On April 9, 2024 Onchilles Pharma, a private biotech company developing cancer therapeutics that leverage a novel innate immune mechanism of action for potent and selective cancer killing, reported the presentation of new preclinical data for systemically delivered N17465 in an oral presentation and tumor-directed N17350 in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place April 5 to 10 at the San Diego Convention Center (Press release, Onchilles Pharma, APR 9, 2024, View Source [SID1234641939]).

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N17350 and N17465 are novel first-in-class oncology programs that harness the potent efficacy of the innate immune system and have the potential to become a major new treatment modality for a wide range of cancer types. Onchilles has engineered N17350 for intratumoral delivery and N17465 for systemic IV delivery and generated significant preclinical data validating the novel mechanism of action that delivers efficacy independent of tumor genetics and immune status by targeting the histone H1-death domain axis. Upregulation of histone H1 is a property common to many cancer cells and responsible for the selectivity of cancer cell killing seen in the N17350 and N17465 programs via immunogenic cell death.

Lev Becker, Ph.D., Scientific Founder, Onchilles Pharma, said, "We are excited to unveil systemically delivered N17465 that has the potential to redefine the treatment of solid tumors. The data presented today demonstrate that N17465 exhibits potent and tumor-selective efficacy, mobilizes the immune system for anti-tumor immunity, and produces durable responses in mouse models as a monotherapy. These data mark a major step forward in our quest to bring N17465 to patients."

Dr. Becker continued, "The new data presented today for N17350 add to our large preclinical data package validating the mechanism of action, confirming it induces immunogenic tumor cell death, and demonstrating selective cancer-cell killing in patient-derived chemotherapy-naive or -experienced ovarian cancer cell lines and CDX models. We believe that these data underscore the potential of N17350 as a potent and safe cancer treatment, and we look forward to advancing tumor-directed N17350 into first-in-human clinical trials this year."

Court R. Turner J.D., Co-Founder & Executive Chair of Onchilles Pharma, said, "The latest data revealed at AACR (Free AACR Whitepaper) on primary tumor samples introduce a significant layer of human validation to our approach before our planned clinical trials. The potent single-agent activity and selectivity of N17350 distinguish it from other tumor-directed approaches currently in development that only show modest to no monotherapy efficacy. We are confident that N17350 and N17465 represent a novel class of molecules that could become the new foundation of cancer treatment. We anticipate strong monotherapy efficacy of N17350 in our upcoming Phase 1 trial with potential approvals in many types of solid tumors by 2028, marking a significant milestone in oncology."

Details of the data presented are as follows:

In a talk for abstract 6578, entitled, "N17465, a systemically deliverable elastase, attenuates tumorigenesis and stimulates anti-tumor immunity," the following data were presented:

N17465 resisted inhibition by serine protease inhibitors found in the blood and maintained its ability to cleave the death domain of CD95 (therapeutic target) to selectively kill cancer cells.
N17465 induced immunogenic cell death (ICD) markers in cancer cell lines and patient ovarian cancer cells and was also well tolerated by non-cancer cells.
Systemically delivered N17465 produced tumor-free mice in a murine CT26 colon cancer model and induced a favorable immune profile
N17465 also exhibited efficacy across a range of xenograft models spanning human lung, colon, breast, and prostate cancer, as well as ovarian cancer patient-derived CDX models.
In a poster for abstract 5895 entitled, "N17350 kills cancer cells, spares immune cells, and regresses CDX tumors from chemotherapy-naive and experienced patients," the following data were presented:

N17350 killed primary cancer cells from all ovarian cancer (OvCa) patients tested but was well tolerated by non-cancer cells from the same patients; in contrast, doxorubicin and oxaliplatin showed similar toxicity to both cell types.
N17350 killed cancer cells from chemotherapy-naïve and -experienced patients with equal efficacy, while doxorubicin and oxaliplatin showed less efficacy in patients previously treated with chemotherapy.
N17350 rapidly regressed tumors in all OvCa CDX models and exhibited markedly improved efficacy over carboplatin.
N17350 mobilizes anti-tumor immunity in the 4T1 model of metastatic breast cancer and outperforms standard-of-care chemotherapy
About N17350 and N17465 and Their Novel Mechanism of Action
First described in research published in Cell from the lab of Onchilles’ Co-Founder Lev Becker, human neutrophils release catalytically active neutrophil elastase (called ELANE), which selectively and potently kills cancer cells independent of their genetics and anatomical origin, mobilizes adaptive immunity, and avoids resistance mechanisms. The team at Onchilles translated this ground-breaking discovery into a proprietary set of molecules, including N17350 and N17465, with the potential to treat a wide variety of tumor types with an optimal efficacy and safety profile.

On April 9, 2024 NuCana plc (NASDAQ: NCNA) reported two posters being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Nucana BioPharmaceuticals, APR 9, 2024, View Source [SID1234641938]).

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Title: Exposing the Heterogeneity of the Lipidome in the TME of Cutaneous Melanoma Following Treatment with NUC-7738 in Combination with anti-PD-1 Therapy
Presentation date and time: April 9, 2024 from 1:30pm-5:00pm PDT
Abstract number: 6222

The tumor microenvironment (TME) is a complex interplay of various cell types, extracellular matrix, signalling molecules and physical factors that collectively influence tumor growth. Lipids play an important role in the TME, contributing to various aspects of cancer progression and therapy resistance. A novel methodology, including imaging mass spectrometry, was developed to investigate the spatial relationship between the lipidome and TME using paired biopsies from patients treated with NUC-7738. NUC-7738 was found to increase polyunsaturated fatty acids within the TME, which is indicative of a shift to a less aggressive cancer type and to decrease monounsaturated fatty acids which are associated with malignant behavior and chemotherapy resistance. In addition, NUC-7738 was shown to reduce lipids associated with protection against cancer cell death and to increase lipids associated with cancer cell death. Multi-modal imaging indicated that this lipid reprogramming is a result of the alteration in enzymes associated with lipid metabolism.

Title: RNA Regulatory Disruption by 3’-dATP: A Novel Approach to Inhibit Ribosome Biogenesis in Cancer
Presentation date and time: April 9, 2024 from 1:30pm-5:00pm PDT
Abstract number: 5650

Ribosome biogenesis is a complex process that plays a pivotal role in protein translation which can become dysregulated in cancer. Thus, ribosome targeting therapies are an attractive treatment modality for anti-cancer medicines. This study investigates the impact of NUC-7738, which generates high intracellular levels of the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP), on the generation of mRNAs and proteins associated with ribosome biogenesis. Data from cancer cell lines, confirmed using paired biopsies of patients treated with NUC-7738, demonstrated that NUC-7738 significantly modulated the levels of RNAs which are important for translational control of protein synthesis. Furthermore, data also highlight NUC-7738’s potential to influence the regulation of genes critical for cancer cell growth and survival.

Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "We are excited to present these results as we believe they demonstrate NUC-7738’s multi-faceted mechanisms of action. They also further explain the compelling clinical data we have generated with NUC-7738 as a monotherapy and in combination with pembrolizumab. We recently presented clinical data from the ongoing NuTide:701 study of NUC-7738 in combination with pembrolizumab which demonstrated that NUC-7738 may potentiate the activity of pembrolizumab in patients who were refractory to PD-1 inhibitor-based therapy. Our translational data help us to understand these clinical observations and guide the optimal development pathway for NUC-7738. We look forward to sharing additional data for NUC-7738 in 2024."

On April 9, 2024 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered cytokine therapies designed to address areas of unmet need for patients with a variety of cancers, reported poster presentations with pre-clinical data from its Interleukin-18 (IL-18) and IL-12 programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting taking place April 5-10 in San Diego, California (Press release, Mural Oncology, APR 9, 2024, View Source [SID1234641937]). This is the first time Mural has shared findings from either program. The details for the presentations are as follows, and both posters are available at View Source

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Interleukin-18 engineered for resistance to IL-18 binding protein (IL-18BP) and half-life extension to enhance its therapeutic potential (Abstract #4076):

