On September 14, 2024 Medigene AG (Medigene or the "Company", FSE: MDG1, Prime Standard), an oncology platform company focused on the research and development of T cell receptor (TCR)-guided therapies for the treatment of cancer, reported updates for its T cell receptor (TCR) library targeting the Kirsten rat sarcoma viral oncogene homolog (KRAS) and also highlighted advancements of its UniTope and TraCR technology, which serves as a universal system for tagging and tracking recombinant TCRs (rTCRs) across multiple modalities, including T cell receptor engineered T cell (TCR-T) therapies, at the ESMO (Free ESMO Whitepaper) Congress 2024 taking place in Barcelona from September 13-17, 2024 (Press release, MediGene, SEP 14, 2024, https://www.pressetext.com/news/20240914005 [SID1234646624]).

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The presented posters " Advancing a multi-dimension KRAS mutation-specific T cell receptor (TCR) library with a 3S TCR targeting the G12D mutation to address large global patient populations " and " UniTope & TraCR – Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region " will be made available after the conference on Medigene’s website:View Source

"We are excited about our expanding library of mKRAS-specific rTCRs targeting different mutations and HLA allotypes, aiming to broaden treatment options and improve outcomes for patients with difficult-to-treat solid tumors," said Dolores Schendel, CSO at Medigene AG. "Our lead KRAS G12D candidate, enhanced by the costimulatory switch protein (CSP) PD1-41BB, has shown very promising T cell functionality. By overcoming the challenges of the tumor microenvironment that have hindered the effectiveness of TCR-T therapies, we are confident that this program could offer best-in-class efficacy and safety. We are expanding our TCR library and also incorporating new proprietary technologies into our End-to-End (E2E) Platform, including UniTope & TraCR, a universal detection system for any rTCR across various modalities like TCR-T therapies, TCR-guided T cell engagers therapies, and TCR-NK cell therapies. Direct integration of the UniTope tag guarantees 100% co-expression of a unique identifier in a rTCR sequence and provides a significant advancement over current methods for detection of rTCRs in TCR-guided therapeutics. UniTope and TraCR will help us streamline quality control and provide precise data for determining the correct drug dosage for TCR-T therapies."

Advancing a multi-dimension KRAS mutation-specific T cell receptor (TCR) library with a 3S TCR targeting the G12D mutation to address large global patient populations

The first data presented showcased recent advancements in the expansion of the Company’s KRAS library, using a high-throughput approach to develop optimal affinity TCRs targeting the mKRAS G12D neoantigen in the context of HLA-A*11 via Medigene’s proprietary E2E Platform. Further in vitro studies characterized the lead TCR candidate in terms of specificity, sensitivity, and safety (3S) while incorporating the PD1-41BB CSP. TCR-expressing T cells, when stimulated by mKRAS G12D-positive tumor cells, showed increased interferon gamma (IFNγ) release. Reduced cancer cell survival was observed when mKRAS G12D-positive tumor cell lines from various origins were exposed to T cells co-expressing the rTCR mKRAS G12D-HLA-A*11 and PD1-41BB CSP. These effects were specific to mKRAS G12D, with no impact on wild-type KRAS cells. The TCR demonstrated an excellent safety profile, with no off-target toxicity against an extensive panel of healthy cell types. Finally, in vitro data showed that co-expression of PD1-41BB CSP enhanced and sustained T cell function in an rTCR-specific manner, with gated activation that only occurred when the specific peptide-HLA complex was present on target cells, and not through PD-L1 expression alone.

UniTope & TraCR – Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region

The second poster displayed the Company´s recently introduced universal TCR tagging and tracking combination technology UniTope & TraCR. Bioinformatic alignment of T cell receptor beta variable sequences enabled a six-amino-acid peptide (UniTope) to be predicted that is not found in natural TCR beta chains and has low immunogenicity. In parallel, an antibody was developed to specifically target this short amino acid peptide (TraCR) and further in vitro experiments demonstrated that TCR-T cells containing the UniTope sequence exhibited similar effects to those of TCR-T cells without the UniTope sequence. Integration of the UniTope sequence in a rTCR guarantees 100% co-expression of the tag and provides a significant advancement over current methods of detection of rTCRs in TCR-guided therapeutics.

In vitro studies confirmed that insertion of UniTope did not alter expression or functionality of rTCRs. In addition, safety assessments confirmed that UniTope-modified rTCRs displayed the same high safety profile as un-modified rTCRs with respect to lack of recognition and killing of 16 healthy cell types.

On September 14, 2024 Sutro Biopharma, Inc. (Sutro or the Company) (NASDAQ: STRO), a clinical-stage oncology company pioneering site-specific and novel-format antibody drug conjugates (ADCs), reported updated data from the ongoing Phase 1b study of luveltamab tazevibulin (luvelta) in combination with bevacizumab for patients with epithelial ovarian cancer (EOC) in a poster presentation at the 2024 European Society For Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Barcelona, Spain (Press release, Sutro Biopharma, SEP 14, 2024, View Source [SID1234646623]).

