On April 11, 2022 CytoImmune Therapeutics, a clinical-stage immunotherapy company developing a novel class of natural killer (NK) cell-based cancer therapies, reported new preclinical data supporting the therapeutic potential of its CYTO-102 and CYTO-201 programs as treatments for patients with cancer (Press release, CytoImmune Therapeutics, APR 11, 2022, View Source [SID1234611986]). New findings demonstrate the utility of its NK cell platform to generate off-the-shelf, tumor-reactive NK cell (TRACK-NK) and chimeric antigen receptor (CAR) engineered NK cell (CAR-NK) therapies, that result in effective tumor cell killing with favorable tolerability for both solid and liquid tumors. The data are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held April 8-13, 2022, in New Orleans.

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CytoImunne’s unique approach aims to engineer NK cells into therapies that can both directly kill cancer cells, while also broadly stimulating the body’s own endogenous immune system to drive cancer cell death. The company is developing two co-lead NK cell therapies: (1) CYTO-102, a TRACK-NK cell therapy engineered to secrete high levels of soluble IL-15 being developed for the treatment of non-small cell lung cancer (NSCLC) and (2) CYTO-202, a FLT3-directed TRACK-CAR-NK cell therapy that the company is developing for the treatment of acute myeloid leukemia (AML).

"We are very excited to present these new data from two of our proprietary NK cell-based programs, both of which have demonstrated meaningful potential in addressing challenging to treat cancers, including NSCLC and AML," said Michael Caligiuri, MD co-founder and chief scientific officer. "For cancers such as NSCLC, we’ve seen advancements in the field with the emergence of checkpoint inhibitors, but the disease remains incredibly difficult to treat and a major cause of cancer-related mortality worldwide. With our TRACK-NK cells, we believe we may be able to enhance tumor destruction in patients, leading to improved and durable outcomes."

Christina Coughlin, chief executive officer, added "For aggressive cancers like AML, we believe there are certain advantages that an off-the-shelf targeted cell therapy could offer patients compared to autologous CAR T cell therapy, which has a long preparation time – a challenging approach in the face of such a fast-progressing disease. Taken together, findings from our preclinical research validate our novel approach to leveraging NK cells to create treatments for both solid and liquid tumors and support their continued advancement toward the clinic."

Abstract Title: LB211. Tumor-reactive and anti-PD-L1 co-stimulated killer cells (TRACK-NK) for immunotherapy of non-small cell lung cancer
Session: Late-Breaking Research: Immunology 2
Session Date & Time: Wednesday, April 13, 2022, from 9:00 a.m. to 12:30 p.m. ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 18
Summary of Findings: CytoImmune is advancing its CYTO-102 program, an anti-PD-L1 co-stimulated TRACK-NK therapy for the potential treatment of non-small cell lung cancer (NSCLC). The novel therapy was generated by genetically modifying NK cells to express soluble IL-15 (sIL15), an immune signaling molecule crucial for optimal antitumor response and primed with cytokines IL-12 and IL-18 to induce PD-L1 expression. In vitro and in vivo evaluation of the TRACK-NK cells showed:

Following cryopreservation, thawed sIL15-PDL1 NK (TRACK-NK) cell product demonstrated high recovery and viability
Significant cytotoxicity against a human NSCLC cell line when compared to NK cells without expression of sIL-15, NK cells without expression PD-L1, or NK cells without expression of both
Repeated infusions of human TRACK-NK cells resulted in a significant tumor suppression compared to cells only expressing sIL15, PD-L1 or neither of both, in a mouse model
Treatment was well tolerated in mice, with no changes in bodyweight or body temperature and no significant changes in liver and kidney functions observed
Abstract Title: LB102. Off-the-shelf cord blood FLT3 CAR-NK cells for immunotherapy of acute myeloid leukemia
Session: Late-Breaking Research: Immunology 1
Session Date & Time: Monday, April 11, 2022, from 1:30 p.m. to 5:00 p.m. ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 18
Summary of Findings: CytoImmune’s CYTO-201 product candidate is a novel, off-the-shelf CAR-NK cell therapy designed to express a specific anti-FLT3-CAR with a secretory soluble form of IL-15. CYTO NK-201 is being investigated as a potential treatment for acute myeloid leukemia (AML), an aggressive hematologic malignancy in which FLT3 expression is present on approximately 20-30% of patients. In vitro and in vivo evaluation of the company’s FLT3 CAR NK cells showed:

