On April 17, 2023 ZielBio, Inc., a clinical stage biotechnology company discovering new treatments for cancer and other serious diseases, reported it will present new, preclinical data showing that its lead asset, ZB131, directed against cancer-specific plectin (CSP), represents a promising approach for antibody-drug conjugates (ADCs) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, ZielBio, APR 17, 2023, View Source [SID1234630203]).

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The AACR (Free AACR Whitepaper) Annual Meeting is taking place April 14-19, 2023 in Orlando and virtually. ZielBio’s Dr. Lindsey Brinton, Principal Scientist and Head of Research, and Dr. Samantha Perez, Senior Scientist, will present the data in a poster session on Wednesday, April 19 from 9:00 am to 12:30 pm in Section 21 of the poster hall.

Major advances in payload and linker technology are increasing the clinical adoption of ADCs, leaving an unmet need for the identification of new targets that differentiate cancer cells from healthy cells across multiple tumor types. ZielBio has validated CSP, a pro-tumorigenic protein expressed on the surface of cancer cells, as a high-value drug target and developed ZB131 as a first-in-class anti-CSP monoclonal antibody. ZB131 is currently being evaluated in a Phase 1/2 clinical trial (NCT05074472) across multiple solid tumors.

Research presented at AACR (Free AACR Whitepaper) will focus on CSP as a target for ADCs, demonstrating its abundance on the surface of cancer cells (and not healthy tissue), its bioavailability in humans, and its application across multiple cancer indications. ZB131 demonstrates favorable pharmacokinetics, is rapidly internalized by CSP-expressing tumor cells in mouse models, and can be conjugated to multiple cytotoxic payloads.

"These findings underscore our enthusiasm for CSP as a therapeutic target and ZB131 as an excellent candidate for conjugation to payloads," said Alan Bash, CEO of ZielBio. "We are excited to share this data with the AACR (Free AACR Whitepaper) community and are committed to exploring new avenues for deploying ZB131 against difficult-to-treat cancers."

On April 17, 2023 City of Hope, one of the largest cancer research and treatment organizations in the United States, reported that it will showcase breakthrough research and innovative studies at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which takes place April 14 to 19 in Orlando, Florida (Press release, City of Hope, APR 17, 2023, View Source [SID1234630202]).

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"In addition to City of Hope providing best-in-class cancer care and treatment, we are also an incubator for innovative clinical research," said Steven T. Rosen, M.D., City of Hope provost and chief scientific officer, Irell & Manella Cancer Center Director’s Distinguished Chair and Morgan & Helen Chu Director’s Chair of the Beckman Research Institute. "City of Hope research presented at the AACR (Free AACR Whitepaper) conference is a testament to this groundbreaking scientific research and our commitment to bringing more cures to patients."

Highlights of City of Hope research presented at the AACR (Free AACR Whitepaper) conference include:

Targeting Proteins to Stop the Progression of Chronic Lymphocytic Leukemia

Yiming Wu, Ph.D., a postdoctoral fellow in the laboratory of Lili Wang, M.D., Ph.D., City of Hope associate professor in the Department of Systems Biology, will present data on chronic lymphocytic leukemia (CLL) research. His presentation, "METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression" will outline important findings from a paper that was published simultaneously in Blood Cancer Discovery journal.

In an effort to understand how damage to regulatory mechanisms at the molecular level contributes to the onset and progression of CLL, Wang, Wu and a team of researchers analyzed a range of molecules and proteins for clues. What they found was that METTL3, an enzyme essential to cell growth, controls splicing factors that lead to RNA splicing dysregulation — a feature common in tumors — in CLL.

"We found that higher levels of either METTL3 protein or splicing complexes are associated with poorer clinical outcomes," Wu said. "Targeting METTL3 or splicing complexes serves as a potential therapeutic target in aggressive CLL."

CLL is one of the most common types of leukemia in adults that is rarely cured, so novel treatment options that could result from the team’s findings are greatly needed, Wu added.