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In this study, luvelta plus bevacizumab has demonstrated encouraging antitumor activity in patients with late-stage ovarian cancer irrespective of Folate Receptor-α (FRα) expression, including patients with no FRα expression, and prior bevacizumab treatment, with an overall response rate of 35%. These early data in combination may offer a non-biomarker driven approach to treat patients with EOC. The expansion phase of the study is ongoing at the recommended phase 2 dose (RP2D) of luvelta (4.3 mg/kg) in combination with bevacizumab (15 mg/kg) with an additional 23 patients enrolled to date; initial data is expected in the first half of 2025.

"We are encouraged by these results achieved with luvelta in combination with bevacizumab, which may offer the opportunity to benefit ovarian cancer patients regardless of FRα expression," said Jane Chung, Sutro’s President and Chief Operating Officer. "We have already seen promising antitumor activity with luvelta as a monotherapy treatment and we believe these combination data support our goal to deliver effective therapies to more patients living with cancer. We look forward to sharing initial results from our expansion phase in the first half of 2025."

ESMO Poster Presentation Highlights:

18 patients were enrolled; one patient remains on treatment.
Luvelta plus bevacizumab demonstrated encouraging antitumor activity in 17 RECIST evaluable patients:
At the RP2D (4.3 mg/kg), an Objective Response Rate (ORR) of 56% (5/9) was observed; no (0/6) patients had a response at 3.5 mg/kg and 50% (1/2) of patients had a response at 5.2 mg/kg.
An ORR of 35% (6/17) was observed in the overall population with a median duration of response of 9.3 months.
In patients with ≥25% FRα expression, an ORR of 44% (4/9) was observed; in patients with <25% FRα expression, an ORR of 29% (2/7) was observed.
No new safety signals were observed compared with either agent alone; consistent with previous reported luvelta safety results, the most common adverse event was neutropenia.
The Presentation will be accessible through the News & Events page of the Investor Relations section of the company’s website at www.sutrobio.com.

About Luveltamab Tazevibulin
Luveltamab tazevibulin, abbreviated as "luvelta" and formerly known as STRO-002, is a FRα-targeting antibody-drug conjugate (ADC) designed to treat a broad range of patients with ovarian cancer, including those with lower FRα-expression who are not eligible for approved treatment options targeting FRα. Developed and manufactured with Sutro’s cell-free XpressCF platform, luvelta is a homogeneous ADC with four hemiasterlin cytotoxins per antibody, precisely positioned to efficiently deliver to the tumor while ensuring systemic stability after dosing. REFRαME-O1, a Phase 2/3 registration-directed study for patients with platinum-resistant ovarian cancer is ongoing. The Company has additional ongoing trials in patients with endometrial cancer, non-small cell lung cancer, and in combination with bevacizumab in patients with ovarian cancer. The Company expects to initiate REFRαME-P1, a Phase 2/3 registration-directed study for patients with CBF/GLIS2 acute myeloid leukemia, a rare subtype of pediatric cancer, in the second half of 2024. The U.S. Food and Drug Administration (FDA) has granted luvelta a Fast Track designation for Ovarian Cancer, as well as Orphan and Rare Pediatric Disease designations for CBF/GLIS2 Pediatric AML.

On September 14, 2024 BioInvent International AB, a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, and Transgene, a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported new initial data from their ongoing Phase 2/2a study on the multifunctional oncolytic virus BT-001, demonstrating antitumor activity in patients with refractory solid tumors (Press release, BioInvent, SEP 14, 2024, https://www.bioinvent.com/en/press/bioinvent-and-transgenes-oncolytic-virus-bt-001-shows-promising-antitumor-activity-ongoing [SID1234646619]). The data presented today at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting, showed that BT-001 induced tumor regression in patients unresponsive to prior anti PD(L)-1 treatment, both as a monotherapy and in combination with MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy KEYTRUDA (pembrolizumab).
Preliminary translational data suggest that BT-001 replicates in the tumor where the payloads are expressed with undetectable systemic exposure. BT-001 alone or in combination with pembrolizumab was well tolerated and showed first signs of efficacy with clinical responses in 2 of 6 refractory patients when given in combination with pembrolizumab. BT-001 treatment turned "cold" tumors to "hot" inducing T cell infiltration, a higher M1/M2 ratio, and a shift to PD(L)-1 positivity in the tumor microenvironment.

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Dr. S. Champiat, Medical Oncologist, Head of the Inpatient Unit, Drug Development Department (DITEP) at Institut Gustave Roussy, commented: "The immunological data generated by BT-001 suggest that, as hoped, BT-001 is replicating in the tumor and its payload of transgenes is expressed, with very limited exposure outside of the tumor thereby limiting systemic toxicity. I look forward to additional results from this ongoing study which will provide further evidence of the safety and clinical activity of BT-001 and its potential role as a new therapy for cancer patients with solid tumors."

