On April 8, 2022 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported that two posters presenting preclinical data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 for zandelisib, an orally administered phosphatidylinositol-3-kinase (PI3K) inhibitor, and ME-344, a tumor selective mitochondrial inhibitor (Press release, MEI Pharma, APR 8, 2022, View Source [SID1234611767]).

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"The preclinical data presented at AACR (Free AACR Whitepaper) is supportive of the promise of our pipeline and we look forward to continuing to advance our clinical candidates in an effort to provide new therapeutic options for patients with cancer," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma.

To view the posters click here.

Title: Efficacy and immune profiling of the PI3K delta inhibitor zandelisib (ME-401) in a preclinical model of chronic lymphocytic leukemia (CLL)
Authors: Dr. Maharaj, et. al.
Date: Friday, April 8, 2022, 8:30 AM ET
AbstractID: 5496

Summary: Data from preclinical studies with zandelisib ex vivo in normal human T cells and in vivo in a murine CLL model suggest that zandelisib has immunomodulatory properties on human T cells. Zandelisib in combination with ibrutinib further reduced normal human T cell proliferation and inducible regulatory T cells (Tregs), while zandelisib alone decreased activation and expression of suppressive markers, such as PD-1 and CTLA-4 on inducible regulatory (Tregs) and CD4+ T cells, comparably to zandelisib/ibrutinib combination. In the murine CLL model, a reduction in Treg numbers, markers of terminal memory differentiation and T-cell exhaustion on CD4+ and CD8+ T cells – all of which are features that have been shown to permit CLL immune evasion – as well as improvement in overall survival was observed.

Title: ME-344, a novel isoflavone mitochondrial inhibitor, in combination with venetoclax constitutes a new metabolism-targeted approach to overcome resistance to Bcl-2 inhibition and standard of care treatment in AML
Authors: Katie Hurrish, et. al.
Date: Wednesday, April 13, 2022, 10:00 AM – 1:30 PM ET
AbstractID: 3785

Summary: ME-344 is an investigational isoflavone that has been shown to suppress OXPHOS in solid tumor cells. However, it has not been tested extensively in hematologic malignancies. This study analyzes the ability of ME-344 to enhance the activity of venetoclax against acute myeloid leukemia (AML). Data from the presented in vitro and in vivo preclinical studies evaluating the combination of ME-344 with venetoclax in standard-of-care-resistant AML cell lines and relapsed or refractory AML patient samples suggest that ME-344, both alone and in combination with venetoclax, inhibits purine biosynthesis, suppresses oxidative phosphorylation, induces apoptosis and decreases Mcl-1, which together target metabolic vulnerabilities of AML cells. The data demonstrated that ME-344 and venetoclax prolong survival in MV4-11- and MV4-11/AraC-R-derived xenograft AML models. Overall, it’s concluded that ME-344 enhances venetoclax activity against AML cells including resistant AML.

About Zandelisib

Zandelisib, a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen (IDT). The IDT leverages molecular and biologic properties specific to zandelisib.

Ongoing zandelisib studies include the Phase 2 TIDAL study (NCT03768505) evaluating patients with relapsed or refractory follicular and marginal zone lymphomas. Also ongoing is the Phase 3 COASTAL study (NCT04745832) comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab, in patients with relapsed or refractory follicular or marginal zone lymphomas who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL is intended to support marketing applications in the U.S. and globally.

About ME-344

ME-344 is a novel and tumor selective mitochondrial inhibitor drug candidate. It directly targets the OXPHOS complex 1, a pathway involved in the production of adenosine triphosphate, or ATP, in the mitochondria. Treatment of tumor cells with ME-344 as a single-agent results in a rapid loss of ATP and cancer cell death.

Although clinical investigation of ME-344 has demonstrated single agent activity in patients with solid tumors, using it in combination with other cancers therapies is thought to hold more significant potential for patients. Data reported from an investigator-initiated, multi-center, randomized study of ME-344 in combination with the VEGF inhibitor bevacizumab (Avastin) demonstrated biologic activity in the ME-344 treatment group supporting further clinical investigation.

A Phase 2 study of ME-344 plus Avastin in patients with relapsed colorectal cancer is planned to start towards the end of 2022.

On April 8, 2022 Hangzhou Qihan Biotechnology Co., Ltd, an innovative biotechnology company dedicated to applying genome editing technology to cell therapies and organ transplants, reported preclinical data from its NK cell programs, presented during the poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 in New Orleans, Louisiana (Press release, Qihan Biotech, APR 8, 2022, View Source [SID1234611766]).

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NK cells derived from genetically engineered human induced pluripotent stem cells (iPSCs) hold great potential to become the next-generation allogeneic cell therapy products.

