On September 19, 2024 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for autoimmune diseases and cancer, reported ADI-001 clinical biomarker data from the Phase 1 GLEAN trial which further reinforces the potential of ADI-001 as a best-in-class allogeneic cell therapy for autoimmune diseases (Press release, Adicet Bio, SEP 19, 2024, View Source [SID1234646757]). Notably, ADI-001 demonstrated robust tissue trafficking resulting in high levels of ADI-001, significant chimeric antigen receptor (CAR) T cell activation, and complete CD19+ B cell depletion in secondary lymphoid tissue. These data will be presented by Dr. Blake Aftab, Chief Scientific Officer, at the 9th Annual CAR-TCR Summit on Thursday, September 19, 2024 in Boston, MA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These results clearly support the potential of ADI-001 and Adicet’s off-the-shelf gamma delta CAR T cell platform, by demonstrating robust trafficking and complete B cell depletion in tissue, while providing superior exposure of ADI-001 in secondary lymphoid tissue compared to published third-party data reported for alpha-beta CAR T therapies," said Blake Aftab, Ph.D., Chief Scientific Officer of Adicet Bio. "Together, the totality of our findings provide multiple levels of evidence highlighting the significant advantages of our approach and present a compelling opportunity for ADI-001 to extend B cell targeting into tissues, as we look to address a range of autoimmune diseases in the clinic."

A summary of the results is reported below:

ADI-001 demonstrated significant levels of CAR T cell activation and tissue exposure in lymph node biopsies in the GLEAN trial, with a mean exposure of 236,701 CAR T cells per million across all dose levels, representing a range of 27-64% of total cellular material detected by ddPCR in evaluable biopsies at the 1E9 dose, and exceeding levels previously reported for patients who received autologous alpha-beta CAR T therapies. CAR T cells detected in tissues also demonstrated a robust activation profile, based on in situ detection of granzyme B.
Recently published studies have demonstrated depletion of CD19+ plasmablasts, memory B cells and naïve B cells in peripheral blood using anti-CD20 targeted antibodies, however, these CD20-targeted antibody modalities failed to deplete B cells within secondary lymphoid tissues.
Concurrent with ADI-001 tissue trafficking and activation, complete depletion of CD19+ B cells within analyzed secondary lymphoid tissue was also observed. These results support ADI-001’s potential for achieving complete B-cell depletion in peripheral blood and within tissues.
Adicet is advancing the ADI-001 clinical program in lupus nephritis, systemic lupus erythematosus, systemic sclerosis and anti-neutrophil cytoplasmic autoantibody associated vasculitis (AAV) and expects to report initial clinical data in the first half of 2025.

Company webcast information

A listen-only webcast with an accompanying presentation by Dr. Aftab is accessible under Presentations & Events | Adicet Bio in the Investors section of Adicet Bio’s website. The archived webcast will be available for 30 days.

About the GLEAN trial

The Phase 1 GLEAN study was an open-label, multi-center study of ADI-001 enrolling adults diagnosed with B-cell malignancies who have either relapsed, or are refractory to, at least two prior regimens.

On September 19, 2024 researchers from City of Hope, one of the largest and most advanced cancer research and treatment organizations in the U.S., and The University of Texas M.D. Anderson Cancer Center, reported safety and efficacy results from a Phase 1 trial that featured a personalized vaccine to treat lymphoplasmacytic lymphoma, a rare and slow-growing type of blood cancer, according to a study published recently in Nature Communications (Press release, City of Hope, SEP 19, 2024, View Source [SID1234646756]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The current approach to lymphoplasmacytic lymphoma care is active surveillance of a patient’s possible symptoms. There is a median time of 3.5 years from diagnosis to progression of symptoms — such as fever, night sweats, weight loss and fatigue — that require chemotherapy.