Testing a New Upfront Treatment Option for Myelofibrosis

Myelofibrosis is a different and rare type of blood cancer that disrupts the production of red blood cells and causes scarring in bone marrow. In a poster session, Haris Ali, M.D., City of Hope associate professor in the Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, will present results from "A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis," which investigated a combination therapy as an upfront treatment of the disease.

In the trial, Ali and other researchers evaluated a combination of the anti-cancer drug selinexor with ruxolitinib, a chemotherapy, in patients who had not yet been treated for myelofibrosis. They found the therapy to be well-tolerated and effective at causing an early response with spleen volume reduction and symptoms improvement.

"The future of myelofibrosis for upfront treatment will be combinations like the one we’ve been testing for a faster, deeper and prolonged response," Ali said. "We hope over time that we will see this combination therapy prevent, or at least delay, progression of myelofibrosis."

Reporting on New Results From Phase 2 of the CAPTIVATE Study

Phase 2 of the CAPTIVATE trial is investigating the use of ibrutinib, a small molecule drug, combined with venetoclax, an anti-cancer medication. The therapy has demonstrated a deep and durable response in patients with previously untreated chronic lymphocytic leukemia (CLL) who received a fixed-duration treatment.

At the AACR (Free AACR Whitepaper) conference, research by Tanya Siddiqi, M.D., a City of Hope associate professor and director of the CLL program in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, and medical director of lymphoma, City of Hope Orange County, and team will present new findings from the CAPTIVATE trial in a poster session titled, "Similar outcomes regardless of post-randomization treatment with ibrutinib or ibrutinib + venetoclax in the Phase 2 CAPTIVATE study of first-line ibrutinib + venetoclax in CLL."

In the group of participants who had minimal residual disease after their initial treatment with ibrutinib plus venetoclax, patients were then randomized to either continue with the combination therapy or receive ibrutinib alone.

"We found that in patients who had minimal residual disease — or very few cancer cells in their blood — but not confirmed completely undetectable minimal residual disease, continued use of ibrutinib plus venetoclax improved rates of undetectable minimal residual disease," Siddiqi said. "However, progression-free disease and overall survival rates were similarly high in patients who continued combination therapy and those who received ibrutinib alone. Adverse event rates also generally decreased over time in both arms."

Additional Highlights From City of Hope Participants at AACR (Free AACR Whitepaper):

Nagarajan Vaidehi, Ph.D., City of Hope professor and chair of the Department of Computational and Quantitative Medicine, is chair of a symposium titled, "SY30: Advances in Quantitative Sciences in Cancer: From Atomic Scale to Patients." From mathematics and computer science to chemistry and engineering and more, quantitative sciences play a huge role in cancer research. The goal of this symposium is to foster interdisciplinary research and collaborations across the many quantitative researchers dedicated to advancing cancer care.
Kimlin T. Ashing, Ph.D., City of Hope deputy director, Division of Health Equities, received an AACR (Free AACR Whitepaper) Team Science Award for her work on the African Caribbean Cancer Consortium. The award recognizes contributions that address cancer and health disparities by furthering the study of risk factors in patients of African descent.
Ajay Goel, Ph.D., M.S., City of Hope professor and chair of the Department of Molecular Diagnostics and Experimental Therapeutics, received the 2023 Lustgarten Foundation-Swim Across America-AACR Pancreatic Cancer Early Detection Research Grant for his study, "A Circulating Epigenetic Signature for Early Detection of Pancreatic Cancer."
Michael Caligiuri, M.D., president of City of Hope National Medical Center and Deana and Steve Campbell Physician-in-Chief Distinguished Chair, moderated a session called, "Fostering Entrepreneurship I: Commercializing Innovative Ideas — Where to Start?" that will discuss important factors to consider when exploring partnerships with industry, like financing, licensing and tech transfer.
Victoria L. Seewaldt, M.D., City of Hope’s Ruth Ziegler Chair in Population Sciences, served as a chair of the "Grant Writing Workshop: Tips for Success From Experienced Scientists." This professional advancement session aims to give new investigators helpful tools for writing competitive grants.
Mark LaBarge, Ph.D., City of Hope professor in the Department of Population Sciences, served as a panelist for the major symposium, "Role of Aging in Cancer." His talk is titled Integrated noise from random damages into signals that presage breast cancer susceptibility.

