On April 9, 2021 Bionomics Limited (ASX: BNO,OTCQB:BNOEF) (Bionomics) reported that it has completed its 1 for 6 pro rata non–renounceable entitlement offer that was announced on 8 March 2021 (Entitlement Offer) and concurrent placement that was announced on 17 March 2021 (Concurrent Placement) which collectively raised approximately A$22.9 million (Press release, Bionomics, APR 9, 2021, View Source [SID1234577811]).

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The Entitlement Offer closed at 5.00pm (Adelaide time) on 30 March 2021 and raised approximately A$20.4 million from the offer of approximately 140.9 million new fully paid ordinary shares in Bionomics (New Shares) at the offer price of A$0.145 per New Share.

The Entitlement Offer was well supported by eligible shareholders who applied for approximately 85.6 million shares aggregating to approximately A$12.4 million of New Shares pursuant to their entitlements (representing a take up rate of approximately 60.7%).

Eligible shareholders subscribed for a further approximately 70.3 million additional New Shares in excess of their entitlement (up to a maximum of 100% of their entitlement) aggregating to approximately A$10.2 million in excess of their entitlement through the Oversubscription Facility. Applications under the Oversubscription Facility were in excess of the approximately 55.3 million shares or A$8 million shortfall and were scaled back in accordance with the terms of the Entitlement Offer on a pro rata basis.

Commenting on the outcome, Bionomics’ Executive Chairman, Dr Errol De Souza said, "Following on from the strong support received under the Company’s oversubscribed capital raise in February 2021, the success of the Entitlement Offer and Concurrent Placement demonstrates the confidence of Bionomics’ shareholders in the direction of the Company and the opportunities presented by progressing the development programme for BNC210 for the treatment of PTSD. We remain on track to starting the Phase 2b BNC210 PTSD trial in mid-2021".

As announced on 17 March 2021, Bionomics also conducted the Concurrent Placement concurrently with the Entitlement Offer pursuant to which certain investors were entitled to apply for new shares at the same price and on the same pro rata basis as was offered to subscribers under the Entitlement Offer. The investors to whom this Concurrent Placement offer was extended were those who participated in the Bionomics placement announced on 9 February 2021 and which completed on 2 March 2021, but who were unable to participate in the Entitlement Offer due to having a registered address outside of Australia or New Zealand.

The Concurrent Placement which was made on substantially the same terms as the Entitlement Offer raised approximately A$2.5 million from the offer of approximately 17.2 million new fully paid ordinary shares in Bionomics (New Concurrent Shares) at the offer price of A$0.145 per New Concurrent Share. New Concurrent Shares applied for under the Concurrent Placement were scaled back on a pro rata basis in the same manner as shareholders who applied under the Entitlement Offer.

The New Concurrent Shares issued under the Concurrent Placement were allocated from Bionomics’ expanded placement capacity following the Entitlement Offer.

Allotment of New Shares and New Concurrent Shares under the Entitlement Offer and the Concurrent Placement occurred on Thursday, 8 April 2021.

New Shares and Concurrent New Shares issued under the Entitlement Offer and the Concurrent Placement rank equally in all respects with existing shares. Shareholders should confirm their holding before trading in New Shares and Concurrent New Shares.

On April 9, 2021 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, reported data from its T cell programs are being presented at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Sana Biotechnology, APR 9, 2021, View Source [SID1234584004]).

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Sana is investing in multiple platform technologies to engineer cells, and several of these have the potential to address unmet needs for patients with cancer. Two of these platforms are highlighted in posters to be presented at AACR (Free AACR Whitepaper). Sana’s fusogen platform has the potential to deliver genetic payloads to specific cells in vivo, or inside a patient’s body, including delivery to T cells of the gene needed to make a chimeric antigen receptor (CAR). Sana’s hypoimmune platform has the potential to enable transplants of allogeneic cells without immunosuppression, including allogeneic CAR T cells.

"We are excited to share data for the first time at AACR (Free AACR Whitepaper), as we are optimistic that Sana’s platforms can be applied to help cancer patients," said Steve Harr, MD, Sana’s President and CEO. "CAR T cells have shown enormous potential for certain cancer patients, and Sana’s goal is to make better and more accessible CAR T therapies so that more patients can benefit."