Transgene and BioInvent are co-developing BT-001, an oncolytic virus developed using Transgene’s Invir.IO platform armed to express GM-CSF and BioInvent’s full-length anti-CTLA-4 monoclonal antibody, to elicit a strong and effective anti-tumoral response in solid tumors.

Alessandro Riva, Chairman and CEO of Transgene, said: "We are pleased to present the first promising clinical data on BT-001 at ESMO (Free ESMO Whitepaper) 2024 which confirm its mechanism of action as a single agent injected intratumorally and importantly demonstrate first signs of anti-tumor activity. Added to its good safety profile alone and in combination with pembrolizumab, BT-001 has the potential to shrink lesions and induce stable disease in refractory patients who may have few other treatment options. We will further explore the safety and efficacy of BT-001 in this development program with our partner BioInvent and report additional data when it becomes available."

Andres McAllister, MD, PhD, Chief Medical Officer at BioInvent International AB, concluded: "We are encouraged by the early clinical results presented at ESMO (Free ESMO Whitepaper) for BT-001, which encodes a potent Treg-depleting recombinant human anti-CTLA-4 antibody generated by our proprietary n-CoDeR and F.I.R.S.T platforms,. This clinical proof of concept confirms our ability to identify antibodies that bind to a selected target but exhibit a differentiated activity, allowing the development of promising new drug candidates such as BT-001."

The abstract and Poster titled: "Initial clinical results of BT-001, an oncolytic virus expressing an anti-CTLA4 mAb, administered as single agent and in combination with pembrolizumab in patients with advanced solid tumors.".

The poster can be accessed at the company’s website https://www.bioinvent.com/en/our-science/scientific-publications.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About the trial
The ongoing Phase 1/2a (NCT: 04725331) study is a multicenter, open label, dose-escalation trial evaluating BT-001 as a single agent and in combination with pembrolizumab (anti-PD-1 treatment). Patient inclusions are ongoing in Europe (France, Belgium) and the trial has been authorized in the US.
Phase 1 is divided into two parts. In part A, patients with metastatic/advanced tumors receive single agent, intra-tumoral administrations of BT-001. Part B explores the combination of intra-tumoral injections of BT-001 with pembrolizumab. In this part, KEYTRUDA (pembrolizumab) is provided to the trial by MSD (Merck & Co).
Phase 2a will evaluate the combination regimen in several patient cohorts with selected tumor types. These expansion cohorts will offer the possibility of exploring the activity of this approach to treat other malignancies not traditionally addressed with this type of treatment.

About BT-001
BT-001 is an oncolytic virus generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode both a Treg-depleting human recombinant anti-CTLA-4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, and the human GM-CSF cytokine. By selectively targeting the tumor microenvironment, BT-001 is expected to elicit a much stronger and more effective antitumoral response. As a consequence, by reducing systemic exposure, the safety and tolerability profile of the anti-CTLA-4 antibody may be greatly improved.
BT-001 is being co-developed as part of a 50/50 collaboration on oncolytic viruses between Transgene and BioInvent. To know more on BT-001, watch our video here.

On September 14, 2024 NuCana plc reported final data from the Phase 2 NuTide:701 study at the ESMO (Free ESMO Whitepaper) Congress on NUC-7738 in combination with pembrolizumab for patients with metastatic melanoma who were refractory to or had relapsed on prior PD-1 inhibitor therapy (Press release, Nucana, SEP 14, 2024, View Source [SID1234646615]). In this cohort of 12 patients, most of whom had received at least two prior lines of PD-1 inhibitor therapy, nine (75%) achieved disease control, including two patients who achieved Partial Responses. One of these patients, who had received two prior lines of PD-1 inhibitor-based therapy and had progressed on their latest treatment of ipilimumab plus nivolumab within two months, achieved a 55% reduction in tumor volume. Seven of the 12 patients had a progression free survival time of greater than five months, which is highly atypical in this patient population. In addition to achieving these encouraging efficacy signals, the combination of NUC-7738 and pembrolizumab had a favorable safety profile.

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NUC-7738’s ability to sensitize PD-1 resistant tumors to rechallenge with PD-1 inhibitors is believed to be due to its ability to target multiple aspects of the tumor microenvironment (TME) via the disruption of RNA polyadenylation and subsequent changes to gene expression in cancer cells. In support of this hypothesis, data presented from tumor biopsies obtained before and after NUC-7738 based treatment demonstrated increases in genes related to antigen presentation and T-cell activation.

Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "We are very excited to share these data on NUC-7738 in combination with pembrolizumab in PD-1 inhibitor refractory and resistant patients with melanoma. Outcomes in this patient population are very poor, with median progression free survival of 2-3 months with the current standard of care, so we are very encouraged that the majority of patients who received this combination achieved a progression free survival of more than five months."

Mr. Griffith continued: "The translational data that has been generated in this study and in previous non-clinical studies give us confidence that the effects we are seeing are a result of NUC-7738 making previously resistant tumors sensitive to rechallenge with PD-1 inhibitors by targeting multiple aspects of the tumor microenvironment. Our data on NUC-7738 obtained in other tumor types indicate that this phenomenon is not restricted to melanoma and that NUC-7738 may have the ability to sensitize other PD-1 inhibitor resistant tumor types. We look forward to sharing our development plans for NUC-7738 in the near future."

On September 14, 2024 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA and genetic testing, reported that new data from the GALAXY arm of the ongoing CIRCULATE-Japan trial was released today at the 2024 Congress of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) in Barcelona, Spain (Press release, Natera, SEP 14, 2024, View Source [SID1234646606]). GALAXY is one of the largest and most comprehensive prospective studies of circulating tumor DNA (ctDNA) testing in resectable colorectal cancer (CRC).

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This latest analysis, which will also be published in Nature Medicine on September 16, provides the first evidence of the ability of Signatera-based molecular residual disease (MRD) detection to predict overall survival (OS). The data also demonstrates Signatera’s ability to predict adjuvant chemotherapy (ACT) benefit in resectable CRC, with ctDNA clearance as an indicator of a superior survival benefit compared to no clearance.

In the study, 2,240 patients with stage II–IV CRC were monitored using Signatera after curative-intent surgery with a median follow-up of 23 months. Key takeaways include:

Signatera status was predictive of overall survival. Signatera-positivity in the post-op MRD window was found to be significantly associated with worse OS compared to Signatera-negative patients (HR: 9.68, p-value < 0.01) with a 36-month OS of 71.80% vs. 96.0%, respectively. This 10x advantage in overall survival compares favorably to all known guideline-recommended biomarkers that have HRs for overall survival in a range of 1-4.
Signatera status was predictive of an overall survival benefit from adjuvant chemotherapy.
High-risk stage II and stage III-IV patients who were Signatera-positive after surgery and received ACT demonstrated superior OS (adjusted HR: 0.53, p-value = 0.05), corresponding to a 50% reduction in the risk of death when treated with ACT. By comparison, the MOSAIC trial1, which was the last practice-changing study in adjuvant CRC, demonstrated a 16% reduction in risk of death (HR: 0.84, p-value = 0.05).
Signatera-negative patients did not derive an OS benefit from ACT (adjusted HR: 0.53, p-value = 0.13).
Signatera status remained the most significant predictor of recurrence. Signatera-positivity after surgery was the single most significant prognostic factor associated with inferior DFS (HR 12.08, p-value <0.01) and OS (HR 9.87, p-value <0.01) in a multivariate analysis that included all clinicopathologic risk factors currently in use. This is also reflected by the 36-month DFS difference between Signatera-positive and Signatera-negative patients at 16.7% (95% CI: 12.1–21.9%) versus 83.5% (95% CI: 81.2%–85.6%), respectively. The association of Signatera-positivity with a significantly increased risk for recurrence was observed across all pathologic stages.
Sustained Signatera clearance after ACT was associated with improved survival. Patients who clear ctDNA and remained Signatera-negative (referred to as "sustained clearance") had superior survival benefit with 24-month OS of 100%. This compares to patients who cleared ctDNA for a period of time but later become Signatera-positive (referred to as "transient clearance"), with 24-month OS of 82%, and patients who did not achieve ctDNA clearance, with 24-month OS of 61%. This finding further supports the utility of sustained ctDNA clearance as a surrogate endpoint for long-term outcomes.
"We now have compelling prospective evidence from a large trial of more than 2,200 patients that clearly reinforces the link between MRD status and overall survival," said Yoshiaki Nakamura, MD, PhD, co-author of the paper and principal investigator of the study from the National Cancer Center Hospital East in Kashiwa, Chiba, Japan. "These findings suggest that Signatera can predict post-surgical outcomes for colorectal cancer patients with great precision, redefining the future of personalized medicine and providing the potential to significantly improve outcomes for a greater number of patients."

"The GALAXY data released today builds on an earlier analysis from the same study that was published in Nature Medicine in 2023," said Minetta Liu, MD, chief medical officer of oncology at Natera. "Introducing 36-month, first-of-its-kind data on overall survival is an important milestone that reinforces the potential to improve outcomes for patients diagnosed with colorectal cancer. The updated data affirms ctDNA status as a critical measure both for prognosis and for predicting which patients may truly benefit from adjuvant chemotherapy."

About Signatera

Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer, ovarian cancer and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 70 peer-reviewed papers.