IL-18 is a potent immune-stimulating cytokine, but it is limited by IL-18 binding protein (IL-18BP) – a secreted high affinity decoy receptor that binds with, and neutralizes, IL-18, thus limiting its efficacy over time.
Mural’s protein engineering approach is twofold: first, it introduces mutations to IL-18 that are designed to minimally impact the structure while eliminating binding to IL-18BP. Secondly, it fuses IL-18 to protein scaffolds to extend the half-life and increase the cytokine’s exposure.
The company believes the half-life enhancement may lead to a more durable immunological effect, as demonstrated by the interferon gamma and Th1 response, proinflammatory reactions necessary for the body’s immune response.
Notably, the duration of Th1 response observed was significantly longer (approximately 7-9 days) than a "naked" approach without this half-life extension, which is generally cleared in 2-3 days.
The optimal balance of potency and pharmacokinetic enhancement is still being determined to nominate a lead IL-18 development candidate.
"Resistance to IL-18BP is the foundation of our approach. The mutations we introduced prevented the binding protein from neutralizing the cytokine’s efficacy. We show that resistance to IL-18BP combined with the drug’s extended half-life leads to a durable immunological effect in preclinical models. Our observation of increases in Th1 cytokines, which have been shown elsewhere to correlate with response to checkpoint inhibitors, are encouraging indications that our engineered IL-18 may provide a therapeutic complement to checkpoint inhibitor immunotherapy1,2," said Mark Whitmore, Ph.D., Principal Scientist of Cancer Biology, and the poster’s lead author.

Generation of tumor targeted self-assembling split IL-12 subunits for the treatment of cancer (Abstract #4066):

IL-12p70 is a potent stimulator of the immune system with profound anti-tumor activity but very poor tolerability.
Mural’s protein engineering approach aims to mitigate IL-12’s hallmark toxicity by splitting the heterodimer into two inactive monomers: IL-12p35 and IL-12p40. These individual subunits are separately fused to two non-competitive antibody fragments.
The goal of this is to assemble active IL-12p70 preferentially in the tumor microenvironment. The sequential administration of these targeted subunits concentrates the IL-12p70 activity primarily at the tumor site, thereby limiting systemic formation and associated toxicities.
In vivo analysis demonstrated that targeting both subunits resulted in the greatest accumulation and retention of IL-12p70 complex in the tumor.
"We believe that by self-assembling the split IL-12 subunits within the tumor microenvironments, we can circumvent native IL-12’s severe toxicities without compromising its efficacy. The data presented today provide strong rationale for our strategy of non-competitively targeting each subunit to a unique epitope on the same molecule," said Joshua Heiber, Ph.D., Director of Research & Development, Cancer Biology, and the poster’s lead author.

On April 9, 2024 Manhattan BioSolutions, Inc. ("Manhattan Bio"), an emerging biotechnology company developing new classes of precision biologics for the treatment of advanced cancers, reported a collaborative poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego, California (Press release, Manhattan BioSolutions, APR 9, 2024, View Source [SID1234641936]). The poster, titled "A potent FGFR4-targeted antibody-drug conjugate therapy for patients with rhabdomyosarcoma and other cancers expressing FGFR4," highlights the promising preclinical efficacy of this innovative therapeutic approach. The research is a result of a collaboration between Manhattan Bio, the National Cancer Institute (NCI), part of the US National Institutes of Health (NIH), and Binghamton University.

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The lead investigator is Javed Khan, MD, Senior Investigator and Deputy Chief of the Genetics Branch at the NCI Center for Cancer Research. The study utilized a highly specific monoclonal antibody that targets FGFR4, a receptor overexpressed in various cancers, including rhabdomyosarcoma (RMS). The antibody was conjugated to the cytotoxic MMAE payload through a protease-cleavable valine-citrulline linker, generating a potent FGFR4-targeted ADC. This work builds on an earlier collaboration agreement between Manhattan Bio, the NCI, and Binghamton University announced in 2023.

