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.

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 Nimbus Therapeutics, a biotechnology company designing breakthrough medicines through structure-based drug discovery and development, reported the presentation of data from the company’s HPK1 inhibitor program in a poster at the AACR (Free AACR Whitepaper) Annual Meeting held virtually April 10-15, 2021 (Press release, Nimbus Therapeutics, APR 9, 2021, View Source [SID1234577755]).

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Newly disclosed data show that Nimbus’ small-molecule HPK1 inhibitor, NMBS-2, demonstrates significant tumor growth inhibition as a single agent and in combination with anti-PD1 in multiple mouse syngeneic tumor models. In combination with anti-PD1, NMBS-2 restored cytokine secretion from exhausted human T cells and induced robust tumor growth inhibition in the CT-26 model. Furthermore, animals treated with NMBS-2 and anti-PD1 showed complete rejection of subsequently reintroduced CT-26 tumor cells, suggesting the establishment of a robust and durable immune memory.

"Building on our promising findings to date demonstrating the anti-tumor immune activity of NMBS-2, these latest data provide a compelling picture of its potential clinical utility in a range of tumor types — both as a single agent and as a combination therapy with anti-PD1 treatment," said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. "We’re rapidly progressing IND-enabling studies of NMBS-2 now with plans to initiate first-in-human studies in the second half of 2021."

On April 9, 2021 Kazia Therapeutics Limited (ASX: KZA; NASDAQ: KZIA), an Australian oncology-focused drug development company, reported to share new data from its ongoing phase II study of paxalisib in glioblastoma, the most common and most aggressive form of primary brain cancer (Press release, Kazia Therapeutics, APR 9, 2021, View Source [SID1234577773]).

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The data is the subject of a poster presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held virtually from 10-15 April 2021, and from 17-21 May 2021.

Key Points

Pharmacokinetic (PK) data, which shows how long paxalisib remains in the human body, strongly supports 60mg once daily dosing, confirming planned administration schedule for commercial launch.

Analysis of food effect shows no significant difference between taking paxalisib with food versus on an empty stomach, allowing for a less restrictive administration schedule in commercial use.

Study remains ongoing, with a number of patients still in follow-up. Final data is now expected in 2H CY2021.

Kazia CEO, Dr James Garner, commented, "this is extremely useful and encouraging data, as we begin to compile regulatory documentation for paxalisib and give shape to its potential commercial approval. These results give us great confidence that we are administering the drug at the right dose, at the right frequency, and under the correct conditions. Moreover, the data helps to confirm the approach that we have taken in the GBM AGILE pivotal study."

He added, "a lot of our efforts at present are focused on assembling the complex package of scientific information that is required to secure FDA approval for any new drug. Today’s data provides one more piece in that jigsaw. More broadly, the phase II study is drawing to a conclusion, and we expect to be able to share final data in the second half of this year."

The poster can be viewed on the Company’s website at View Source

Background

The phase II study of paxalisib (NCT03522298) opened to recruitment in May 2018. It was designed to establish the most appropriate dose for use in newly-diagnosed patients, and to seek initial indications of potential clinical efficacy.

The study had previously determined a maximum tolerated dose (MTD) of 60mg, administered once daily. This determination was based primarily on safety findings, which suggested increased toxicity at a higher dose. Today’s PK data corroborates this finding, and shows that increased doses provide limited additional benefit in terms of drug exposure. In effect, these two independent variables both point to a dose of 60mg, giving a high degree of confidence that this is appropriate for future studies and for commercialisation.

Interim analyses of efficacy data from this study have previously shown encouraging signals of clinical efficacy, with a median overall survival (OS) of 17.5 months and a median progression-free survival (PFS) of 8.4 months reported at the most recent data cut. These figures compare very favourably to historical controls for temozolomide, which provide an OS of 12.7 months and a PFS of 5.3 months.

The phase II study remains ongoing, with a number of patients in follow-up, and is expected to deliver final data in 2H CY2021.

In January 2021, paxalisib opened to recruitment in the GBM AGILE pivotal study, which is expected to provide the basis for registration in the US and other territories.

On April 9, 2021 Mersana Therapeutics, Inc. (NASDAQ:MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported plans to host a conference call and webcast on Friday, April 16, 2021 at 8:00 a.m. ET to discuss the selection of the NaPi2b biomarker cutoff and the commercial diagnostic development path for the ongoing UPLIFT registration strategy in platinum-resistant ovarian cancer (Press release, Mersana Therapeutics, APR 9, 2021, https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-host-conference-call-and-webcast-discuss [SID1234577791]). The presentation will review the Company’s plan to deliver a robust, predictive and reproducible commercial diagnostic assay.

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To access the call, please dial 877-303-9226 (domestic) or 409-981-0870 (international) and provide the Conference ID 4598737. A live webcast of the presentation will be available on the Investors & Media section of the Mersana website at www.mersana.com.