"The data presented in these abstracts highlight the potential of our fusogen and hypoimmune platforms to make high quality, functional CAR T cells without the logistical complexities of autologous CAR T cell therapies," said Terry Fry, MD, Sana’s Head of T Cell Therapeutics. "The goal of our CD8-targeted fusogen program is to deliver the CAR gene directly to the T cell in vivo, and our data highlight the potential of these genetically modified CAR T cells to kill tumors. Separately, we modify gene expression in donor T cells to create hypoimmune allogeneic CAR T cells, and data highlight the potential of these cells to evade both the innate and adaptive immune systems while retaining anti-tumor effects. These results represent important progress in validating Sana’s platforms as we continue towards the clinic."

Data from two late-breaker abstracts were made available to the AACR (Free AACR Whitepaper) community today and are outlined below. The full posters will be available to conference participants online beginning Saturday, April 10 at 8:30 a.m. Eastern Time.

In vivo CAR T therapy: targeted in vivo gene delivery of a CAR using a CD8-specific fusogen results in tumor eradication
Authors: Terry Fry, MD et al.

Key takeaways include:

A single intravenous delivery of a CD8 fusogen containing a second-generation CD19 CAR transgene resulted in the generation of CD8 CAR Ts that eradicated the CD19+ tumor xenografts;
CD8 fusogen delivery resulted in a high percentage of T cells engineered to express the CAR with specificity for the CD8+ cells; and
The fusogen was able to generate a functional CAR response regardless of prior activation status of the T cells.
Overexpression of CD47 protects hypoimmune CAR T cells from innate immune cell killing
Authors: Sonja Schrepfer, MD, PhD et al.

Key takeaways include:

Innate immune cell assays show that CD47 overexpression protects HLA-I/II deficient CAR T cells from natural killer cell and macrophage killing both in vitro and in vivo;
Hypoimmunogenic CAR T cells have shown the ability to functionally evade the innate and adaptive immune system in allogeneic recipients with cytotoxic anti-tumor capacity; and
Hypoimmune CAR T cells have the potential to provide universal CAR T cells that are able to persist without immunosuppression.

On April 9, 2021 Medical researchers from Case Western Reserve University, New York University (NYU), and University Hospitals reported that have been awarded a five-year, $3 million National Cancer Institute grant to develop and apply artificial intelligence (AI) tools for predicting which lung cancer patients will respond to immunotherapy (Press release, Case Western Reserve University, APR 9, 2021, View Source [SID1234577779]).

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A unique aspect of the Case Western Reserve-led study is that it will involve testing of their specific AI tools—for the first time during an ongoing clinical trial.

While these real-time treatment predictions will be used exclusively for research–and not for clinical diagnosis or treatment–the work is the next step toward trials that would allow physicians to apply the tools with participating patients.

"Clinical trials down the road will be our biggest test, but now we will be—for the first time—studying changes in the tissue-scan patterns of patients as they are being treated, and that will provide real-world context of our tools," said Anant Madabhushi, director of Case Western Reserve’s Center for Computational Imaging and Personalized Medicine . "Our AI tools have excelled in previous studies, but they have all been after-the-fact."

The researchers hope to predict which patients will have successful immunotherapy treatments based on previously unseen indicators in their initial computerized tomography (CT) scans. If successful, they will have more data to support using the AI diagnosis for lung cancer patients in clinical trials.

Madabhushi will again work with longtime collaborator Vamsidhar Velcheti, MD, director of thoracic oncology at NYU Langone’s Perlmutter Cancer Center, who previously worked in Cleveland.

Lung cancer remains the leading cause of cancer-related deaths worldwide, according to the World Health Organization. Dr. Velcheti said advances like the work by our team "to match patients to the right treatment—can improve outcomes and significantly reduce costs for patients with lung cancer" and that "tests to identify patients for appropriate immunotherapy treatments are a critical unmet need in the field of oncology.

"Using novel and sophisticated AI approaches, we are developing personalized strategies to identify patients who may benefit from combination-based immunotherapy approaches," Velcheti said. "This NIH grant will help advance our efforts to developing innovative approaches for patient selection and monitor patients on immunotherapy."

The team will also include the University Hospitals Radiology Department Amit Gupta, MD, and Robert Gilkeson, MD, both professors at the Case Western Reserve School of Medicine; Pingfu Fu, PhD, professor of Population and Quantitative Health Sciences at the School of Medicine.

AI and immunotherapy
The CCIPD digital imaging lab has become a global leader in using machine learning to discern patterns in digital images of tissue scans that can’t be seen by the human eye, including for various cancers.

