On November 4, 2023 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported novel preclinical data of their MDG2011 program lead candidates which are optimal affinity Kirsten rat sarcoma viral oncogene homologue mutation (mKRAS)-specific T cell receptors (TCRs) targeting human leukocyte antigens (HLA) A*11, in combination with a PD1-41BB costimulatory switch protein (CSP) at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2023 November 1-5, 2023, in San Diego, USA (Press release, MediGene, NOV 4, 2023, View Source [SID1234636974]).

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The poster with the title "A novel library of optimal affinity KRAS mutation-specific T cell receptors associated with multiple HLAs, in combination with a PD1-41BB armoring and enhancement costimulatory switch receptor" is available on Medigene’s website: View Source

"The unique approach of our End-to-End (E2E) Platform has enabled us to generate three strong lead candidates for our MDG2011 program, of which we have prioritized one, targeting mKRAS G12V-HLA-A*11, confirming our ability to identify optimal affinity TCRs not only for cancer-testis antigens but also for neoantigens, both validated targets for the treatment of solid tumor patients. Our preclinical work revealed fifteen potential TCR candidates specific to mKRAS G12V, from which these three unique TCRs fulfilled and exceeded our criteria of excellent specificity, high sensitivity and safety" said Dr. Selwyn Ho, Chief Executive Officer at Medigene. "Further armoring and enhancing these TCR-T cells with technologies like the PD1-41BB CSP showed that this has clear potential to overcome the immunosuppressive solid tumor microenvironment, leading to improved and sustained outcomes of TCR-T therapies in difficult-to-treat solid tumors."

Neoantigens (also known as oncogenic driver mutations) are related to mutations that alone are sufficient to initiate and maintain cancer, with the KRAS gene being one of the most frequently altered mutations in solid cancers. To date, 21 so-called missense mutations (in which single amino acids are exchanged) have been identified in the KRAS gene, with G12D, G12V and G12C being the most common. Given the high prevalence of various mutations within the KRAS gene and the limitations of current therapeutic approaches, there is an unmet need to further improve targeted therapies.

The presented data demonstrate, utilizing a high-throughput approach, the generation of optimal affinity TCRs targeting the mKRAS G12V neoantigen presented by multiple HLA-A*11 subtypes through use of the Company’s unique E2E Platform and shows further in vitro characterization with regards to specificity, sensitivity, and safety (3S), of the multiple TCR candidates in combination with the PD1-41BB-CSP.

Robust co-expression of the recombinant TCRs (rTCRs) and the PD1-41BB CSP was demonstrated for the three TCR candidates. The TCRs showed excellent specificity for the mKRAS G12V target, verified by release of interferon-gamma (IFNγ) only detected after stimulation with mKRAS G12V targets but not after stimulation with naturally occurring wild-type KRAS. Each of the three TCR candidates exhibited a unique peptide-specific recognition pattern of G12V peptide presented by different HLA-A*11 subtypes, underpinning the fine specificity of the selected TCR candidates.

All three TCR candidates displayed high sensitivity, responding to very low levels of the mKRAS-G12V peptide presented by antigen-presenting cells pulsed with varying amounts of the mKRAS G12V peptide.

Furthermore, elevated IFNγ release was seen after stimulation of TCR-expressing T cells with tumor cell lines expressing only low levels of mKRAS antigen and cancer cell survival was limited in mKRAS G12V-positive tumor cell lines of different origin following exposure to the T cells co-expressing any of the three rTCR mKRAS G12V-HLA-A*11 with PD1-41BB CSP. These effects were limited to mKRAS G12V-expressing cells, as cancer cells harboring wild-type KRAS were not affected. In addition, increased and sustained killing ability of 3D tumor spheroids was detected with the selected TCR candidates, demonstrating the potent cytotoxic activity directed towards cancer cells with mKRAS G12V.

Finally, the three TCR candidates each showed a favorable safety profile. None of the TCRs recognized HLA allotypes other than HLA-A11 in a panel of cell lines expressing globally common HLA allotypes. Most importantly, healthy cells representing major tissues or organs did not trigger IFNγ release upon exposure to the TCR candidates, approving that cytotoxicity is restricted to cancer cells with no signs of toxicity to healthy tissue.

On November 4, 2023 sairopa.com – a clinical-stage company that develops novel treatments for cancer by modulating the patient’s immune system, reported early clinical data on ADU-1604, its proprietary anti-CTLA4 antibody at the SITC (Free SITC Whitepaper) 38th Annual Meeting (Press release, Sairopa, NOV 4, 2023, View Source [SID1234636973]). Data obtained from the ongoing Phase 1 dose-escalation stage in PD1 relapse/refractory melanoma patients (N=17) were presented. ADU-1604 is well tolerated at the dosages tested (25, 75, 225 and 450 mg Q3W). No dose-limiting toxicities or treatment-related severe adverse events have been reported up to now. Pre-clinical data was presented that potentially explains the suggested improved safety profile of ADU-1604 vs. other anti-CTLA4 antibodies. ADU-1604 was shown to dose-dependently increase pharmacodynamic biomarkers, which correlates with early signs of clinical activity. Finally, early clinical efficacy data was reported showing one unusually long stable disease and two ongoing tumor regressions.

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On November 4, 2023 Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, reported data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells (Press release, Promontory Therapeutics, NOV 4, 2023, View Source [SID1234636971]). Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego.

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The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112’s immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling.

"Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling."

Study findings include:

PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD.

PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1.

PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR).

There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses.

PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD.

For more information about Promontory Therapeutics and PT-112, visit www.PromontoryTx.com.