Enhanced cytotoxicity in FLT-3 positive human AML cells
Reduced tumor burden and prolonged survival in an aggressive AML mouse model when compared to cells only expressing IL-15 or to the control group
Good tolerability with no signs of toxicity against normal hematopoietic stem cells that also express the FLT-3 marker

On April 11, 2022 MiNA Therapeutics Limited ("MiNA" or the "Company"), the pioneer in small activating RNA (RNAa) therapeutics, reported that preclinical proof of mechanism data on MTL‑STING as a novel cancer immunotherapy (Press release, MiNA Therapeutics, APR 11, 2022, View Source [SID1234611985]). The data validates the drug candidate’s ability to upregulate the STING protein and related downstream pathways of innate immunity through gene activation. The data was presented at a poster session on 10 April 2022 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s (AACR) (Free AACR Whitepaper) annual meeting in New Orleans, entitled ‘MTL-STING restores endogenous STING expression for improving efficacy of cancer therapeutics.’

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Robert Habib, CEO of MiNA Therapeutics, commented:

"We are very pleased to present this encouraging data and to advance MTL-STING further in development. It is the second drug candidate in our internal pipeline of RNAa therapeutics. Upregulation of the STING protein is a radically new approach to improving the innate immune response in cancer patients and enhancing the effectiveness of existing anti-cancer therapies. Demonstrating that MTL‑STING can increase levels of STING protein and activate downstream innate immune pathways is a major step towards this goal, and in expanding the possibilities of RNAa therapeutics."

STING (stimulator of interferon genes) is a master regulatory protein that is essential for identification of cancer cells by the immune system. Downregulation of STING has been reported as a key immune-evasion mechanism in cancer patients and a root cause of inactivation of the cGAS-cGAMP-STING pathway of innate immune response.

Upregulating STING presents a novel therapeutic approach to address immune evasion and improve the effectiveness of existing immunotherapies in cancer patients. To date, therapeutics seeking to drug the cGAS-cGAMP-STING pathway have provided limited benefit to cancer patients. Largely small molecule agonists, they have failed to address the underlying downregulation of STING itself and, in addition, have been limited by safety and bioavailability.

The preclinical data presented at AACR (Free AACR Whitepaper) demonstrated that MTL‑STING upregulated STING mRNA production by more than fivefold, consistent with the activity required to restore STING to homeostatic levels in cancer patients. Importantly, upregulation of STING mRNA was durable, leading to increased levels of STING protein and downstream functional activation of innate immune pathways. MTL-STING is initially being developed as a combination treatment for solid tumour malignancies, with the expectation to enter Phase 1 evaluation in 2023.

MTL‑STING is the second drug candidate to be advanced from MiNA’s internal pipeline of RNAa therapeutics. MiNA’s first drug candidate, MTL-CEBPA, is currently being evaluated in a global Phase 2 clinical trial in combination with sorafenib in advanced hepatocellular carcinoma (HCC or liver cancer). RNAa therapeutics are a revolutionary new class of medicines that can restore or boost normal function within patients’ cells by selectively activating genes.

The poster presented at AACR (Free AACR Whitepaper) will be made available on the Company’s website at View Source

On April 11, 2022 Sapience Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery and development of peptide therapeutics to address difficult-to-treat cancers, reported the presentation of late-breaking research from its lead programs, ST101 and ST316, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Sapience Therapeutics, APR 11, 2022, View Source [SID1234611984]). These data illustrate the potential of targeting intracellular interactions to address cancer pathways that are well-validated but have previously been considered undruggable.