The lab pioneered the use of AI to predict which patients would benefit from chemotherapy. And recent research by CCIPD scientists has demonstrated that AI and machine learning can help predict which lung cancer patients will benefit from immunotherapy.

Immunotherapy uses drugs to help the immune system fight the cancer, while chemotherapy uses drugs to directly kill cancer cells, according to the National Cancer Institute.

As with their chemotherapy work, the researchers can accurately predict who will or won’t benefit from immunotherapy by training a computer to find minuscule changes in patterns in CT scans taken when the lung cancer is first diagnosed. Those scans are then compared to scans taken after the first two to three cycles of immunotherapy.

Many cancer patients benefit from immunotherapy, but the treatment is expensive. Researchers hope to find a better way to identify which cancer patients would likely benefit. And those who wouldn’t avoid having to pay for what turns out to be ineffective and costly treatment.

Multiple partners, sites
The Case Western Reserve-led team will also work with the ECOG-ACRIN cancer research group, a membership-based organization that oversees scientific programs and research into cancer control and outcomes, therapeutic studies and biomarker sciences. Its members include the Case Comprehensive Cancer Center.

Stanton Gerson, director of the center and interim dean of the Case Western Reserve School of Medicine, called the new work a "pivotal study."

"When these data mature, we hope they will lead to improved clinical decision-making," Gerson said. "Such an advance could be transformative for physicians making those complex decisions on which treatment is best for a patient."

Madabhushi said the partnership with ECOG-ACRIN is significant because it marks the first time his center will work with a broader, cooperative oncology group. It would also further establish the "generalizability of our tools," he said, meaning the AI analysis developed at one site or with one set of patients should also be valid at a second testing site—something that has yet to be proven in AI-driven precision medicine.

Madabhushi said his team would also benefit from partnerships with pharmaceutical partners who provide researchers with access to completed retrospective clinical trial datasets of lung cancer patients previously treated with immunotherapy. This data will also help the researchers validate their tools.

The new work will also investigate how lung cancer tumors change in size and shape during immunotherapy. Oncologists now rely on whether tumors shrink or grow to determine whether treatment is working.

"But it turns out that is not a good way of assessing treatment response, and our AI research has shown that," Madabhushi said. "There are a certain percentage of patients whose tumors grow in size, but the immunotherapy is working, a phenomenon called ‘pseudoprogression.’ There are now other features that the computer can pull from the CT scan—both inside and in the vessels outside the tumor—that will give us a better indication."

He also said the AI would reveal the less frequent but troubling cases of "hyper-progression," in which a patient’s condition is actually worsened by immunotherapy.

On April 9, 2021 Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, reported that David Meline, Chief Financial Officer, and Lavina Talukdar, Senior Vice President & Head of Investor Relations, will participate in a fireside chat at the 20th Annual Needham Virtual Healthcare Conference on April 15th, 2021 at 11:45 a.m. ET.

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A live webcast will be available under "Events and Presentations" in the Investors section of the Moderna website at investors.modernatx.com. A replay of the webcast will be archived on Moderna’s website for 30 days following the presentation.

On April 9, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported initial promising results from a Phase I study combining intravenous (IV) oncolytic virus TG6002 and oral 5-FC in patients with advanced gastrointestinal carcinomas (Press release, Transgene, APR 9, 2021, View Source [SID1234621819]). These data provide a clinical proof of concept for Transgene’s double deleted VVcopTK-RR- patented virus backbone: after IV administration, TG6002 reached the tumor, multiplied within tumor cells, and induced the local expression of its payload (the FCU1 gene).

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These results will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual meeting taking place from April 10-15, 2021.

DATA CONFIRM THAT THE CHEMOTHERAPY AGENT 5-FU IS PRODUCED IN PATIENTS’ TUMORS AFTER INTRAVENOUS ADMINISTRATION

TG6002 is a novel oncolytic virus that has been engineered to combine multiple mechanisms of action. It has been designed to:

selectively replicate within cancer cells. This is due to the deletion of the viral genes encoding TK and RR, which reduces the virus’s ability to grow in normal cells. This selective viral replication leads to the breakdown of the infected tumor cells in a process called oncolysis,
prime an immune response against the primary tumor and metastases,
and to induce the local expression of a biologically active enzyme able to convert 5-FC into its active cytotoxic metabolite 5-FU, directly in the tumor.
The data demonstrate that high concentration and continuous production of 5-FU chemotherapy can be obtained within the tumors through the local conversion of the pro-drug 5-FC (administered orally). This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been integrated within the genome of TG6002.