"We are thrilled to share the compelling preclinical data generated through our ongoing collaboration with the NCI and Binghamton University," said Dr. Borys Shor, CEO of Manhattan Bio. "While this proof-of-concept study utilized a standard linker-payload system, we are excited to continue our work with cutting-edge topoisomerase 1 inhibitor warheads currently being developed at Manhattan Bio. We believe that by combining the highly selective FGFR4 antibody with our proprietary linker-payload technologies, we can further enhance the therapeutic potential of this ADC for pediatric patients with RMS and for patients with other types of tumors."

On April 9, 2024 IN8bio, Inc. (Nasdaq: INAB) a clinical-stage biopharmaceutical company developing innovative gamma-delta T cell therapies, reported new preclinical data from its non-signaling gamma-delta T cell based Chimeric Antigen Receptor-T cell (nsCAR) platform, known as INB-300, that demonstrated improved selectivity to target leukemia cells while preserving healthy ones (Press release, In8bio, APR 9, 2024, View Source [SID1234641935]). The data support the potential for nsCAR to have a wider therapeutic window and to be used to prevent on-target off-tumor killing of healthy tissue that may express the CAR-T target. The data was presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 on April 9, 2024.

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IN8bio’s nsCAR platform is based on the natural ability of gamma-delta T cells to distinguish between healthy and malignant tissue. By using a Chimeric Antigen Receptor (CAR) that lacks a signaling domain, IN8bio believes it has created a technology that enables these cells to differentiate between tumor and healthy tissue, even when both express the CAR-targeted antigen.

Approved CAR-T therapies have shown remarkable efficacy against B cell malignancies, offering hope to patients with limited treatment options. However, extending this therapy to myeloid malignancies and solid tumors has proven challenging since the antigens they target are also often found on the surface of healthy blood cells and tissues. This unintended targeting of healthy cells and tissues has led to many of the toxicities, including patient deaths, observed in prior CAR-T therapies and has limited their utility. Unlike traditional CAR-T therapy, IN8Bio’s nsCAR is designed to direct the gamma delta T cell to its target while maintaining their unique gamma-delta T cell receptors, allowing them to identify and specifically eliminate heterogeneous tumor cells through recognition of tumor-associated stress antigens.

The new data presented at AACR (Free AACR Whitepaper) included results from proprietary constructs targeting CD33 and/or CD123 for in vitro evaluation against various types of leukemia, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The study results demonstrated notable differences between cells expressing traditional signaling CARs and those expressing the nsCAR constructs, which include a reduction in activation-induced cell death with nsCAR constructs.

The nsIL3-33mb15 CAR (CD123+CD33+IL-15) enhancement of the gamma delta T cells against leukemia cells demonstrated an average 1.8x increase in tumor killing capability across three AML cell lines (HL-60, KG-1a and MOLM-13), compared to unmodified gamma-delta T cells as measured by a 24-hour cytotoxicity assay. Importantly, the nsCAR cells did not lead to significant killing of healthy cells expressing the CD33 or CD123 target, demonstrating the selectivity of the nsCAR platform. Results were run in triplicate and on average the selectivity was increased by 5.5x. Across all runs, killing by the nsIL3-33mb15 construct against healthy CD34+ HPCs was below that of un-transduced control gamma-delta T cells.

"INB-300 can selectively target leukemia cells while preserving healthy tissue. We are now conducting further optimization to improve the integration of membrane-bound IL-15 co-expression to potentially enhance both the efficacy and safety of next-generation adoptive cell therapies against a wider spectrum of cancers," said Lawrence Lamb, Ph.D., co-founder and Chief Scientific Officer of IN8bio. "These results can potentially improve INB-300, as we advance towards IND enabling studies of our next-generation gamma-delta T cell therapies to treat cancers."

About INB-300

INB-300 is an nsCAR gamma-delta T cell platform with several preclinical product candidates, including the INB-330 program against AML targets, that combine our expertise in gamma-delta T cells and genetic engineering. These nsCAR constructs lack signaling domains in order to take advantage of the unique properties of gamma-delta T cells to differentiate between healthy and tumor tissues. IN8bio is advancing new nsCAR constructs against multiple targets to treat both solid and liquid tumors.