"By doing an early intervention with the vaccine, we nearly doubled the disease-free progression time to an average of just under seven years," said Larry Kwak, M.D., Ph.D., director of City of Hope’s Toni Stephenson Lymphoma Center within the Hematologic Malignancies Research Institute, who developed the vaccine and is the study’s corresponding author. "In addition to being effective, the vaccine appears to be safe. It didn’t have any of the harsh side effects associated with other types of common cancer treatments."

Toxicity among trial participants was also limited, Dr. Kwak said. That’s because the vaccine uses patient-specific biologic components called tumor neoantigens that can help the body mount an immune response to a particular tumor type.

The clinical trial, led by M.D. Anderson, enrolled nine patients, who were able to tolerate the therapy without negative side effects. After a median follow up of 7.5 years, all of the patients had stable disease and more than half had not progressed to a symptomatic state.

"Using sophisticated technology called single-cell sequencing, we could see that these personalized vaccines activated T cells in the tumor microenvironment, which help destroy tumor cells," said Dr. Kwak, who is also the deputy director of City of Hope’s comprehensive cancer center and the Dr. Michael Friedman Professor in Translational Medicine. "Furthermore, we saw that the tumor cells rely on signaling from myeloid cells to survive, which we didn’t know before, and the vaccine reduced that protumoral signaling, too."

According to Dr. Kwak, disease progression was halted and one patient had a minor reduction in tumor shrinkage. The research teams believe this is because two different subtypes of cells give rise to tumors in lymphoplasmacytic lymphoma — mature B cells and plasma cells — and the vaccine only had an effect on the B cell population.

"The takeaway from that observation is that when we do the next phase clinical trial, we will want to combine the vaccine with another agent that does have more of a direct effect on plasma cells, like a monoclonal antibody," he said.

Dr. Kwak and the research team are working on the next generation of the vaccine for a possible clinical trial that may take place at City of Hope. As part of a Sponsored Research Agreement with Renhaim Inc., Dr. Kwak and team plan to adapt the vaccine to an mRNA platform, which has become a new frontier for vaccine production since the original was developed using DNA nearly a decade ago. The team is also exploring additional therapies to pair with the neoantigen for more vaccine efficacy. Dr. Kwak is a paid consultant with Renhaim Inc.

The neoantigen vaccine research builds upon three decades of investigations by Dr. Kwak, who is a world-renowned physician and pioneering scientist in immunology and cancer vaccines. Dr. Kwak was named one of TIME magazine’s "100 Most Influential People" in 2010 for his work in cancer immunology.

In 2011, Dr. Kwak and colleagues published research in the Journal of Clinical Oncology on the first iteration of the neoantigen vaccine. It was a protein-based vaccine for follicular lymphoma that garnered positive results.

"It was actually one of the first positive cancer vaccine positive trials in the field, but 15 years ago, no drug company was interested in talking with us about a personalized vaccine," Dr. Kwak said. He noted that the "one drug for one patient" model was a tough sell until CAR T cell therapies set a precedent for individualized cancer medicines. "Now they’re much more open to it. I think the future of cancer vaccines is really in this kind of setting, where we’ve shown the effectiveness of early intervention as a way to prolong and maybe even prevent progression to symptomatic disease."

The research reported in the Nature Communications paper, "Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial," was supported by the National Cancer Institute and the International Waldenstrom’s Macroglobulinemia Foundation.

On September 19, 2024 Rakuten Medical, Inc., a global biotechnology company developing and commercializing precision, cell-targeting therapies based on its proprietary Alluminox platform, reported that the research results of the preclinical studies for PD-L1-targeted photoimmunotherapy were presented at the 83rd Annual Meeting of the Japanese Cancer Association (JCA2024) in Fukuoka, Japan on September 20, 2024 (JST) (Press release, Rakuten Medical, SEP 19, 2024, View Source [SID1234646755]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The key findings presented at JCA2024
Abstract Title: PD-L1 photoimmunotherapy kills immunosuppressive myeloid cells to activate local and systemic antitumor immunity
Presenter: Amy H. Thorne, Ph.D. (Rakuten Medical, Inc.)
Abstract Number: 30050