In this study, extensive analyses are being performed including metastasis biopsy with synchronous blood sampling, assessment of virus presence, quantification of 5-FC and 5-FU and assessment of neutralizing antibody titers.

These analyses have allowed Transgene to document TG6002’s pharmacokinetics (PK) and biodistribution, and the functioning of the FCU1 gene when given by IV administration.

Detailed results:

✔ TG6002 infects tumors after intravenous administration, remains active and effectively express FCU1 gene selectively in tumor tissue;
✔ Absence of widespread virus distribution in the body and association of FCU1 activity with high virus concentration in tumor tissue suggest that the replication of TG6002 is concentrated in tumor cells;
✔ None of the patients presented clinical signs of extra-tumoral dissemination of the virus suggesting a high tumor specificity of the viral replication;
✔ The study is continuing with escalating dosing of TG6002.

CLINICAL PROOF OF CONCEPT OF THE FEASIBILITY OF THE IV ADMINISTRATION OF TRANSGENE’S PROPRIETARY ONCOLYTIC VIRUS

To-date, the only oncolytic virus that has received regulatory approval is only approved for intra-tumoral administration, restricting its use to superficial lesions.

Transgene aims to enlarge the number of solid tumors, such as gastro-intestinal tumors, that could be addressed by an oncolytic virus, by developing oncolytics that can be administered intravenously.

The findings that will be presented at AACR (Free AACR Whitepaper) demonstrate the relevance of intravenous administration of Transgene’s next generation oncolytic viruses including TG6002.

These data also suggest that candidates derived from Transgene’s unique Invir.IO platform could also be given intravenously, extending the use of these therapies to a broad range of solid tumors.

Title of the poster: "Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas"
Authors: Kaidre Bendjama, Philippe Cassier, Victor Moreno, Bernard Doger, Emiliano Calvo, Maria De Miguel, Christiane Jungels, Philippe Erbs, Damien Carpentier, Alain Sadoun.
Abstract/Poster Number: LB179
Session: PO.IM02.11 – Vaccines
The e-poster presentation will be available on the AACR (Free AACR Whitepaper) website beginning at 8:30 am US EDT on Saturday, April 10, until Monday, June 21. The text of this abstract will be posted at 12:01 am US EDT on Friday, April 9 on the AACR (Free AACR Whitepaper) website.

About the trial (NCT03724071)
This trial is a single-arm open-label Phase I/II trial evaluating the safety and tolerability of multiple ascending doses of TG6002 administered intravenously in combination with oral 5-FC, a non-cytotoxic pro-drug that can be converted in 5-FU, its active metabolite. Based on the safety profile of TG6002, several dose levels have been added to the initial Phase I clinical protocol. At the end of this Phase I part, Phase II patients will receive the recommended dose of TG6002. The trial has safety as primary endpoint for the Phase I part and efficacy for the Phase II part. The trial also evaluates pharmacokinetic properties and biodistribution of TG6002, along with immune modulation of the tumor micro-environment. This European study will enroll up to 40 patients suffering from advanced gastrointestinal carcinomas who have failed and/or are intolerant to standard therapeutic options in the Phase I part. Patients with colon cancer and liver metastases will be enrolled in the Phase II part.

Dr. Philippe Cassier, M.D., PhD, head of the early-phase trials unit at Centre Léon Bérard (Lyon, France) is the principal investigator of the trial.

About TG6002
TG6002 has been engineered to directly kill cancer cells (oncolysis), to enable the production of a chemotherapy agent (5-FU) within the tumor, and to elicit an immune response by the body against the tumor cells. In preclinical experiments, TG6002 has been shown to induce the shrinkage of the primary tumor as well as the regression of distant metastases (Foloppe, et al., Molecular Therapy Oncolytics, View Source).

The production of 5-FU directly in the tumor aims to achieve a better anti-tumoral effect with limited chemotherapy-induced side effects.

TG6002 induces the production of 5-FU in the cancer cells it has infected, by enabling the local conversion of the pro-drug 5-FC (administered orally) into 5-FU. 5-FU is a common chemotherapy agent for patients with gastro-intestinal cancers. This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been encoded in the genome of TG6002, taking advantage of the virus selective replication in the tumor cells.

When administered systemically, 5-FU is associated with side effects that can lead to treatment discontinuation. With TG6002, 5-FU is produced within the tumor where it is expected to be present at a high concentration level in contrast to the very low levels anticipated in the rest of the patient’s body.