On April 17, 2023 EXUMA Biotech, Corp., a clinical-stage biotechnology company discovering and developing cell and gene immunotherapies for solid and hematological tumors, presented a poster entitled "In vivo delivery of CD3-directed CD19-CAR lentivectors leads to the generation of CAR T and NK-like (CAR-TaNK) cells capable of complete ablation of B cells in the blood, bone marrow, and tissue of NSG-SGM3 CD34+ humanized mice" and gave an oral presentation in the "25th Anniversary of Trastuzumab: Impact and Future Directions" major symposium at the American Association of Cancer Research Annual Meeting 2023 held in Orlando (Press release, EXUMA Biotechnology, APR 17, 2023, View Source [SID1234630201]).

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EXUMA’s presentation, "Can cellular therapy provide another arrow in the quiver for HER2 positive malignancies?" reviewed the potential for novel modalities to continue targeting HER2 in late-stage HER2-positive cancers and provided translational and clinical insights from a novel HER2 targeted CAR-T product (CCT303-406) developed by the company in addition to next-generation technologies. Similar to many solid tumor targets, early clinical research with CAR-T therapies targeting HER2 were challenged by on-target, off-tumor toxicity. EXUMA developed CCT303-406 to provide Tumor Microenvironment Restricted (TMR) CAR binding based upon characteristics unique to the tumor microenvironment. Updates from an investigator-initiated, dose escalation study in patients with advanced relapsed/refractory HER2+ solid tumors reported no dose-limiting toxicities to date attributable to CCT303-406 through 9 patients across the planned dose cohorts. Encouraging, early evidence of clinical activity correlated with subjects with cell expansion in the periphery at the highest planned dose cohort (1×107 cells/kg), with post-treatment tumor biopsy data suggesting enrichment of CCT303-406 CAR T cells within the tumor. Based upon the clinical profile to date, further dose escalation, enrichment within select HER2-overexpressing malignances, and backfill of the 1×107 cells/kg cohort is planned.

Dr. Gregory Frost, Chairman & CEO, remarked that "The safety profile to date, the evidence of pharmacokinetic amplification of CCT303-406 in patients receiving higher doses of therapy, and preliminary evidence of clinical activity, see us cautiously optimistic that our preclinical findings will continue to translate in the clinic. Investigation of higher doses in defined HER2+ malignancies may be warranted to establish CCT303-406’s complete safety profile and potential efficacy in these patient populations with significant unmet clinical needs."

Also today, Dr. Sidharth Kerkar, VP, Research & Development, presented preclinical data highlighting the ability of the Company’s next-generation CAR platform (GCAR) to generate CAR cells in vivo and eliminate CD19 B cells in a dose-dependent manner following direct administration of a CD3-directed lentivector encoding a CD19 CAR and EXUMA’s proprietary FITNESS DRIVER.

Dr. Kerkar commented "We’re exceptionally pleased with the progress EXUMA is making with its in vivo CAR therapy program, and excited that our FITNESS DRIVER generates the unique CAR-TaNK effector cell phenotype with both T and NK features when incorporated into GCAR."

About CCT303-406

CCT303-406 is EXUMA Biotech’s tumor microenvironment restricted (TMR) autologous CAR-T product candidates targeting HER2, which is currently part of an investigator-initiated clinical trial in patients with metastatic HER2+ solid tumors. HER2 overexpression is a hallmark of several tumors, including those originating from breast, stomach, bladder, and colon. A significant proportion of patients relapse or become unresponsive to antibody-based products targeting HER2 in early lines of treatment, yet still retain overexpression of HER2. CCT303-406 may be a promising option for this patient population providing T cell-mediated antitumor activity via targeting of HER2. Differentiating itself from other HER2 CAR-T therapies, CCT303-406 incorporates EXUMA’s TMR safety technology, which helps restrict CAR-T activity to the tumor microenvironment potentially reducing the risk of on-target, off-tumor cytotoxicity.

