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.

On April 8, 2022 Primmune Therapeutics, a biotech company harnessing the power of the innate immune system to treat solid tumors in the advanced cancer setting and for the clearance of human papillomavirus and related pre-cancerous cervical lesions, reported the presentation of interim data from a first-in-human, Phase 1 study evaluating PRTX007, a novel, small molecule toll-like receptor 7 (TLR7)-specific agonist, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans (Press release, Primmune Therapeutics, APR 8, 2022, View Source [SID1234611760]). The study is a single-center, prospective, randomized, double-blind, placebo-controlled study with 9 single-ascending dose (SAD) cohorts and 4 multiple-ascending dose (MAD) cohorts where PRTX007 is administered orally to adult healthy volunteers. In addition to assessing the safety, tolerability and pharmacokinetics of PRTX007, the study is designed to evaluate pharmacodynamic responses relevant to dose selection for patients with cancer.

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"These data from our ongoing first-in-human trial indicate that Primmune’s lead candidate, PRTX007, is well-tolerated in healthy volunteers and activates the desired components of innate and downstream adaptive immune responses while avoiding induction of proinflammatory cytokines," said James Appleman, Ph.D., Co-Founder and Chief Scientific Officer at Primmune Therapeutics. "We look forward to the clinical advancement of PRTX007 for the treatment of solid tumors in combination with checkpoint inhibitors and as a monotherapy for the treatment of human papillomavirus-driven pre-cancerous cervical lesions and the underlying infection."

Data show that PRTX007 was well-tolerated and expressed a favorable safety profile in the analyzed patient cohorts, with most adverse events (AEs) considered incidental and no instances of moderate, severe or serious AEs. In addition, every other day (QOD) dosing demonstrated stable systemic immune induction without evidence of counter-regulation. Both the clinical characteristics and unique pattern of immune induction by PRTX007 support its use in combination with immune checkpoint inhibitors.

Presentation Title: PRTX007, an Optimized TLR7 Agonist for Systemic Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)s: Interim Analysis of Phase I Study in Healthy Volunteers
Presenting Author: Curtis Scribner, M.D., Chief Medical Officer, Primmune
Abstract Number: 8165
Poster Number: CT189
Poster Board Number: 14
Poster Session: Phase I Clinical Trials 2 Session
Session Date and Time: Tuesday, April 12, 9 a.m. to 12:30 p.m. CT
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 33

Additional highlights from the poster presentation include:

Most AEs were incidental and not dose related. The most common drug-related AE was headache, seen across both treated and placebo groups independent of dose.
At the interim analysis, PRTX007 demonstrated a favorable safety profile when administered orally to all 9 SAD and 3 MAD cohorts tested.
PRTX007 demonstrated induction of interferon-stimulated genes (ISGs) without significant increases in circulating interferons (IFNs). There was no increase in expression or circulating levels of proinflammatory cytokines (e.g., TNFα, IL-6, IL-1β).
About PRTX007

PRTX007, Primmune’s lead clinical development candidate, is designed to provide well-tolerated, controlled, long-term stimulation of the innate immune response while also potentiating long-term effective innate and adaptive immune responses. PRTX007 uniquely activates plasmacytoid dendritic cells (pDCs), leading to a systemic immune poly-IFN response without stimulating production of NF-κB-driven proinflammatory factors like IL-6, TNFα or IL-1β. Furthermore, activated pDCs directly deliver interferons to target cells by paracrine transfer. This is functionally equivalent to administering a cocktail of all Type I/III IFN while avoiding the associated side effects and adverse events. PRTX007 is being rapidly advanced towards clinical trials for solid tumors in the advanced cancer setting and for clearing human papillomavirus-driven pre-cancerous cervical lesions.

On April 8, 2022 AbCellera (Nasdaq: ABCL), a technology company focused on next-generation antibody discovery, reported the release of data on its new T cell engager platform at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting (Press release, AbCellera, APR 8, 2022, View Source [SID1234611759]). AbCellera’s poster presentation describes the discovery, characterization, and validation of a diverse panel of CD3-binding antibodies that can be used to develop bispecific CD3 T cell engagers for new cancer treatments.

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"T cell engagers are widely recognized for their tremendous potential as precision oncology therapeutics. However, a limited pool of available CD3-binding antibodies and technological challenges in engineering bispecifics have hindered development, leading to many first-generation molecules with poor efficacy or safety," said Bo Barnhart, Ph.D., VP, Translational Research at AbCellera. "Our discovery engine has allowed us to build a panel of hundreds of diverse and fully human CD3-binding antibodies. Combined with our OrthoMabTM bispecific platform, this enables rapid screening of many combinations of CD3- and tumor antigen-binding antibodies to find pairs with optimal biological function and good developability."

CD3 T cell engagers, which bind to T cells and cancer cells simultaneously, are able to redirect T cells to tumor cells, regardless of T cell specificity. Two different parental antibodies, a CD3-targeting antibody that fine-tunes T cell activation and a tumor-targeting antibody with high specificity for cancer cells, are needed to create an optimal bispecific T cell engager. Highly diverse panels of developable and functionally validated parental antibodies increase the probability of finding effective and manufacturable CD3 T cell engagers and reduce the need for downstream engineering to eliminate liabilities.

AbCellera used its technology stack to discover a panel of CD3-binding antibodies from humanized mice. Bioinformatic analysis revealed high sequence diversity, including somatic hypermutation, a range of CDR3 lengths, and diverse V gene usage. The panel was also found to be functionally diverse, including a broad range of CD3 affinities and T cell activation potencies. Biophysical characterization demonstrated that AbCellera’s CD3-binding antibodies have favorable developability properties, which may reduce the time and technical risks of downstream protein engineering, including low mean hydrophobicity, self-association, and polyspecificity.

AbCellera used its clinically validated bispecifics platform, OrthoMabTM, to pair the CD3-binding antibodies with a single EGFR-binding arm to validate the panel in bispecific formats. The resulting bispecific antibodies activated T cells with a range of potencies and led to T cell-mediated tumor cell killing of EGFR-expressing cell lines.

"The data from our T cell engager program, which we initiated in late 2021, show the power and speed of AbCellera’s robust platform," said Neil Berkley, AbCellera’s Chief Business Officer. "Our panel of CD3-binding antibodies offers partners the ability to unlock this promising modality and accelerate their oncology programs by streamlining the development of new cancer treatments."

Details on AbCellera’s presentation at AACR (Free AACR Whitepaper) are as follows:

Title: Redirecting T cells to tumor targets with functionally diverse CD3-binding antibodies
Presenter: Bryan (Bo) C. Barnhart, Ph.D., VP Translational Research, AbCellera
Session: Antibodies and Immune Therapies — Abstract #312
Date and time: Sunday, April 10 at 1:30-5:00 PM CDT

The poster is available for viewing here.