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"With these late-breaking data at AACR (Free AACR Whitepaper) 2022, we have a growing body of preclinical and clinical evidence across our pipeline demonstrating that targeting protein-protein interactions can address cancer targets previously considered undruggable, including C/EBPβ and β-catenin, which we believe offer a wealth of therapeutic promises," said Dr. Barry Kappel, CEO and President of Sapience. "We look forward to advancing ST101 through Phase 2 and progressing ST316 through IND-enabling studies and into the clinic."

ST101 is a first-in-class peptide antagonist of C/EBPβ currently being evaluated in the Phase 2 portion of an ongoing Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors (NCT04478279).

Sapience scientists presented preclinical data from a triple negative breast cancer (TNBC) model used to: (i) characterize and predict the exposure-response relationship of ST101; (ii) provide rationale to select a dose for the Phase 2 clinical study cohorts; and (iii) support the continued development of ST101 as a potent therapeutic for patients with solid tumors.
Following administration of ST101 in TNBC mice, significant tumor growth inhibition was observed, and the exposures required to achieve IC50 and IC90 predicts that 1 mg/kg in humans will exceed the exposure associated with the IC90 in mice.
ST316 is a first-in-class peptide antagonist of β-catenin currently being evaluated in IND-enabling studies.

Sapience designed ST316 to disrupt the interaction of β-catenin with its co-activator BCL9, an interaction essential for oncogenic Wnt/β-catenin signaling but not homeostatic functions.
Sapience scientists presented preclinical data on ST316 demonstrating target engagement with β-catenin, in vitro activity demonstrating disruption of β-catenin nuclear localization, changes in target gene expression in HCT116 cells and significant anti-tumor activity in vivo.
Following once weekly administration of ST316 in HCT116 colorectal cancer subcutaneous xenograft tumors, a 99% tumor growth inhibition was observed.
Details of the late-breaking posters are as follows:

Abstract Number: 8125
Title: Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 2
Session Date and Time: 4/13/2022 9:00 AM
Location: New Orleans Convention Center, Poster Section 16

Abstract Number: 8148
Title: β-catenin antagonist peptide, ST316, attenuates Wnt-dependent oncogenic activity
Session Title: Late-Breaking Research: Molecular/Cellular Biology and Genetics 1
Session Date and Time: 4/11/2022 9:00 AM
Location: New Orleans Convention Center, Poster Section 16

Abstracts and full session details can be accessed through the AACR (Free AACR Whitepaper) meeting planner: AACR (Free AACR Whitepaper) Annual Meeting 2022 | April 8-13, 2022 | New Orleans

About ST101
ST101, a first-in-class antagonist of C/EBPβ, is currently being evaluated in the Phase 2 portion of an ongoing Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors (NCT04478279). This is an open-label, two-part, Phase 1-2 dose-finding study designed to determine the safety, tolerability, PK, PD, and proof-of-concept efficacy of ST101 in patients with advanced solid tumors. The study consists of two phases: a Phase 1 dose escalation/regimen exploration phase and a Phase 2 expansion phase. In the ongoing dose escalation study, ST101 has demonstrated clinical proof-of-concept with a RECIST 1.1-confirmed partial response (PR) in a patient with cutaneous melanoma and evidence of long-lasting stable disease in several additional patients. In the ongoing Phase 2 dose expansion part of the study, Sapience has initiated enrollment in patients with GBM, metastatic cutaneous melanoma, refractory, locally advanced or metastatic hormone-receptor-positive breast cancer and castrate-resistant prostate cancer. ST101 has been granted Fast Track designation for recurrent GBM and advanced cutaneous melanoma in patients who have disease progression on or after anti-PD-1/anti-PD-L1 therapy, as well as Orphan designation from the U.S. Food and Drug Administration and the European Commission for the treatment of glioma.

