On October 7, 2021 Kineta, Inc., a clinical stage biotechnology company focused on the development of novel immunotherapies in oncology, reported the presentation of preclinical data on the company’s new immuno-oncology program targeting CD27 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Conference on Tumor Immunology and Immunotherapy (Press release, Kineta, OCT 7, 2021, View Source;utm_medium=rss&utm_campaign=kineta-presents-preclinical-data-on-its-new-cd27-program-at-the-aacr-conference-on-tumor-immunology-and-immunotherapy [SID1234590928]). Thierry Guillaudeux, PhD, Senior Vice President Immuno-oncology at Kineta, presented a poster detailing new preclinical data on the company’s lead anti-CD27 agonist antibodies.

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CD27 is a member of the TNF receptor superfamily and plays a critical role in T-cell activation by providing a co-stimulatory signal together with its ligand CD70. CD27 is highly expressed on naïve T cells and also provides a co-stimulatory signal for NK cell activation. A major challenge in cancer immunotherapy is T cell "exhaustion". Anti-cancer T cells, through repeated stimulation, begin to lose their cancer-fighting effector functions. Once a T cell is exhausted, further stimulation becomes ineffective. CD27 agonist immunotherapy may reprogram the immune system to generate new and more diverse populations of anticancer "memory" T cells from naïve T cells to elicit a strong anti-tumor response.

"This is a significant milestone for Kineta as we expand our pipeline with another exciting immuno-oncology antibody program," said Shawn Iadonato, PhD, Chief Executive Officer of Kineta. "Our immuno-oncology strategy is to develop differentiated immunotherapies to address key mechanisms of cancer resistance including immunosuppression, exhausted T cells, and lack of tumor antigens. CD27 is a promising immunotherapy target to address exhausted T cells and restore anti-tumor T cell function".

Key results from the AACR (Free AACR Whitepaper) poster presentation include the following:

147 fully human monoclonal anti-CD27 antibodies with unique sequences were generated
Kineta’s anti-CD27 antibodies are highly specific and cross-react with cyno-CD27
Anti-CD27 agonist assay showed particularly strong induction for eight of the anti-CD27 antibodies
Human peripheral blood T cell activation assay showed increased proliferation and cytokine secretion
"We are encouraged with the results of our anti-CD27 antibodies as they performed exceedingly well across multiple preclinical experiments", said Thierry Guillaudeux, PhD, SVP Immuno-oncology at Kineta. "We are currently in lead selection and will nominate a clinical candidate to advance into IND-enabling studies in 2022."

Presentation Details:

Title: A promising cancer immunotherapy target: Novel fully human agonist antibodies against the human T-cell costimulatory receptor CD27
Date Presented: October 5-6, 2021
Presenter: Thierry Guillaudeux, PhD
Poster: Click on the link below to view the poster:
Kineta CD27 Poster Presentation at AACR (Free AACR Whitepaper) Conference on Tumor Immunology and Immunotherapy

On October 7, 2021 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported that new data with PH-894, Phio’s self-delivering RNAi compound targeting the bromodomain-containing protein 4 (BRD4) at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Phio Pharmaceuticals, OCT 7, 2021, View Source [SID1234590927]). The data presented add to the growing body of evidence that BRD4 not only plays a role in tumor cells, but can also regulate T cell function and that PH-894 can reprogram T cells to provide enhanced immunotherapeutic activity.

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"The data we presented today at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting demonstrates silencing BRD4 with our INTASYL compound PH-894 has a significant impact on T cell function and phenotype promoting T cell activation and immunosuppression in the tumor microenvironment," said Simon Fricker, Phio’s Vice President of R&D. "Our new data shows how BRD4 can regulate immune cells activity and therefore BRD4 silencing with PH-894 could become an important approach to treat cancer."

In this study conducted in collaboration with the Karolinska Institutet in Sweden, it was shown that PH-894 resulted in a strong, concentration dependent and durable silencing of BRD4 in T cells, which in an in vivo study translated to pronounced and dose associated inhibition of tumor growth. These data demonstrate that Phio’s PH-894 INTASYL compound can reprogram T cells to provide enhanced immunotherapeutic activity.