About PT-112
PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112’s mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112’s potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The company’s Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition.

On November 3, 2023 Theralink Technologies, Inc. (OTC: THER) ("Theralink"), a precision oncology company with its exclusive commercial RPPA (reverse phase protein array) technology that can help predict which FDA-approved drug is effective in each cancer, reported that their long-standing, strategic partnership with the Inova Schar Cancer Institute (Inova) is beginning to deliver promising results by way of assessing the feasibility and impact of the actionable information provided by the Theralink assay into Inova’s Molecular Tumor Board (MTB)-based treatment decisioning making for cancer patients (Press release, Theralink Technologies, NOV 4, 2023, View Source [SID1234636909]).

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The partnership involves the integration of the Theralink assay, protected by ten patents, into Inova’s molecular tumor board’s operational workflow. Over the past year, Inova has undertaken a feasibility study to develop and implement the procedures and infrastructure necessary for proteomic analysis within the context of the Inova Schar Molecular Tumor Board. The Theralink assay provides a direct means of determining the actionability of genomic derangements identified, as well as directly measuring the activation/elevation of protein drug targets otherwise missed by genomic analysis alone. Thus, the incorporation of key phosphoprotein and protein data generated by Theralink’s RPPA technology into the Inova MTB could synergize with current genomics analysis to produce more accurate treatment selection and patient-tailored therapy regimes.

Interim results of this pan-tumor study were presented at the 2023 ASCO (Free ASCO Whitepaper) Conference in Chicago. Specifically, the analysis examined the feasibility of incorporating laser capture microdissection (LCM) enrichment of tumor specimens and reverse phase protein array (RPPA) analysis with next generation sequencing (NGS) into a molecular tumor board for improving selection of targeted cancer therapy. Integrated review of the RPPA and NGS data by the MTB supported a clinical recommendation change for over half of the patients overall. Further, the proteomics data from the Theralink assay provided additional treatment considerations for 59% of the patients, the outcomes for whom continue to be monitored. Moreover, the collaboration with Inova and their MTB resulted in a recent finding1 wherein the Theralink proteomics data revealed a specific mechanism of resistance and likely lack of benefit to a targeted therapy being considered by the MTB for a patient with a rare form of inflammatory myofibroblastic cancer.

Lastly, Inova and Theralink presented the results of another important study at ASCO (Free ASCO Whitepaper) 2023 that focused on Theralink’s unique ability to quantitatively measure HER2 abundance and activation and found that nearly 50% of pancreatic tumor actually express moderate amounts of HER2 protein, which could be missed by existing commercial HER2 assays. While HER2 expression is not routinely evaluated in clinical practice for pancreatic cancer these results may have clinical implications, especially as new classes of HER2 antibody drug conjugates are considered for patients with HER2 non amplified tumors across organ sites.

"Theralink is extremely encouraged by the work done to date at Inova Schar Cancer Institute- the interim results and clinical intelligence speak for themselves. We look forward to completing this study with Inova for our mutual goal of improving outcomes for all cancer patients", said Faith Zaslavsky, President and Chief Executive Officer of Theralink.

Dr. Timothy Cannon, who is the Sheridan Director of the Inova Molecular Tumor Board and Co-Director of the Gastrointestinal Cancer Program at Inova said, "We have tested over 100 patients with Theralink’s RPPA technology as part of this study. We are hopeful final study analysis and results will continue to underscore the importance of real-time clinical integration of functional protein drug target activation data provided by the Theralink assay with NGS in the Inova MTB for cancer patients."

Theralink and Inova will update findings and results post study completion. Published results are anticipated in early 2024.

On November 3, 2023 Acerand Therapeutics reported the approval of their next generation PARP1 selective inhibitor, ACE-86225106, for a first-in-human, open-label, multi-center Phase I/II study by the Center for Drug Evaluation of China National Medical Products Administration (Press release, Acerand Therapeutics, NOV 3, 2023, View Source [SID1234641763]).

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ACE-86225106 is a next generation PARP1 selective inhibitor with excellent in vitro and in vivo activity. Its markedly increased selectivity over other PARP isoforms, especially PARP2 and PARP3, has significantly improved its safety profile in in vitro and in vivo studies. Its differentiated pharmacokinetic property may result in better tolerability and more durable clinical activity. The low projected human dose in combination with high starting first in human dose could lead to rapid identification of recommended phase 2 dose. Due to its excellent potency, selectivity, and pharmacokinetic properties, ACE-86225106 can be used as a single agent and more importantly as a preferred combination partner with chemotherapies and targeted therapies in treating multiple solid tumors.

Given these promising data, Acerand Therapeutics will promptly initiate phase 1 dose escalation study in patients in China followed by the US to further assess the potential of ACE-86225106 as an effective mono- or combination therapy for treating different types of cancers, especially those with BRCA mutations or other homologous recombination deficiency.

Remarks by Dr. Genshi Zhao, Acerand Co-Founder, President and CSO:

We are very excited to begin clinical trials for our PARP1 inhibitor, ACE-86225106. The first-generation PARP inhibitors are known to have serious hematological and gastrointestinal toxicities due to the lack of selectivity over PARP2 and other isoforms. These serious toxicities have limited their clinical utility, especially in combination therapies. With its markedly increased selectivity over PARP2, significantly improved safety profile, excellent in vitro and in vivo potency, and PK profile, ACE-86225106 is expected to have great potential as a safer and more effective treatment option for cancer patients. We are confident that ACE-86225106’s clinical performance will greatly benefit cancer patients in China and elsewhere.