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BioInvent and Transgene’s BT-001 Achieves Outstanding Tumor Cure Rates in Preclinical Models

On June 22, 2020 BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, and Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported preclinical data demonstrating high cure rates in solid tumors of BT-001, an anti-CTLA4 antibody-encoding oncolytic virus (Press release, BioInvent, JUN 22, 2020, View Source [SID1234561331]).

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Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development, with a phase I clinical trial expected to start before the end of 2020.

BT-001 is a next-generation oncolytic virus (OV) being co-developed by Transgene and BioInvent. It was generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR oncolytic virus, which has been engineered to encode a Treg-depleting, anti-CTLA4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, as well as the cytokine GM-CSF.

BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells.

These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors and as such, underpin the effectiveness of both BioInvent’s and Transgene’s technology platforms.

Main points from the presentation included:

The anti-CTLA-4 antibody and GM-CSF accumulate in tumors with low systemic exposure. Concentrations of the anti-CTLA-4 antibody in the tumor after intratumoral injection of BT-001 is more than 10-fold higher than after intraperitoneal injection of 3 mg/kg of the recombinant antibody in a xenograft tumor model.
When new tumor cells were implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice.
BT-001, even at sub-optimal dose, reinforced the therapeutic activity of an anti-PD-1 antibody – opening up potential combinations for powerful dual checkpoint blockade treatment regimens.
These promising findings are available in a poster being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, on June 22-24, 2020. It can be downloaded from the AACR (Free AACR Whitepaper) website and from both BioInvent’s and Transgene’s websites.

Title of the poster: "BT-001, an oncolytic Vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment."
Authors: Jean-Baptiste Marchand, Monika Semmrich, Laetitia Fend, Matilda Rehn, Nathalie Silvestre, Ingrid Teige, Johann Foloppe, Linda Mårtensson, Eric Quéméneur, Björn Frendeus
Session Date: June 22-24, 2020
Poster Session Title: Inflammation, Immunity, and Cancer / Modifiers of the Tumor Microenvironment 2
Poster Number: 5602 // Abstract Number: 2902
About BioInvent

BioInvent International AB (OMXS: BINV) is a clinical stage company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapies, with two ongoing programs in Phase l/ll clinical trials for the treatment of hematological cancer and solid tumors, respectively. Two preclinical programs in solid tumors are expected to enter clinical trials by the end of 2020. The Company’s validated, proprietary F.I.R.S.TTM technology platform simultaneously identifies both targets and the antibodies that bind to them, generating many promising new drug candidates to fuel the Company’s own clinical development pipeline or for additional licensing and partnering.

The Company generates revenues from research collaborations and license agreements with multiple top-tier pharmaceutical companies, as well as from producing antibodies for third parties in the Company’s fully integrated manufacturing unit. More information is available at www.bioinvent.com.

Poster presentation at the AACR Virtual Annual Meeting II, 22 – 24 June 2020

On June 22, 2020 Medigene AG (Medigene, FSE: MDG1), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, reported insights from preclinical studies on its PD1-41BB switch receptor at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II taking place from 22 – 24 June 2020 (Press release, MediGene, JUN 22, 2020, View Source;s%20scientists%20demonstrated%20that%20the,especially%20against%20solid%20tumor%20cells.&text=One%20prominent%20inhibitory%20axis%20exploited,T%20cell%20activity%20in%20tumors. [SID1234561330]). The e-poster is available online today on the first day of the virtual conference as well as on Medigene’s website.

Medigene’s scientists demonstrated that the PD1-41BB switch receptor significantly improves the functional activity of T cell receptor-modified T cells (TCR-Ts) especially against solid tumor cells. Many solid tumors create a "hostile" microenvironment that suppresses immune cell attack, enabling tumors to survive and grow. To this end, tumor cells employ so-called "checkpoint mechanisms" to impede T cell activity. One prominent inhibitory axis exploited by tumors, the PD1-PDL1 pathway, is known to shut down T cell activity in tumors. Medigene’s PD1-41BB molecule is designed to convert the PD-1 "stop" signal induced by tumor cells to a "go" command by switching signals inside the T cells to activation, thereby overcoming the PD1-PDL1 inhibitory checkpoint blockade.