"We are very excited by these data, which suggest that PH-894’s potency is not solely a consequence of its direct effect on tumor cells, but also its ability to reprogram and activate T cells to further boost the anti-cancer effect. As such, we are working hard on IND-enabling studies to bring this promising compound to the clinic," continued Dr. Fricker.

Phio’s presentation detailing the data presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) titled, "Targeting BRD4 in T cells with self-delivering RNAi PH-894 for immunotherapy" will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

On October 7, 2021 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported preclinical data providing further evidence of bezuclastinib as a differentiated, potent, and selective KIT inhibitor (Press release, Cogent Biosciences, OCT 7, 2021, View Source [SID1234590926]). The data were presented in a virtual poster at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

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"Today Cogent presented new preclinical data that reinforces bezuclastinib’s selectivity for targeting KIT mutations while demonstrating minimal brain penetration," said Andrew Robbins, President and CEO of Cogent Biosciences. "We are excited with bezuclastinib’s differentiated profile among KIT inhibitors and continue to work quickly to have three clinical trials for AdvSM, NonAdvSM and GIST patients open for enrollment in 2021."

Preclinical studies evaluated the selectivity of bezuclastinib, and other KIT mutant inhibitors, against closely related kinases including PDGFRα, PDGFRβ, and CSF1R. Inhibition of these kinases has been linked to off-target toxicities such as edema and pleural effusions. Comparative screening was performed against a broad spectrum of 71 ion channels, transporters, enzymes, and cell based models, confirming prior evidence that bezuclastinib is a potent and unique inhibitor of KIT A-loop mutations (exon 17/18). In head-to-head studies comparing KIT mutant inhibitors, bezuclastinib demonstrated no activity against closely related kinases, in contrast to other KIT mutant inhibitors with demonstrated potency against PDGFRα and PDGFRβ.

In a nonclinical safety pharmacology study in rodents, bezuclastinib and another KIT A-loop mutant inhibitor were evaluated at doses which closely correlate with clinical exposures previously shown in clinical studies of GIST patients. After three days, bezuclastinib demonstrated minimal brain penetration with a low brain to plasma ratio. These data are supported by a separate neurobehavioral study of bezuclastinib in rodents in which no CNS-related effects were observed. The absence of brain penetration is a preferred feature for a KIT mutant inhibitor as CNS-related adverse events have been observed clinically with some commercially available mutant KIT inhibitors.

Poster Presentation Details for Bezuclastinib:
Title: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration
Virtual Poster Number: P257
Date/Time: All poster presentations are made available by the conference at the opening of the meeting on October 7, 2021, at 9:00 am ET.

The presentation is available on the Cogent Biosciences website at: View Source

On October 7, 2021 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported preclinical data providing further evidence of bezuclastinib as a differentiated, potent, and selective KIT inhibitor (Press release, Cogent Biosciences, OCT 7, 2021, View Source [SID1234590926]). The data were presented in a virtual poster at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

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"Today Cogent presented new preclinical data that reinforces bezuclastinib’s selectivity for targeting KIT mutations while demonstrating minimal brain penetration," said Andrew Robbins, President and CEO of Cogent Biosciences. "We are excited with bezuclastinib’s differentiated profile among KIT inhibitors and continue to work quickly to have three clinical trials for AdvSM, NonAdvSM and GIST patients open for enrollment in 2021."

Preclinical studies evaluated the selectivity of bezuclastinib, and other KIT mutant inhibitors, against closely related kinases including PDGFRα, PDGFRβ, and CSF1R. Inhibition of these kinases has been linked to off-target toxicities such as edema and pleural effusions. Comparative screening was performed against a broad spectrum of 71 ion channels, transporters, enzymes, and cell based models, confirming prior evidence that bezuclastinib is a potent and unique inhibitor of KIT A-loop mutations (exon 17/18). In head-to-head studies comparing KIT mutant inhibitors, bezuclastinib demonstrated no activity against closely related kinases, in contrast to other KIT mutant inhibitors with demonstrated potency against PDGFRα and PDGFRβ.

In a nonclinical safety pharmacology study in rodents, bezuclastinib and another KIT A-loop mutant inhibitor were evaluated at doses which closely correlate with clinical exposures previously shown in clinical studies of GIST patients. After three days, bezuclastinib demonstrated minimal brain penetration with a low brain to plasma ratio. These data are supported by a separate neurobehavioral study of bezuclastinib in rodents in which no CNS-related effects were observed. The absence of brain penetration is a preferred feature for a KIT mutant inhibitor as CNS-related adverse events have been observed clinically with some commercially available mutant KIT inhibitors.