About ST316
ST316, a first-in-class β-catenin antagonist, is currently being evaluated in IND-enabling studies. β-catenin is a critical member of the canonical Wnt signaling pathway, a well-known development stage pathway that has been considered an "undruggable" cancer target, as small molecules have proven ineffective or toxic. Wnt/β-catenin signaling drives cancer initiation and contributes to tumor growth, angiogenesis and metastasis. ST316 exerts its activity through disruption of the BCL9/β-Catenin interaction to suppress transcription of Wnt target genes regulating proliferation, migration, invasion, and the metastatic potential of tumor cells.

On April 11, 2022 aTyr Pharma, Inc. (Nasdaq: LIFE), a biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways, reported a poster presentation at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held April 8 – 13, 2022, in New Orleans, LA, and virtually (Press release, aTyr Pharma, APR 11, 2022, View Source [SID1234611983]). The poster and corresponding abstract are available for browsing on the AACR (Free AACR Whitepaper) website through July 13, 2022. The poster is also available on the aTyr website.

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The poster presents findings from a preclinical study, conducted in collaboration with Dr. Arthur M. Mercurio and his lab at the University of Massachusetts Medical School, characterizing the subtypes of breast cancer that are most responsive to treatment with ATYR2810, a fully humanized monoclonal antibody that selectively and functionally blocks the interaction between neuropilin-2 (NRP2) and VEGF by directly binding at the site of the VEGF binding pocket. Interrogation of ATYR2810 activity in combination with chemotherapy across a panel of breast cancer cells lines using an in vitro 3D colony formation assay revealed that highly aggressive and more mesenchymal cell lines associated with metastasis, including triple negative breast cancer (TNBC), were most responsive. Data from both patient derived organoid and patient derived xenograft models from TNBC where ATYR2810 demonstrated anti-tumor activity showed downregulation of key genes known to promote metastasis and drug resistance, including CXCR4 and a set of genes linked to the process of epithelial-mesenchymal transition (EMT). Furthermore, ATYR2810 monotherapy inhibited spontaneous lung metastasis in an experimental model of TNBC, demonstrating the potential therapeutic effects of blocking the NRP2/VEGF signaling axis on preventing tumor persistence.

"Highly aggressive tumors such as TNBC have been shown to have elevated NPR2 expression and are typically treated with resection and chemotherapy, though the potential for metastasis and tumor regrowth, which is thought to be strongly linked to the process of EMT, is high. The ability of ATYR2810 to downregulate genes associated with EMT, reduce metastasis and enhance chemosensitivity in these highly aggressive subtypes of breast cancer provides valuable insight regarding the types of tumors that may benefit from treatment with ATYR2810," said Leslie A. Nangle, Ph.D., Vice President, Research at aTyr. "These findings suggests that ATYR2810 may serve as a novel therapeutic agent for the treatment of advanced and metastatic cancers. We look forward to advancing ATYR2810 to a Phase 1 study in cancer patients in the second half of the year."

Details of the poster and corresponding abstract are as follows:

Title: ATYR2810, a fully humanized monoclonal antibody targeting the VEGF-NRP2 pathway sensitizes highly aggressive and chemoresistant TNBC subtypes to chemotherapy
Authors: Zhiwen Xu, Alison G. Barber, Christoph Burkart, Hira Lal Goel, Justin Rahman, Kristina Hamel, Zachary Fogassy, Lisa Eide, Clara Polizzi, Jasmine Stamps, Luke Burman, Kaitlyn Rauch, Ann Menefee, Yanyan Geng, Sofia Klopp Savino, Yeeting E. Chong, Darin Lee, Suzanne Paz, Arthur M. Mercurio, Leslie A. Nangle. aTyr Pharma, University of Massachusetts Chan Medical School, Pangu BioPharma, IAS HKUST – Scripps R&D, Hong Kong University of Science and Technology.
Abstract Control Number: 7998
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 1 / Chemistry
Session Date and Time: Monday, April 11, 2022 from 1:30PM – 5:00PM ET
Location: New Orleans Convention Center, Exhibit Halls D – H, Poster Section 16
Poster Board Number: 10
Permanent Abstract Number: LB085