"We are excited to share the promising data with the community, as we believe that we can utilize our platform to advance the cell therapy medicine to the patients," said Dr. Luhan Yang, CEO of Qihan Biotech. "The data presented in one poster highlight the "Super NK" cells, genetically engineered with enhanced NK function, demonstrating superior killing capacity against blood and solid tumors. Additionally, we presented our immune privileged cell therapy platform in a non-human primate model in a separate poster. Creating a library of monkey iPSCs with up to 21 genetic modifications to evade allogeneic immune rejection and successfully differentiating them into functional monkey NK cells provided us with the unique translational opportunity to study NK Pharmacokinetics (PK) and Pharmacodynamics (PD)."

Poster Presentations:

Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks.
Session: OPO.TB02.01 – Stem Cell Biology
"Super NK cells" – natural killer cells derived from engineered hiPSC with enhanced NK receptor expression demonstrate excellent anti-tumor effects for solid tumors.
Session: PO.TB02.02 – Stem Cells and Regulatory Pathways in Cancer

On April 8, 2022 Researchers at City of Hope, one of the largest cancer research and treatment organizations in the United States, reported that it will present late-breaking and clinical trial findings at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which begins today (Press release, City of Hope, APR 8, 2022, View Source [SID1234611765]). These additional presentations showcase a pilot program in tobacco use cessation and new developments in cell therapy.

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Engineering natural killer cells for a new type of cell therapy (two presentations)
(1) "Off-the-shelf cord blood FLT3 CAR-NK cells for immunotherapy of acute myeloid leukemia"
Poster Presentation LB102: Monday, April 11, 1:30 to 5 p.m. CT

Jianhua Yu, Michael Caligiuri and colleagues have developed a new cell therapy approach using natural killer cells that, in lab models, induced a greater response against acute myeloid leukemia (AML) and lengthened the survival of mice with AML without damaging healthy blood stem cells. The treatment could one day provide a viable cell therapy option for patients with AML, who traditionally have not benefited from innovative cell therapy treatments. When these patients experience relapse, it often occurs rapidly, so there is not enough time to prepare patient-derived chimeric antigen receptor (CAR) T cell therapy. City of Hope researchers believe the off-the-shelf cord blood approach they are developing will provide a breakthrough treatment option for a subpopulation of AML patients with the FLT3 gene.

(2) "Tumor-reactive and anti-PD-L1 co-stimulated killer cells (TRACK-NK) for immunotherapy of non-small cell lung cancer"
Poster presentation LB211, Wednesday, April 13, 9 a.m. to 12:30 p.m. CT

Ting Lu, Jianhua Yu, Michael Caligiuri and colleagues have engineered off-the-shelf natural killer cells to make a protein that causes them to be 10 times more potent in killing human lung cancer cells grown in the lab. When tested in mice transplanted with human non-small cell lung cancer, the innovative cell therapy City of Hope developed worked better than un-engineered natural killer cells and did not appear to affect body weight, liver or kidney function, or blood counts, suggesting a safe and effective approach to test clinically.

Priming brain tumors with an oncolytic virus before CAR T cell therapy will soon be tested in humans
"Oncolytic viral reshaping of the tumor microenvironment to promote CAR T cell therapy for glioblastoma"
Poster Presentation CT541, Wednesday, April 13, 9 a.m. to noon CT

Christine Brown will present data to support the initiation of a Phase 1 clinical trial combining CAR T cell therapy with a cancer-killing oncolytic viral therapy for the treatment of recurrent glioblastoma. This combination trial builds on interim clinical findings from City of Hope and the University of Alabama at Birmingham (UAB). A CAR T cell therapy Phase 1 trial being carried out at City of Hope for recurrent glioblastoma suggests that the more immune cells within the tumor, the longer the patient’s survival. The oncolytic viral clinical Phase 1 trial conducted by UAB used an oncolytic virus engineered for improved gene expression and viral replication to kill specific brain tumor cells; early findings suggest that the virus could activate immune responses in the brain. Based on these human clinical trials, the research team treated mice with brain tumors first with the oncolytic virus, then with cell therapy, and showed that together the two treatments did not cause any side effects. Based on these findings, a clinical trial under a Mustang Bio investigational new drug application will soon open to try this combination on two types of brain tumors.

Empowering cancer patients to design their own smoking cessation program increases desire to quit
"Empowering tobacco-using cancer patient initiation of tobacco cessation by a personal pathway to success program during preoperative patient counseling: a feasibility study"
Poster Presentation LB553, Friday, April 8, noon to 1 p.m. CT

Cary Presant, Kimlin Ashing, Steven Rosen and colleagues developed a novel Personal Pathway to Success program where cancer patients were able to choose from 27 individualized tobacco cessation services to help them quit smoking prior to surgery. The pilot program was offered to 54 patients in a preoperative anesthesia testing clinic, and 23 completed counseling. The availability of the program increased initial patient interest from less than 10% to more than 50% of patients working to quit smoking. The innovative, personalized intervention program appears to be effective, partially because it reaches cancer patients during presurgery visits, when they seem to be more receptive to a "teachable moment" of behavioral changes to prevent disease.