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer of Medigene: "In preclinical studies we could show that the addition of the PD1-41BB switch receptor to our TCR-Ts strongly enhances the antigen-specific functions of the TCR-Ts against solid tumors.

"Based on these promising results, we believe that the PD1-41BB switch receptor will ultimately enable our TCR-Ts to be more active in patients with solid tumors which have previously been very difficult to treat due to multiple mechanisms of immunosuppression. Furthermore, exploiting the PD1-PDL1 pathway to increase TCR-T activity through our switch receptor can be done in a targeted, localized manner, thereby avoiding the challenges of systemic side-effects that accompany treatment with existing checkpoint inhibitors."

Presentation Details:

Poster #3231 "The chimeric co-stimulatory receptor PD1-41BB enhances the function of T cell receptor (TCR)-modified T cells targeting solid tumors"

(E-poster with an audio description)

Session Adoptive Cell Therapy 3

Link to abstract https://bit.ly/3g3Q44H

Date 22 June 2020, 9:00 am – 06:00 pm (EDT)

Download www.medigene.com/technologies/abstracts
About Medigene’s PD1-41BB switch receptor:

Checkpoint inhibition via PD1-PDL1 pathway: Solid tumor cells are known to be sensitive to killing by activated T cells. Tumor cells can escape this killing activity by expressing inhibitory molecules, so-called ‘checkpoint proteins’, such as Programmed Death Ligand 1 (PD-L1) on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 by tumors represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.

The 4-1BB co-stimulatory signaling pathway: Effective T cell immune responses to antigens typically require costimulatory signals to be received alongside the primary antigenic stimulation via the T cell receptor (TCR). The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to positively enhance T cell responses.

Medigene’s PD1-41BB switch receptor takes advantage of the binding of PD-1 on the T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signaling domain of PD-1 has been substituted with the activating signaling domain of 4-1BB. As a result, the switch receptor then delivers an activating signal to the TCR-T cells (not the usually inhibitory signal of PD-1). This enables the PD1-41BB-modified TCR-T cells to proliferate strongly in the presence of PD-L1-positive tumor cells and to mediate greater killing of tumor cells upon repeated exposure. Additionally, signals mediated through the switch receptor also enhance metabolic fitness of TCR-T cells, enabling better function in conditions of low levels of glucose or high levels of the immunosuppressive factor TGF-ß, two conditions that are characteristic of strongly hostile tumor microenvironments.

OncoSec Presents Two Late-Breaking Abstracts on TAVO-PLUS at the American Association for Cancer Research (AACR) Virtual Annual Meeting II

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.

"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.

Preclinical Data for PRGN-3005 UltraCAR-T® Demonstrate Superior Expansion and Persistence of UltraCAR-T Compared to Traditional CAR-T

On June 22, 2020 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported preclinical data for its innovative investigational PRGN-3005 UltraCAR-T in patients with advanced, recurrent platinum resistant ovarian, fallopian tube or primary peritoneal cancer has been published as an e-poster and accompanying audio presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II (Press release, Precigen, JUN 22, 2020, View Source [SID1234561328]). The e-poster presentation titled PRGN-3005 UltraCAR-T: Multigenic CAR-T Cells Generated Using Non-viral Gene Delivery and Rapid Manufacturing Process for the Treatment of Ovarian Cancer (Abstract 6593) is part of the Immunology/Adoptive Cell Therapy session and is accessible on the AACR (Free AACR Whitepaper) e-poster website.

Traditional methods for CAR-T cell manufacturing involve the use of viral vectors and ex vivo cell expansion at centralized manufacturing facilities, contributing to potentially high costs and extended waiting periods. Precigen’s UltraCAR-T platform, in contrast, is based upon a non-viral multigene delivery system combined with a rapid, decentralized manufacturing process without ex vivo expansion. Following isolation of the patient’s own T cells after blood draw, non-viral gene transfer occurs overnight at the medical center’s cGMP facility. The next day, UltraCAR-T cells are infused into the patient.

PRGN-3005 is an autologous CAR-T treatment simultaneously expressing three gene products, which results in a uniform, homogenous CAR-T cell therapy: 1) CAR to specifically target the unshed portion of Mucin 16 (MUC16), which is overexpressed on over 80% of ovarian tumors with limited expression found in healthy tissues; 2) membrane-bound IL-15 (mbIL15) to provide improved UltraCAR-T persistence and maintenance of preferred stem cell like memory phenotype; and 3) a kill switch to eliminate the CAR-T cells, if needed.