It has been observed in in vitro studies that this photoimmunotherapy has a dual mechanism of action (MoA): depletion of PD-L1 expressing tumor cells and depletion of PD-L1 expressing immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). In addition to this dual MoA, the potential for systemic immune checkpoint inhibition was also observed.
It has been observed in in vivo studies that the treatment resulted in more effective tumor growth suppression compared to anti-PD-L1 antibody alone in an anti-PD-L1 sensitive mouse tumor model and tumor growth suppression compared to saline control in an anti-PD-L1 resistant mouse tumor model.
It has been observed in in vivo studies that the treatment affects the tumor microenvironment balance by depleting immunosuppressive tumor microenvironment cells and maintains checkpoint inhibition to enhance CD8+ T cell activation.
RM-0256 was well-tolerated in a GLP toxicity study in which the drug was administered repeatedly to cynomolgus monkeys.
Based on the preclinical study data, Rakuten Medical is currently considering new clinical development opportunities.

About RM-0256
RM-0256 is a conjugate of a newly developed anti-PD-L1 antibody and IRDye700DX (IR700), a light-activatable dye, that accumulates specifically on PD-L1-expressing cells. PD-L1 is a protein that inhibits the anti-cancer immune response by deactivating killer T cells, via binding to PD-1 which is abundantly expressed on the T cell surface1. PD-L1 is expressed in many solid tumors such as melanoma, lung, urothelial, gastrointestinal, gynecological, breast, and head and neck, among others, helping these tumors evade the immune system2. In addition to being present on tumor cells, PD-L1 is also expressed on suppressive immune cells within the tumor microenvironment such as tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs)3. In preclinical studies, PD-L1-targeted photoimmunotherapy resulted in the necrosis of PD-L1 expressing target cells and activation of an anti-cancer immune response. Furthermore, RM-0256 was shown to inhibit the PD-L1:PD-1 interaction, and thus is expected to act systemically as an immune checkpoint inhibitor, further enhancing the anticancer immune response after PD-L1-targeted photoimmunotherapy.

On September 19, 2024 Biosyngen, an innovative biotechnology company specializing in immune cell therapies, reported its groundbreaking "Conditional Activation + Armor Enhancement" T-cell technology at this year’s ESMO (Free ESMO Whitepaper) conference (Press release, BioSyngen, SEP 19, 2024, View Source;armor-enhancement-super-t-technology-at-esmo-2024-302253153.html [SID1234646754]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Biosyngen has secured ten clinical trial approvals in China and the U.S. for its innovative fourth-generation oncology therapies. Currently, our leading pipeline product, BRG01, is in the pivotal Phase II clinical trial stage for solid tumors. Additionally, the first patients have been enrolled in the Phase I trials for our other groundbreaking therapies, BST02 and BRL03, with completion of Phase I trials anticipated later this year.

Abstract Title
Anti-tumor Efficacy and Safety of Conditionally Activated Armored CAR-T Cells against Gastrointestinal Tumor

Title No.
1033P

Gastrointestinal tumors have been found to exhibit significantly elevated levels of tumor-associated antigens (TAAs) compared to normal tissues, presenting potential targets for immune cell therapies. However, these TAAs are also expressed at certain levels in normal tissues, which poses a challenge for CAR-T cell therapies. Current CAR-T cells often fail to distinguish between tumor and normal tissues, leading to damage to normal organs and adverse clinical reactions. This on-target off-tumor toxicity not only raises safety concerns in clinical treatment but also limits dosage and efficacy enhancement.

To overcome this technical challenge and balance safety with efficacy in solid tumor immune cell therapies, Biosyngen has developed the SUPER-T T cell safety optimization platform and created the Conditional Activation CAR-T cell BTRP003L. This technology allows CAR-T cells to activate only under hypoxic conditions typical of the tumor microenvironment (0.3% ~ 2.0% O2), while remaining inactive in normal tissues (3.4% ~ 6.8% O2). Remarkably, this approach not only regulates CAR-T cell activation levels under different conditions effectively but also enhances their antitumor capabilities (Figure 1). Further advancements include the co-expression of a TGFβRII dominant-negative mutant, resulting in the "Conditional Activation + Armor Enhancement" CAR-T cell BTRP011L, which shows improved efficacy and in vivo persistence at lower doses (Figure 2). Toxicology studies using the SUPER-T platform showed no weight loss or other adverse effects in mice injected with BTRP003L or BTRP011L, demonstrating robust safety.

On September 19, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that the first patient has been dosed in the REMARK study, a Phase II clinical trial investigating RVU120 as a monotherapy for the treatment of patients with LR-MDS (Press release, Ryvu Therapeutics, SEP 19, 2024, View Source [SID1234646753]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are glad to announce the initiation of the REMARK study for RVU120, which can potentially help patients with lower-risk MDS. This study builds upon the promising results from our Phase Ib study in patients with AML and high-risk MDS, where we observed hematologic improvement in several patients, including cases of transfusion independence. The objective is to further assess the safety and efficacy of RVU120 in patients with lower-risk MDS, underpinned by robust preclinical and mechanistic evidence. We believe this represents a significant advancement toward our objective of developing effective treatments for hematological diseases and offering therapeutic options for patients. I am delighted that we can count on the support of the EMSCO network and Prof Uwe Platzbecker in this endeavor." – said Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics.

REMARK is an open-label, multicenter Phase II study of RVU120, a novel small-molecule cyclin-dependent kinase (CDK) 8/19 inhibitor. The study aims to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS). In REMARK, RVU120 is being explored as a single agent in patients with LR-MDS who have exhausted available treatment options.

The REMARK study is being conducted as an investigator-initiated study through the EMSCO network with Prof. Uwe Platzbecker, a globally renowned expert in the field of LR-MDS, as the Coordinating Principal Investigator.

"I am proud that we could start the REMARK study in line with our ambitious plans. RVU120 has shown promising hematologic improvement in patients with off-hematologic impaired bone marrow function. I am optimistic that this clinical evidence will translate into a positive outcome of the REMARK study. RVU120 has important features that should be considered a potential new treatment option for patients with LR-MDS. It may aid in achieving our ultimate aim to alleviate the need for red blood cell transfusions in these patients." – said Uwe Platzbecker, M.D., Director of the Clinic and Poliklinik for Hematology, Cell Therapy and Hemostaseology at the Leipzig University Hospital.

REMARK is being initiated based on the clinical safety and efficacy data gathered so far, as well as strong preclinical and mechanistic rationale. MDS pathogenesis is influenced by gene expression alterations that hinder the maturation of hematopoietic cells. RVU120 triggers erythroid gene expression programs orchestrated by STAT5 and GATA1 in aberrant stem cells from MDS patients. Importantly, RVU120’s activity does not lead to significant toxicity in the hematopoietic system. As a result, RVU120 emerges as a promising drug candidate for treating transfusion-dependent MDS patients.

In REMARK, patients will receive RVU120 for at least 8 complete cycles (24 weeks). The primary goal is to achieve hematologic improvement in the form of an erythroid response (HI-E), with secondary goals including independence from RBC transfusions, improvement in hemoglobin levels, quality of life, disease progression, and analysis of specific gene mutations.

REMARK represents the third of four planned RVU120 Phase II clinical studies scheduled for launch in 2024. Ryvu has already started patient treatment in the RIVER-52 and RIVER-81 studies in AML, and the fourth Phase II trial is the planned to be initiated shortly POTAMI-61 study, evaluating both monotherapy and combination therapy for the treatment of patients with myelofibrosis (MF).