About the FITNESS DRIVER

EXUMA Biotech’s FITNESS DRIVER is a proprietary, synthetic, intracellular, membrane-bound protein composed of two homodimers identified from an unbiased, comprehensive, in vitro and in vivo screen of thousands of signaling pairs for the ability to drive optimal in vivo proliferation, persistence, and cytotoxicity of CAR+ cells in the absence of lymphodepletion. The FITNESS DRIVER is encoded within the Company’s next-generation CAR therapy lentivectors (LVs) that power the rPOC and GCAR platforms, both of which are engineered to generate CAR-T cell therapy in the patient, preserving T cell stemness and eliminating lengthy and costly ex vivo manufacturing steps. Moreover, the CD3-positive lymphocytes transduced with the FITNESS DRIVER take on a unique effector cell phenotype with features of both T and NK (TaNK) cells (CD3+, NKG2D+, CD8+, CD56+). EXUMA is the only company to have conducted a comprehensive screen of candidate pairs of signaling proteins to optimize the biology of CAR-T cells for safety, efficacy, and potentially eliminating the need for lymphodepleting chemotherapy prior to cell therapy, all of which are designed to improve and expand the setting of CAR-T cell therapy beyond the transplant ward.

About GCAR

GCAR is EXUMA Biotech’s next-generation, in vivo CAR engineering, LV platform. GCAR LVs have the potential to be directly administered to patients and target T cells through a CD3-directed element on the LV surface. Once inside the patient’s T cells, the LV payload encoding a CAR and the FITNESS DRIVER produce T cells with enhanced proliferation, persistence, and greater cytotoxicity compared to traditional CAR-T cells. The modular nature of the GCAR platform may allow for other CARs to function with the FITNESS DRIVER, thereby enabling a robust, off-the-shelf, CAR therapy platform without the need for preparative chemotherapy and ex vivo cell processing.

On April 17, 2023 Gamida Cell reported that the U.S. Food and Drug Administration approved Omisirge (omidubicel-onlv), a substantially modified allogeneic (donor) cord blood-based cell therapy to quicken the recovery of neutrophils (a subset of white blood cells) in the body and reduce the risk of infection (Press release, Gamida Cell, APR 17, 2023, View Source [SID1234630200]). The product is intended for use in adults and pediatric patients 12 years and older with blood cancers planned for umbilical cord blood transplantation following a myeloablative conditioning regimen (treatment such as radiation or chemotherapy).

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"Today’s approval is an important advance in cell therapy treatment in patients with blood cancers," said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. "Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation. This approval reflects the FDA’s continued commitment to supporting development of innovative therapies for life-threatening cancers."

Blood cancers are a form of cancer caused by uncontrolled growth of cells in the blood, disrupting the ability of blood cells to perform their normal functions. This abnormal cell growth often begins in the bone marrow, which is made up of stem cells that form into different types of blood cells with specific functions in the body. Blood cancers represent about 10% of all cases of cancer each year in the U.S. Blood cancers can be fatal, with varying survival rates based on multiple factors including the specific type of blood cancer diagnosed. This type of cancer can also cause serious and damaging effects to the body and lead to symptoms such as fatigue, bone and joint pain, night sweats, infections, weakness, weight loss and fever.

Stem cell transplantation is a common treatment for blood cancers. It involves putting healthy stem cells into the body to help restore the normal production and function of blood cells. One source of healthy stem cells is umbilical cord blood. Generally, before receiving this kind of transplant, the patient will undergo a course of treatments to remove their own stem cells and prepare the body for the new stem cells. This process may include undergoing therapies such as radiation or chemotherapy, both of which may weaken an individual’s immune system. As a result, a frequent and serious risk of this treatment is the occurrence of severe and sometimes deadly infections.

Omisirge, administered as a single intravenous dose, is composed of human allogeneic stem cells from umbilical cord blood that are processed and cultured with nicotinamide (a form of vitamin B3). Each dose is patient-specific, containing healthy stem cells from an allogeneic pre-screened donor, meaning it comes from a different individual rather than using the patient’s own cells.