Poster Presentation Details for Bezuclastinib:
Title: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration
Virtual Poster Number: P257
Date/Time: All poster presentations are made available by the conference at the opening of the meeting on October 7, 2021, at 9:00 am ET.

The presentation is available on the Cogent Biosciences website at: View Source

On October 7, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported the presentation of preclinical data from the Company’s first-in-class selective ULK kinase inhibitor, DCC-3116, in combination with EGFR inhibitors in non-small cell lung cancer (NSCLC) models at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Deciphera Pharmaceuticals, OCT 7, 2021, View Source [SID1234590925]).

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"The data presented today show that DCC-3116 inhibits the autophagy that develops as a resistance mechanism after treatment with EGFR inhibitors in multiple EGFR-mutant NSCLC cell lines and that DCC-3116 decreases tumor burden when combined with EGFR inhibitors. These findings are particularly important as EGFR is mutated in approximately 30% of NSCLC patients, the vast majority of whom develop resistance to EGFR inhibitors," said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. "These results reinforce the broad potential of autophagy inhibition as a mechanism to address the challenge of drug resistance in the treatment of cancer."

Results from the study, presented in a poster titled "DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, synergizes with EGFR inhibitors osimertinib and afatinib in NSCLC preclinical models" are summarized below. The poster presentation is available on-demand via the meeting website and on the Company’s website at www.deciphera.com/presentations-publications.

In Vitro Data Show Ability of DCC-3116 to Reduce Autophagy that Develops as a Resistance Mechanism after Treatment with EGFR Inhibitors in NSCLC Cell Lines

– EGFR inhibitors gefitinib, erlotinib and osimertinib, and the ErbB-family inhibitor, afatinib, activated autophagy three to four-fold over basal levels as measured by pATG13, a cellular substrate of autophagy-initiating kinases ULK1/2, in the EGFR exon 19-deleted HCC827 NSCLC cell line. DCC-3116, a potent inhibitor of ULK1 and ULK2, was shown to inhibit both basal and EGFR-induced phosphorylation of pATG13.

– Treatment of the EGFR T790M-mutated NSCLC cell line H1975 with osimertinib or afatinib, which inhibit the T790M mutation, induced autophagy three-fold over basal levels while treatment with gefitinib or erlotinib, which are not able to inhibit the T790M mutation, did not induce ULK-mediated ATG13 phosphorylation. DCC-3116 potently inhibited osimertinib and afatinib-induced phosphorylation of ATG13 and inhibited the increase in autophagosomes induced by these agents.

In Vivo Data Show that Combination of DCC-3116 with EGFR Inhibitors Resulted in Significantly Greater Tumor Responses in NSCLC Xenograft Model

– The combination of DCC-3116 with osimertinib or afatinib resulted in significantly greater tumor responses than single agent treatments in the H1975 EGFR-mutant xenograft model.

The clinical development plan for DCC-3116 will initially focus on documented RAS and RAF cancer mutations, which utilize autophagy for tumor growth and survival. DCC-3116 is currently being investigated in a Phase 1, multicenter, open-label, first-in-human study designed to evaluate the safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of DCC-3116 as a single agent and in combination with trametinib, a commercially available MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene. Following the dose escalation phase, combination expansion cohorts are currently planned in patients with advanced or metastatic pancreatic ductal adenocarcinoma with KRAS or BRAF mutations, non-small cell lung cancer (NSCLC) with KRAS, NRAS, or BRAF mutations, colorectal cancer with KRAS, NRAS, or BRAF mutations, and melanoma with NRAS or BRAF mutations. Combination expansion cohorts are planned to evaluate DCC-3116 in combination with trametinib. Initial data from the Phase 1 dose escalation cohorts is expected in 2022.

About DCC-3116

DCC-3116 is an investigational first-in-class small molecule designed to inhibit cancer autophagy, a key tumor survival mechanism, by inhibiting the ULK kinase. DCC-3116 is currently being studied in a Phase 1, multicenter, open-label, first-in-human study as a single agent and in combination with trametinib, a commercially available MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene.