On June 22, 2020 Ikena Oncology, a clinical-stage biotechnology company that discovers and develops patient-directed, biomarker-driven therapies, reported the presentation of new preclinical research highlighting the anti-proliferative and anti-tumor effects of Ikena-developed compounds targeting the Hippo signaling pathway through the inhibition of TEAD at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020 (Press release, Ikena Oncology, JUN 22, 2020, View Source [SID1234561351]).

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The TEAD (TEA domain) family of transcription factors downstream of the Hippo signaling pathway elicits a gene expression signature that plays a prominent role in cancer development, progression, and metastasis. Increased Hippo pathway activity sustains proliferation, inhibits apoptosis, promotes angiogenesis, and is associated with resistance to multiple therapies. Inhibition of TEAD has been and remains an attractive opportunity for a novel targeted cancer therapy.

"The Hippo pathway is highly mutated across many cancer types, including in mesothelioma, ovarian and breast cancers, and its activation is correlated with an overall poor prognosis in patients. Therefore, we have insights into which patients will most likely benefit from a TEAD-targeted therapy," said Jeffrey Ecsedy, Ph.D., Chief Scientific Officer of Ikena Oncology. "The AACR (Free AACR Whitepaper) presentation this year highlights promising pharmacokinetic, pharmacodynamic, and in vivo efficacy results in mesothelioma models for multiple lead TEAD inhibitor candidates identified by Ikena. These compounds are in studies to narrow in on a development candidate that we look forward to progressing into IND-enabling studies during the second half of 2020."

Ikena’s Novel Small Molecule TEAD Inhibitors

Ikena researchers rationally designed and developed multiple novel, potent, orally bioavailable small molecule inhibitors that reversibly and irreversibly bind to the central lipid (palmitate) binding pocket of TEAD family members. These inhibitors prevent TEAD palmitoylation, a process that is essential for the interaction between the transcriptional co-regulators YAP (Yes-associated protein) or TAZ (transcriptional co-activator with PDZ-binding motif) with TEAD, and lead to downregulation of the YAP/TAZ-TEAD-dependent transcription. Binding of these TEAD inhibitors to the central lipid binding pocket was observed using crystallography.

The Effects of TEAD Inhibition In Vitro and In Vivo

When evaluated in vitro, Ikena’s TEAD inhibitors demonstrated anti-proliferative properties in Hippo pathway-driven cancer cell lines, but not in Hippo pathway wildtype cancer cell lines. Subsequent in vivo experiments in human tumor xenograft mouse models demonstrated that oral administration of these TEAD inhibitors was well tolerated and that TEAD-dependent transcription in the tumors was inhibited. Robust anti-tumor activity was observed in two separate Hippo pathway-mutated mesothelioma xenografts. Translational studies to identify additional tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress.

"The Hippo pathway is hijacked in many cancer types and we believe that by disrupting TEAD transcription, we can prevent tumors from proliferating and evading the body’s immune system," said Mark Manfredi, Ph.D., President and Chief Executive Officer of Ikena Oncology. "We believe our TEAD inhibitor candidates have the potential to be active across several types of Hippo-driven cancers, both as single-agent therapy and in combination with other standard of care oncology agents to overcome therapeutic resistance."

Details for the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II presentation are as follows:

Title: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Lead author: Ben Amidon, Ikena Oncology
Abstract #: 2474
Poster Board #: 18
Session: PO.MCB04.02 – Gene Regulation and Transcription Factors 2
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. ET
URL: View Source!/9045/presentation/6122

On June 22, 2020 Minerva Biotechnologies (Minerva) reported that it has licensed from Memorial Sloan Kettering Cancer Center (MSK) "1XX" technology for use with Minerva’s proprietary anti-MUC1* antibodies to increase CAR T cell persistence in patients (Press release, Minerva Biotechnologies, JUN 22, 2020, View Source [SID1234561350]).

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"This promises to be a great step forward for CAR T cell treatment of solid tumors," said Minerva CEO Dr. Cynthia Bamdad. "We are combining Minerva’s demonstrated cancer-specific antibodies with MSK’s innovative T cell signaling technology that sustains CAR T cell function and persistence."

Minerva is currently in a first-in-human clinical trial for metastatic breast cancers with a CAR T (huMNC2-CAR44) targeting a cleaved form of MUC1 called MUC1* (NCT04020575). MUC1* is the growth factor receptor form of MUC1 that is aberrantly expressed on over 75% of all solid tumors and on over 90% of breast cancers.

CAR T cell persistence, which is the amount of time that infused CAR T cells have the potential to kill tumor cells, is a recognized problem in the revolutionary field of cancer immunotherapy. Since over-activation drives CAR T cell exhaustion, calibrating their activation potential through 1XX mutations in their signaling domain staves off expression of exhaustion molecules that turn CAR T cells off. With this agreement, Minerva will gain non-exclusive access to two of MSK’s innovative CAR T technologies, including the 1XX CAR T cell signaling construct, whose activation potential more closely resembles that of naturally occurring T cells. Minerva expects its next-generation anti-MUC1* CAR T cell therapies to have enhanced therapeutic profiles due to their extended persistence.

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering at MSK and inventor of the 1XX technology said, "We are excited by the prospect of targeting MUC1* with MSK’s 1XX CAR technology."

On June 22, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting an abstract on RGX-104, RGENIX’s lead therapy in development (Press release, Rgenix, JUN 22, 2020, View Source [SID1234561349]). RGENIX’s abstract, "Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors" was accepted for the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which this year was scheduled as two virtual meetings. The abstract results will be presented as a virtual poster presentation (#LB-133/7) in the Late-Breaking Research: Clinical Research 1 session on June 22, by clinical investigator Dr. Monica Mita, Co-Director, Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, who is lead author on the study.

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RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. RGX-104 inhibits tumor angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104.

For the dose escalation stage of the Phase 1 study, RGX-104 was tested as a monotherapy or in combination with either nivolumab, ipilimumab, or docetaxel in heavily pre-treated patients with refractory or relapsed solid tumors, including patients who had progression on prior checkpoint inhibitors (CPI). As outlined in the presentation, objective clinical activity was observed in all treatment arms, including the monotherapy arm, with partial responses achieved in patients with NSCLC, SCLC, melanoma, SCCHN, and endometrial cancer.

Of note, in the combination arms, a 28.6% objective response rate was observed in all evaluable patients who had previously progressed on CPI, with 4 of 14 evaluable patients achieving PRs. Responses included ongoing durable PRs – some exceeding 11 months – in CPI refractory/resistant patients whose tumors were PD-L1 low/negative.

Importantly, clinical activity across all treatment arms was associated with RGX-104 related pharmacodynamic effects, including ApoE activation, MDSC depletion, and CD8 T cell activation with associated induction of IFNγ. Robust ApoE induction was achieved with BID dosing of RGX-104 and was correlated with the magnitude of MDSC depletion. Additionally, in comparison to PD-L1 positive tumors, PD-L1 negative tumors were found to have significantly lower baseline (pre-treatment) levels of ApoE, a feature associated with higher likelihood of clinical benefit to RGX-104. The data demonstrate that MDSC depletion via ApoE induction with RGX-104 can overcome resistance to CPI or chemotherapy, resulting in durable clinical activity.

As a result, RGX-104 is being evaluated in combination with the front-line standard-of-care regimen of pembrolizumab plus carboplatin/pemetrexed in a phase 1b/2 study currently enrolling patients with advanced non-squamous non-small cell lung cancer (NSCLC) whose tumors are PD-L1 negative. RGX-104 is also being evaluated in combination with docetaxel in a phase 1b/2 expansion study that has begun enrolling patients with relapsed/refractory extensive stage small-cell lung cancer (ES-SCLC) or high grade-neuroendocrine tumors (HG-NET).

Monica Mita, M.D., principal investigator from Cedars-Sinai Medical Center and lead author and presenter of the poster, said, "These exciting results provide clinical validation of the novel MDSC-targeting mechanism of RGX-104. The durable clinical responses observed in patients who have previously progressed on checkpoint inhibitors are very promising."

Masoud Tavazoie, M.D., Ph.D., and Chief Executive Officer of RGENIX, said, "We are very encouraged by the results presented today as they demonstrate that our first-in-class drug candidate RGX-104 can robustly target MDSCs, a key drug resistance mechanism, to provide durable clinical benefit to patients. The findings further strengthen the foundation for our ongoing Phase 1b/2 studies. We look forward to sharing results from these ongoing studies."

On June 22, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting an abstract on RGX-019, RGENIX’s pre-clinical antibody program in development (Press release, Rgenix, JUN 22, 2020, View Source [SID1234561348]). RGENIX’s abstract, "In Vivo Safety and Efficacy of RGX-019, a MerTK Targeting Monoclonal Antibody" was accepted for the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which this year was scheduled as two virtual meetings. The abstract results will be presented as a virtual poster presentation (LB-090) during the Late-Breaking Research: Immunology 1 session on June 22, by RGENIX’s Vice President of Research Dr. Isabel Kurth, who is senior author on the abstract.