The safety and effectiveness of Omisirge was supported by a randomized, multicenter study comparing transplantation of Omisirge to transplantation of umbilical cord blood, in subjects between the ages of 12 and 65 years. The study enrolled a total of 125 subjects. All subjects in the study had confirmed blood cancers. The efficacy of Omisirge was based on the amount of time needed for recovery of the subject’s neutrophils (a type of white blood cell that helps protect the body from infections) and the incidence of infections following transplantation.

Eighty-seven percent of subjects who were randomized to receive Omisirge achieved neutrophil recovery with a median of 12 days following treatment with the product, compared to 83% of subjects who were randomized to receive umbilical cord blood transplantation and who achieved neutrophil recovery with a median of 22 days. Bacterial or fungal infections by 100 days following transplantation were seen in 39% of subjects receiving Omisirge versus 60% of subjects in the control group who received umbilical cord blood.

Treatment with Omisirge has the potential to cause severe side effects, which must be considered in assessing the risks and benefits of using this product. Similar to all approved umbilical cord products, the label carries a Boxed Warning for infusion reactions, graft versus host disease (GvHD – a condition that occurs when donor bone marrow or stem cells attack the graft recipient), engraftment syndrome (characterized by a noninfectious fever and rash), and graft failure (occurs when new cells do not produce white blood cells, red blood cells and platelets).

The most common adverse reactions associated with Omisirge included infections, GvHD, and infusion reactions. Patients who receive Omisirge should be monitored for signs and symptoms of infusion reactions, GvHD, engraftment syndrome, graft failure, transmission of serious infections or rare genetic diseases from the donor cells, as well as life-long for secondary malignancies (cancers that can spread from the original site or emerge following treatment).

This application received Priority Review, Breakthrough Therapy and Orphan designations.

The FDA granted regular approval of Omisirge to Gamida Cell Ltd.

On April 17, 2023 Myeloid Therapeutics, Inc. ("Myeloid"), a clinical stage mRNA-immunotherapy company, reported its presentation of two posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in Orlando, Florida (Press release, Myeloid Therapeutics, APR 17, 2023, View Source [SID1234630199]).

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"At AACR (Free AACR Whitepaper) 2023, we are pleased to present late-breaking research on our in vivo engineering capabilities and clinical data from our Phase I IMAGINE study of MT-101 in PTCL patients," said Daniel Getts, Ph.D., Chief Executive Officer of Myeloid. "These data demonstrate the power of myeloid cells to orchestrate broad immune responses. We look forward to advancing our platform and expanding our clinical portfolio of in vivo programming candidates and ATAK CAR cell therapy candidates."

Details of the poster presentations are below:

Title: "In vivo delivery of novel CD89 fusion receptor to myeloid cells by mRNA activates anti-tumor immunity"
Session: Late-Breaking Research: Experimental and Molecular Therapeutics 1
Session Date and Time: Sunday April 16, 2023, 1:30 PM – 5:00 PM
Location: Poster Section 35
Poster Board Number: 19
Abstract Presentation Number: LB027

Abstract Highlights:

