonly experienced with conventional chemotherapy. Unlike other therapeutic approaches, Shasqi’s technology is solely based on chemistry and is independent of tumor biology such as biomarker expression and enzymatic activity.

This new therapeutic modality can precisely control the duration of exposure and magnitude of activated drugs at a specific area in the body. This allows the exploration of therapeutic benefits of a drug that had been previously limited by existing routes of administration in the clinic (oral, intravenous, direct injection or controlled release).

"SQ3370 is powered by an innovative chemistry based approach to precisely deliver high doses of a cancer drug locally and potentially activate the immune system against human tumors, independent of biological markers," said Carolyn R. Bertozzi, Ph.D., professor of chemistry and HHMI investigator at Stanford University.

SQ3370 consists of two components – SQL70, a hyaluronic acid-based biomaterial and SQP33, a prodrug of Doxorubicin, a commonly used chemotherapy. During treatment, SQL70 biomaterial is first injected at the target tumor site. SQP33 prodrug is then given systemically through daily IV infusions for 5 days. SQP33 prodrug remains in attenuated form in the body until it reaches the target tumor site and is captured by SQL70. Once captured, SQP33 is converted and released as active Doxorubicin at the target tumor.

In the study, Shasqi’s scientists evaluated SQ3370 in a preclinical cancer model in mice bearing two tumors, where the target lesion was injected with the SQL70 biomaterial and the distal lesion was not.

Treatment with SQ3370 significantly prolonged overall survival by reducing target lesions compared to controls. Interestingly, SQ3370 also reduced tumor growth at the distal lesion, which was not injected with the SQL70 biomaterial. Together, this suggests SQ3370 can induce both local and systemic anti-tumor responses.

"Our data demonstrate that SQ3370 can significantly reduce tumor size in both, tumors injected with the biomaterial, and at distal lesions. The preclinical data suggests that our approach can be relevant against the critical challenges facing clinicians today: undetectable lesions or widely disseminated solid tumors," said Nathan Yee, Ph.D., Senior Scientist at Shasqi and an author of the study.

Immune biomarker analysis indicates that SQ3370 triggers an immune response as shown by an increase in cytotoxic and helper T cells, and a decrease in regulatory T cells in both target and distal lesions. To further validate the immune activating properties, combination treatment with SQ3370 and an immune-activating agent led to more robust and sustained anti-cancer responses than controls with conventional Doxorubicin.

Additionally, in a separate study in rats, SQ3370 reduced adverse exposure to heart, kidney and liver tissue compared to conventional Doxorubicin treatment, indicating lower off-target toxic effects.

"Because of its highly modular nature, we can use our platform on numerous cancer drugs with doses traditionally limited due to toxicity and uncover new pharmacological benefits," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "To evaluate the translation of our findings to humans, we are initiating our first clinical trial of SQ3370 as a monotherapy in advanced solid tumors, and expect to dose our first patient shortly."

The entire AACR (Free AACR Whitepaper) poster presentation plus an audio description of the data by Dr. Yee, can be found here. In addition, the abstract for the poster can be found here.

On June 22, 2020 Targovax ASA (OSE: TRVX), a clinical stage immuno-oncology company developing oncolytic viruses to target hard-to-treat solid tumors, reported 12-month efficacy and immunological data from the randomized phase I/II trial of ONCOS-102 in combination with standard of care chemotherapy in malignant pleural mesothelioma (MPM) (Press release, Targovax, JUN 22, 2020, View Source [SID1234564002]).

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The trial is an open label, exploratory phase I/II trial adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (and later) line MPM to assess safety, immune activation and clinical efficacy vs SoC only. In total, 31 patients have been treated in the trial, with 20 patients in the experimental group receiving the ONCOS-102 and SoC combination, and 11 patients in a control group receiving SoC only. The 31 patients have now completed the 12-month follow-up. The first set of data was reported in January 2020, see press release here, with an update in May 2020, see press release here.

The median Progression Free Survival (mPFS) for ONCOS-102 treated first line patients remains at 8.9 months, which is identical to the previously reported early data. mPFS for the control group first line patients treated with SoC chemotherapy only is 7.6 months. The first line mPFS data continues to compare favorably to SoC historical controls, which have shown mPFS of 5.7-7.3 months[1]. As there is now longer follow-up and few censored patients left in the PFS analysis, the updated figures can be considered close to final.

The 12-month survival rate was 64% in the first line ONCOS-102 treated patients, compared to 50% in the first line control group treated with SoC chemotherapy only (median Overall Survival is too early to report). The patients continue to be followed and updated Overall Survival (OS) figures will be published as they mature. This 64% 12-month survival rate is encouraging compared to the control group, but there are few historical control reference points. Recently, at ASCO (Free ASCO Whitepaper) 2020, results from a first line mesothelioma trial assessing SoC chemotherapy in combination with the anti-PD-L1 checkpoint inhibitor durvalumab showed a 70% 12-month survival rate. This suggests that ONCOS-102 alone plus SoC chemotherapy may already achieve a level of benefit close to that observed with checkpoint inhibition plus SoC chemotherapy. It is expected that addition of checkpoint inhibition to ONCOS-102 and Soc will provide even further clinical benefit due to engagement of distinct and complementary biological mechanisms. As such, Targovax’s future clinical development of ONCOS-102 will focus on first line mesothelioma with the triple combination of a checkpoint inhibitor, ONCOS-102 and SoC. A randomized phase II trial is currently being planned in collaboration with a pharma partner.

Tumor biopsy immunohistochemistry and gene expression analyses from the present trial confirm the predicted mode of action of ONCOS-102. Importantly, profound innate and adaptive immune activation is observed in the ONCOS-102 treated patients compared to the control group, and this immune activation is associated with better clinical outcome. The immune activation is hallmarked by an increase in intra-tumoral cytotoxic T-cells and upregulation of adaptive immunity and cytotoxicity related gene expression, in parallel with polarization from M2 to M1 macrophage phenotype and upregulation of PD-L1 expression, indicating that ONCOS-102 is driving a favorable remodeling of the tumor microenvironment. This powerfully demonstrates the immune activation potential of ONCOS-102 far beyond what is achieved by chemotherapy alone and suggests that patients may be effectively sensitized to treatment with an anti-PD1/L1 antagonist, thereby providing strong scientific rationale for the combination of ONCOS-102 and checkpoint inhibition in first line mesothelioma.

Dr. Magnus Jäderberg, Chief Medical Officer of Targovax, said: "We are very pleased to see the encouraging first line PFS data holding up in the 12-month analysis, with early signs of positive survival outcomes. We are particularly excited to observe a broad and profound immune activation in the ONCOS-102 treated patients, which confirms the proposed mode of action. ONCOS-102 treatment clearly drives a favorable remodeling of the tumor microenvironment, and this remodeling is linked to better clinical outcomes. This immune activated tumor micro-environment provides the key scientific rationale and an ideal backdrop for combination treatment with a checkpoint inhibitor. These data set us up perfectly to move forward with a trial combining ONCOS-102 and a checkpoint inhibitor, which we believe will release the full potential of immunotherapy in this hard-to-treat patient population".

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.