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MerTK is a member of the TAM family of receptor tyrosine kinases and is predominantly expressed on macrophages as well as on cancer cells from a number of solid and hematologic malignancies. The binding of ligands to MerTK on cancer cells activates signaling that increases proliferation, angiogenesis, and drug resistance. On immune-suppressive M2 macrophages, MerTK signaling promotes immune tolerance. Therefore, there is rationale to target MerTK both to suppress tumor growth and activate anti-tumor immunity.

RGX-019 is a novel humanized MerTK targeting monoclonal antibody with a unique mechanism of action. As outlined in the presentation, RGX-019 was found to bind with high affinity to human and monkey MerTK, without detectable binding to related TAM receptors AXL or Tyro. RGX-019’s unique mechanism drives MerTK degradation through receptor internalization and lysosomal trafficking, resulting in the elimination of MerTK from the surface of treated cells. In vitro, RGX-019 inhibited human cancer cell viability and induced immune-stimulatory cytokine expression in M2 macrophages, consistent with robust inhibition of MerTK signaling. RGX-019 treatment in vivo led to near complete elimination of MerTK from the surface of tumor cells, which was associated with anti-tumor efficacy in mouse xenograft models.

Importantly, RGX-019 demonstrated a favorable safety profile in a 28-day dose-range finding toxicology study in monkeys. Of note, retinal toxicity – a finding associated with other MerTK targeting approaches – was not observed at any dose of RGX-019. The results overall demonstrate that RGX-019 can potently target MerTK signaling on both cancer cells and immune-suppressive M2 macrophages with a novel mechanism, resulting in anti-tumor activity with a wide therapeutic window.

Masoud Tavazoie, M.D., Ph.D., and Chief Executive Officer of RGENIX, said, "The results presented today demonstrate the potential for RGX-019 to be a best-in-class MerTK inhibitor. Its unique characteristics have yielded a favorable safety and efficacy profile in animals that provides a solid foundation for further development of RGX-019. We are excited to move RGX-019 through further IND-enabling studies and ultimately into clinical development."

On June 22, 2020 KIYATEC, Inc. reported that it will present data at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, June 22-24, revealing how its 3D cell culture models characterize ex vivo tumor response and immunoreactivity to immune checkpoint inhibitors (i.e. PD-1, PD-L1 inhibitors) in solid tumors (Press release, KIYATEC, JUN 22, 2020, View Source [SID1234561347]). These emerging capabilities address a significant unmet need in both preclinical drug development and clinical decision-making in oncology.

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PD-1/L1 inhibitors have experienced meteoric growth over the last decade, offering hope to hundreds of thousands of cancer patients every year in the US alone. However, typically no more than 25-30% of eligible cancer patients who receive PD-1/L1 inhibitors actually respond to them. Given that the direct costs associated with PD-1/L1 therapy can run into the hundreds of thousands of dollars per patient, KIYATEC believes that pre-treatment, patient-specific PD-1/L1 response prediction could one day offer clinicians, patients and payers a more objective basis for determining PD-1/L1 inhibitor patient eligibility vs. today’s commonly used population-based biomarkers.

Evidence presented by KIYATEC at AACR (Free AACR Whitepaper) 2020 will highlight findings of the company’s ability to detect dose-dependent response to checkpoint blockade and corresponding correlation with immune cell activation in high-throughput ex vivo 3D tumor spheroid models. KIYATEC believes these recent advances may represent key building blocks toward the eventual development and validation of clinical assays capable of accurate pre-treatment, patient-specific prediction of response to immuno-oncology drugs.

"We’re constantly innovating and expanding the capabilities of our 3D cell culture technologies to reduce the cost and risk of preclinical drug development for our immuno-oncology customers," said Matthew Gevaert, CEO of KIYATEC. "As we continue to make these advances in immuno-oncology drug response on higher-throughput platforms, we can begin to envision a time when such capability would inform clinical decision-making for cancer patients as well."

KIYATEC’s poster presentations at AACR (Free AACR Whitepaper) 2020 are as follows:

Title: Multifaceted functional assessment of checkpoint inhibitor efficacy using 3D tumor spheroids

Abstract: 7397 / Poster: 315 / Session: 3D & Tissue Recombinant Models / June 22-24
Title: PARP inhibition in combination with pembrolizumab enhances cytotoxicity in ovarian cancer patient-derived 3D spheroids

Abstract: 7132 / Poster: 2244 / Session: Immune Checkpoints 2 / June 22-24
Title: The perfused 3DKUBE rare tumor assay models in vivo drug response

Abstract: 7132 / Poster: 2244 / Session: Immune Checkpoints 2 / June 22-24