Preclinical data demonstrate the specificity and efficacy of using the rapidly manufactured PRGN-3005 UltraCAR-T cells for the treatment of ovarian tumors. Specifically, a single administration of PRGN-3005 showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free. Furthermore, rechallenging these tumor-free mice three months later with ovarian tumors for a second time (to simulate tumor relapse) led to the elimination of tumor burden without additional PRGN-3005 UltraCAR-T treatment. These data demonstrate the potential of UltraCAR-T cells to persist long-term in vivo, prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability to continue to respond upon tumor rechallenge.

"We are pleased to be able to share the preclinical data for PRGN-3005 that led to the IND clearance and initiation of the Phase I study," said Helen Sabzevari, PhD, President and CEO of Precigen. "Our preclinical results demonstrate that PRGN-3005 UltraCAR-T administered one day after non-viral gene transfer has superior anti-tumor efficacy and persistence compared to traditional CAR-T cells and represents a promising opportunity for ovarian cancer treatment. We look forward to sharing the first clinical data for PRGN-3005 in the second half of 2020."

Based on these preclinical results, the FDA approved the IND application, and the first-in-human PRGN-3005 Phase I clinical trial for advanced ovarian cancer is currently under way (clinical trial identifier: NCT03907527). The PRGN-3005 UltraCAR-T Phase I clinical study is an open-label, dose escalation study to evaluate the safety and maximal tolerated dose of PRGN-3005 UltraCAR-T delivered by intraperitoneal infusion (IP) or intravenous infusion (IV). The study population includes patients with advanced stage (III/IV) recurrent ovarian, fallopian tube, and primary peritoneal cancer who are platinum-resistant and have progressed after receiving standard-of-care therapies or are not eligible to receive available therapies with known clinical benefit.

About Ovarian Cancer
Worldwide, nearly 300,000 women are diagnosed with ovarian cancer every year1 with approximately 22,000 of them in the US2. Since early ovarian cancer is often without obvious symptoms, the disease is frequently diagnosed at an advanced stage where cancer has spread to distant parts of the body, such as the liver or lungs2,3. Five-year survival rates depend on stage and type of ovarian cancer with rates decreasing for advanced stage cancers that have spread to distant parts of the body3.

Precigen: Advancing Medicine with Precision
Precigen (Nasdaq: PGEN) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in our core therapeutic areas of immuno-oncology, autoimmune disorders, and infectious diseases. Our technologies enable us to find innovative solutions for affordable biotherapeutics in a controlled manner. Precigen operates as an innovation engine progressing a preclinical and clinical pipeline of well-differentiated unique therapies toward clinical proof-of-concept and commercialization. For more information about Precigen, visit www.precigen.com or follow us on Twitter @Precigen and LinkedIn.

Precigen’s UltraCAR-T Therapeutic Platform
Precigen’s UltraCAR-T platform has the potential to disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time, decreasing manufacturing-related costs, and improving outcomes using advanced approaches for precise tumor targeting and control of the immune system. The platform brings several key advancements: 1) Non-viral gene transfer using multigenic vectors for expression of multiple effector genes leads to better precision and control of tumor targeting and eliminates the need for virus; 2) Sustained persistence and desired phenotype of infused UltraCAR-T helps address T-cell exhaustion, a common issue with current CAR-T therapies; 3) T-cell control by incorporation of kill switch technology to potentially improve the safety profile; and 4) Rapid manufacturing of UltraCAR-T cells using our proprietary non-viral gene transfer process, which eliminates the need for ex vivo propagation, thus dramatically reducing wait times for patients from weeks to one day after gene transfer.

Trademarks
Precigen, UltraCAR-T, and Advancing Medicine with Precision are trademarks of Precigen and/or its affiliates. Other names may be trademarks of their respective owners.

Myovant Sciences Announces Priority Review and FDA Acceptance of New Drug Application for Once-Daily, Oral Relugolix for Advanced Prostate Cancer

On June 22, 2020 Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, reported that its New Drug Application (NDA) for once-daily, oral relugolix (120 mg) for the treatment of men with advanced prostate cancer has been accepted for Priority Review by the U.S. Food and Drug Administration (FDA) (Press release, Myovant Sciences, JUN 22, 2020, https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-announces-priority-review-and-fda-acceptance [SID1234561327]).

"We are delighted that the FDA has accepted for Priority Review our New Drug Application for relugolix, bringing us one step closer to providing a one pill, once a day potential new treatment option to men with advanced prostate cancer," said Lynn Seely, M.D., chief executive officer of Myovant Sciences. "As recently published in the New England Journal of Medicine, relugolix demonstrated superior efficacy and a 54% lower risk of major adverse cardiovascular events compared to the current standard of care, leuprolide acetate injections, in the Phase 3 HERO study."

The FDA grants Priority Review to applications for potential therapies that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. The FDA has set a target action date of December 20, 2020 under the Prescription Drug User Fee Act (PDUFA). In its acceptance letter, the FDA also stated that it is currently not planning to hold an advisory committee meeting for this application. If approved, relugolix would be the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist treatment for men with advanced prostate cancer.

In May 2020, Myovant submitted a separate NDA for once-daily, oral relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with heavy menstrual bleeding associated with uterine fibroids. A Marketing Authorization Application for relugolix combination tablet in women with moderate to severe symptoms associated with uterine fibroids is also under review by the European Medicines Agency.

About the Phase 3 HERO Program in Advanced Prostate Cancer
Myovant’s Phase 3 clinical program for advanced prostate cancer consisted of a randomized, open-label, parallel-group, multinational clinical study designed to evaluate the safety and efficacy of relugolix in over 900 men with androgen-sensitive advanced prostate cancer who required at least one year of continuous androgen deprivation therapy. Men were randomized 2:1 to receive a single loading dose of relugolix 360 mg followed by relugolix 120 mg once daily, or to treatment with leuprolide acetate 3-month depot injection, respectively.

Relugolix met the primary efficacy endpoint, with 96.7% of men treated with relugolix achieving sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks versus 88.8% of men treated with leuprolide acetate. Relugolix also met all six key secondary endpoints, demonstrating superiority to leuprolide acetate in rapid and profound suppression of testosterone and PSA response, in addition to improved testosterone recovery after discontinuation of treatment. Men in the relugolix group had a 54% lower risk of major adverse cardiovascular events (MACE) compared to men in the leuprolide acetate group (2.9% vs. 6.2%, respectively). In men with a reported history of MACE, the relugolix group had 80% fewer MACE events reported compared to the leuprolide acetate group (3.6% vs. 17.8%, respectively). The overall incidence of adverse events in the relugolix and leuprolide acetate groups was comparable (92.9% vs. 93.5%, respectively).

Data from an additional key secondary endpoint, castration resistance-free survival, are expected in the third quarter of 2020.

About Prostate Cancer
Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the U.S. Cardiovascular mortality is the leading cause of death in men with prostate cancer and accounts for 34% of deaths in men with prostate cancer in the U.S. More than three million men in the U.S. are currently living with prostate cancer, and approximately 190,000 men are estimated to be newly diagnosed in 2020. Advanced prostate cancer is prostate cancer that has spread or come back after treatment and may include men with biochemical recurrence (rising PSA in the absence of metastatic disease on imaging), locally advanced disease, or metastatic disease. Front-line medical therapy for advanced prostate cancer typically involves androgen deprivation therapy, which reduces testosterone to very low levels, commonly referred to as castrate levels. GnRH receptor agonists, such as leuprolide acetate, are depot injections and the current standard of care for androgen deprivation therapy. However, GnRH receptor agonists may be associated with mechanism-of-action limitations, including the potentially detrimental initial surge in testosterone levels that can exacerbate clinical symptoms, which is known as clinical or hormonal flare, and delayed testosterone recovery after the drug is discontinued. Approximately 210,000 men are treated with androgen deprivation therapy with a GnRH agonist or antagonist each year.

About Relugolix
Relugolix is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces production of testicular testosterone, a hormone known to stimulate the growth of prostate cancer, and ovarian estradiol, a hormone known to stimulate the growth of uterine fibroids and endometriosis. Myovant is developing relugolix as a monotherapy tablet (120 mg once daily) for men with advanced prostate cancer. Myovant is also developing a relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with uterine fibroids and for women with endometriosis.