Myeloid illustrates with this poster its ability to engineer circulating and tumor-penetrating myeloid cells so that these cells are activated within the tumor setting and elicit anti-tumor adaptive immunity. This approach is an attractive, novel manner to harness systemic anti-tumor immunity.
Myeloid has applied its engineering insights to overcome challenges of specifically targeting and activating myeloid cells in vivo.
Myeloid has developed a novel in vivo myeloid cell engineering platform, in which a chimeric antigen receptor (CAR) is generated by fusing a tumor recognition scFv with the alpha chain of human Fc receptors (CD89). The stable expression and function of these receptors requires the endogenously expressed common Fc receptor gamma chain (FcRg), which expression is mostly restricted to myeloid cells.
For in vivo engineering, the construct is encapsulated and delivered in lipid nanoparticles (LNP).
Myeloid’s most-advanced in vivo programming candidate is a candidate referred to as MT-302, targeting trophoblast cell surface antigen 2 (TROP2) on cancer cells. TROP2 is overexpressed in most human solid epithelial cancers, as compared to low expression in corresponding normal tissue. Increased TROP2 expression has been linked to increased tumor growth and has been implicated as a prognostic marker in these cancers, supporting the development of earlier therapies targeting TROP2.
Within immunodeficient xenograft models of hepatocellular carcinoma and triple negative breast cancer, delivery of LNP mRNA encoding GPC3-CD89 or TROP2-CD89 fusion proteins resulted in anti-tumor efficacy, confirming the ability of this approach to program myeloid cells. Repeat dosing studies showed significant anti-tumor efficacy following bi-weekly administration of TROP2-CD89.
These studies highlight the potential of in vivo delivery of CD89 fusion proteins to program myeloid cells to recognize and kill cancer, thus providing a novel, promising approach to treating cancer.
Title: "Initial Preclinical and Clinical Experience of Autologous Engineered Monocytes in T cell Lymphoma Patients"
Session Category: Clinical Trials
Session: Phase I Clinical Trials in Progress
Session Date and Time: Monday April 17, 2023, 1:30 PM – 5:00 PM
Location: Poster Section 46
Poster Board Number: 19
Published Abstract Number: CT131

Abstract Highlights:

Myeloid developed the first engineered monocyte cell product, by engineering autologous monocytes to express a novel chimeric antigen receptor (CAR). This CAR contains a tumor recognition domain that is fused to a CD8 hinge domain, Fcγ and PI3K intracellular signaling domains. In addition to imparting tumor specificity, the Fcγ and PI3K signaling domains promote phagocytosis, cytokine production and antigen presentation upon activation.
In a rodent model of melanoma (gp75+ B16/F10-OVA), Ly6C+ monocytes engineered with this receptor were able to phagocytose tumor cells and cross present antigen in vitro. In vivo infusion of engineered monocytes was associated with significant suppression of tumor growth. FACS analysis of tumor-infiltrates demonstrated that engineered monocytes preferentially infiltrated tumors and differentiated into antigen presenting cells.
Based on these promising data, MT-101 is being assessed in humans in the Phase 1, open-label, first-in-human trial in patients with refractory or relapsed T cell lymphoma, IMAGINE trial (NCT05138458). The primary objective is the assessment of safety and tolerability at Day 28, following 3 weekly cycles of 2 infusions. Secondary objectives include assessment of correlative markers of response, pharmacokinetics, and efficacy.
In the first 3 subjects, MT-101 was well-tolerated, with no evidence of CRS, ICANS, or infusion reactions. Examination of biomarkers by CyTOF in one subject showed changes in circulating leukocytes, including B cells. In this subject, survival has been greater than 10 months, while the median overall survival of patients with R/R PTCL is 5.5 months.
Abstracts and full session details can be accessed through the AACR (Free AACR Whitepaper) meeting planner: AACR (Free AACR Whitepaper) Annual Meeting 2023 | Meetings | AACR (Free AACR Whitepaper).

About Myeloid’s ATAK CAR receptors and in vivo mRNA Programming

Myeloid’s novel class of CARs, known as ATAK Receptors, combine tumor recognition with multiple proprietary innate-immune signaling domains. Myeloid scientists have screened multiple unexplored combinations of innate-immune signals and uncovered optimal multi-signal pathways. The combination of cancer recognition binders with these novel intracellular signaling domains allows myeloid cells to be reprogrammed with previously unexplored combinations of immune signals, leading to tumor killing and broad systemic anti-tumor responses.

Myeloid’s novel in vivo engineering platform specifically targets and activates myeloid cells to elicit broader anti-tumor adaptive immunity. Through this approach, Myeloid demonstrates that delivery of lipid-nanoparticles (LNPs) encapsulating mRNA results in selective uptake and expression by myeloid cells in vivo, leading to potent tumor killing in multiple cold tumor models. These data demonstrate the potential for Myeloid’s technology to program cells directly in vivo.