About ATYR2810

aTyr is developing ATYR2810 as a potential therapeutic for certain aggressive tumors where neuropilin-2 (NRP2) is implicated. ATYR2810 is a fully humanized monoclonal antibody that is designed to specifically and functionally block the interaction between NRP2 and one of its primary ligands, VEGF. ATYR2810 is the first Investigational New Drug (IND) candidate to arise from aTyr’s in-house research program designing monoclonal antibodies to selectively target the NRP2 receptor and its associated signaling pathways. NRP2 is a cell surface receptor that is highly expressed in certain tumors, in the lymphatic system and on key immune cells implicated in cancer progression. Increased NRP2 expression is associated with worse outcomes in many cancers. Preclinical data suggest that ATYR2810 could be effective against certain types of solid tumors. ATYR2810 is currently undergoing IND-enabling studies.

On April 11, 2022 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies for patients with unmet needs, reported positive results from preclinical studies evaluating an anti-HER3 antibody, conjugated with an Actinium-225 (Ac-225) radioisotope payload, for targeting HER3-positive non-small cell lung cancer (NSCLC) cells (Press release, Actinium Pharmaceuticals, APR 11, 2022, View Source [SID1234611981]). These data were presented at the American Association of Cancer Research (AACR 2022) annual meeting, which is being held April 8th – 13th at the Ernest N. Morial Convention Center in New Orleans, Louisiana.

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AACR Poster Highlights:

Ac-225-HER3 antibody radio conjugate (ARC) eliminated HER3-postive tumors in an in vivo animal model of human non-small cell lung cancer (NSCLC) at multiple dose levels with increased survival
A dose-dependent cytotoxic effect against HER3 expressing cells was observed in vitro with the Ac-225-HER3-ARC
Biodistribution data demonstrates accumulation of the Ac-225-HER3-ARC in HER3 expressing tumors in the in vivo model of NSCLC
Conjugation of Ac-225 to the HER3 antibody did not affect the antibody’s targeting properties as determined by binding to HER3 expressing cells
Dr. Helen Kotanides, Vice President, Translational Research and Preclinical Development, stated, "HER3 is a well-validated target that is overexpressed in a number of cancers and associated with poor survival in breast, ovarian, lung, gastric and prostate cancer. It is also upregulated in response to HER1 and HER2 targeted therapies as part of acquired resistance against these EGFR therapies. These data show that arming a HER3-targeting agent with Actinium-225 results in potent anti-tumor agent, which improved survival in our NSCLC models. These data support our goal of developing a HER3 targeted radiotherapy for use in a patient population in need of new treatments and give us great excitement for our ongoing collaboration with AVEO centered around HER3."

Sandesh Seth, Chairman and CEO of Actinium, stated, "We are excited to continue to demonstrate Actinium’s enhanced R&D capabilities and commitment to developing potent radiotherapies targeting solid tumors. We look forward to sharing these data, which show the efficacy for our novel approach of conjugating Actinium-225 to a HER3 antibody at AACR (Free AACR Whitepaper) 2022. The development of Ac-225-HER3-ARC, a product of our validated Antibody Warhead Enabling (AWE) technology platform, represents a departure from conventional HER3-targeting approaches, such as naked antibodies and antibody drug conjugates, that are currently being explored for this tumor antigen. These exciting data highlight Actinium’s leadership in developing novel targeted radiotherapy approaches for treating cancers having high unmet needs."

The full poster is available as an e-poster on the AACR (Free AACR Whitepaper) 2022 platform and will be presented in-person at the conference with details below:

AACR Poster Details

Title: Targeting HER3 receptor positive cancers with a novel anti-HER3 antibody radioconjugate (ARC)
Session Category: Experimental and Molecular Therapeutics
Session Title: Preclinical Radiotherapeutics
Session Date and Time: Tuesday, April 12, 2022, 1:30 PM – 5:00 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 25
Poster Board Number: 4
Permanent Abstract Number: 3306

The poster will be accessible via Actinium’s website here.