On April 8, 2022 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data from our CDK12 inhibitor program, demonstrating robust anti-tumor activity of our oral, selective CDK12 inhibitors in models of breast, lung, and ovarian cancer, including in a PARP inhibitor resistant model (Press release, Syros Pharmaceuticals, APR 8, 2022, View Source [SID1234611763]). The data support the advancement of a development candidate from Syros’ CDK12 inhibitor program towards clinical development. These findings were presented in an e-poster as part of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022.

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"CDK12 is an attractive cancer target due to its role in transcription and DNA damage repair regulation. Leveraging our selective CDK inhibition expertise, we discovered potent, selective, and oral CDK12 inhibitors, which affect the expression of genes involved in DNA damage response to drive anti-tumor activity," said Eric R. Olson, Ph.D., Chief Scientific Officer of Syros. "Based on the promising new data presented at AACR (Free AACR Whitepaper), in which CDK12 inhibition induced strong tumor growth inhibition and demonstrated synergies in combination with existing standard of care approaches, we believe a CDK12 inhibitor has the potential to play a key role in breast, lung, and ovarian cancer treatment. We look forward to nominating our next development candidate from our CDK12 program in the second half of this year, as we aim to address a significant unmet need for patients, including those who are resistant to DNA damaging agents or PARP inhibitors."

Preclinical Data from Oral CDK12 Inhibitor Program

Syros designed a series of CDK12 inhibitors that were profiled in biochemical and cellular assays. The data presented at AACR (Free AACR Whitepaper) detail for the first time the potency, selectivity, and anti-tumor activity from a representative member of the class, which exhibited low nanomolar potency and selectivity over CDK2, CDK7, and CDK9 of 46-, 27-, and 9-fold, respectively.

As a single agent in cancer cell models, this CDK12 inhibitor induced DNA damage, cell cycle dysregulation and genomic instability leading to growth inhibition and apoptosis. Additionally, as a single agent in in vivo cancer models this CDK12 inhibitor demonstrated tumor regressions in small cell lung cancer and breast cancer models, at well tolerated doses.

In combination in vitro, this CDK12 inhibitor showed synergistic or additive antiproliferative effects in combination with the DNA damaging agent, lurbinectedin, and the PARP inhibitor, olaparib, with increases in DNA damage and impaired DNA damage repair. In vivo, CDK12 inhibition in combination with lurbinectedin showed enhanced anti-tumor activity in a cell line derived model of small cell lung cancer, and in combination with olaparib showed enhanced anti-tumor activity in a PARP inhibitor resistant patient-derived model (PDX) of ovarian cancer.

The poster is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

On April 8, 2022 Tachyon Therapeutics, Inc. ("Tachyon" or "the Company"), a private biotechnology company developing transformative cancer therapies against novel targets, reported preclinical data for TACH101, the Company’s first-in-class KDM4 inhibitor, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022 (Press release, Tachyon Therapeutics, APR 8, 2022, View Source [SID1234611762]). TACH101 is an investigational agent for the potential treatment of adult patients with diffuse large B-cell lymphoma (DLBCL).

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"These preclinical data on TACH101 highlight its anti-tumor activity in DLBCL, the most common and aggressive type of non-Hodgkin lymphoma," said Frank Perabo, M.D., Ph.D., CEO of Tachyon Therapuetics. "This work has increased our understanding of the potential for TACH101 in hematologic malignancies and also attests to its broad applicability in cancer, including solid tumors as was presented at AACR (Free AACR Whitepaper) previously. We look forward to advancing TACH101 into clinical study."

The data presented from both in vitro and in vivo preclinical studies demonstrated that targeting KDM4 with TACH101 resulted in significantly reduced growth of DLBCL cell lines representing the major DLBCL subtypes (GCB, ABC, and PMBL). Additionally, in vivo studies showed TACH101 treatment resulted in significant inhibition of tumor growth leading to complete remission in patient-derived xenograft models.

Highlights from the poster presentation (Poster #3720) are summarized below:

TACH101 showed potent anti-proliferative activity in DLBCL cell lines with IC50 as low as 0.01 µM.
Further evaluation demonstrated DLBCL cell lines were 100% sensitive to TACH101 treatment independent of their molecular subtype.
In vivo, TACH101 triggered effective tumor control (100%) in xenograft models of DLBCL (OCI-LY19).
TACH101 treatment caused downregulation of PNUTS gene expression. PNUTS is a direct target of KDM4 and can serve as a potential pharmacodynamic marker of TACH101 activity in clinical studies.
TACH101 demonstrated favorable pharmacologic and ADME profile without significant off-target activity and low probability of drug-drug interactions.
AACR 2022 is taking place both virtually and in-person at the Ernest N. Morial Convention Center in New Orleans from April 8-13, 2022. The poster presentation titled, "TACH101, a First-in-Class Inhibitor of KDM4 Histone Lysine Demethylase for Treatment of Diffuse Large B-Cell Lymphoma," will be available for viewing to registered attendees starting on Friday, April 8 at 1 pm ET through Wednesday, July 13 on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website. The poster will be presented on April 13 from 10am to 1:30pm ET in the session: PO.MCB05.04 – Chromatin Modifiers: Mutations and Novel Therapeutics.