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.

On April 9, 2024 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that its research collaborators presented positive preclinical data for Reqorsa Immunogene Therapy (quaratusugene ozeplasmid) and NPRL2 gene therapy, which both utilize the Company’s non-viral Oncoprex Delivery System for the treatment of lung cancer (Press release, Genprex, APR 9, 2024, View Source [SID1234641934]). These studies were presented at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held April 5-10, 2024 in San Diego, California.

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"We continue to expand our growing body of preclinical evidence supporting REQORSA’s therapeutic potential to treat a variety of cancers, as well as the therapeutic potential of our non-viral delivery system to deliver tumor suppressor genes for the treatment of cancer," said Rodney Varner, Chairman, President and Chief Executive Officer at Genprex. "We are especially delighted to have three preclinical studies presented at one of the largest professional cancer research meetings among the world’s top oncologists and the cancer research community."

Featured Genprex-supported posters presented at AACR (Free AACR Whitepaper) 2024 include:

Title: "Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis"

Session Category: Molecular/Cellular Biology and Genetics

Session Title: Apoptosis and Ferroptosis

Session Date and Time: Sunday, April 7 from 1:30 p.m. – 5:00 p.m. PT

Location: Poster Section 15

Poster Board Number: 7

Abstract Presentation Number: 351

Title: "Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC"

Session Category: Immunology

Session Title: Inflammation, Host Factors, and Epigenetic Influences on Cancer Development and Treatment

Session Date and Time: Monday, April 8 from 9:00 a.m. – 12:30 p.m. PT

Location: Poster Section 5

Poster Board Number: 18

Abstract Presentation Number: 1420

Title: "Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells"

Session Category: Experimental and Molecular Therapeutics

Session Title: Cancer Biology and Metastasis

Session Date and Time: Monday, April 8 from 1:30 p.m. – 5:00 p.m. PT

Location: Poster Section 22

Poster Board Number: 6

Abstract Presentation Number: 3158

In the first poster, entitled "Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis," researchers reported that REQORSA induced apoptosis in alectinib resistant EML4-ALK positive non-small cell lung cancer (NSCLC) cell lines. Alectinib is an ALK-inhibitor commonly used to treat patients with ALK rearrangements such as EML4-ALK positive NSCLCs. This research suggests that REQORSA may be an effective treatment in patients progressing on alectinib.

The second poster, entitled, "Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC" detailed a humanized mouse model study in which the researchers investigated the anti-tumor immune responses to NPRL2 gene therapy in pembrolizumab resistant KRAS/STK11mt NSCLC. In the study, lung metastases in humanized mice were treated through I.V. injection of NPRL2 nanoparticles, made with the ONCOPREX Delivery System, with or without pembrolizumab. The study found that the NPRL2 treatment by itself led to a marked decrease in the size of lung metastases but pembrolizumab had no effect. Additionally, a greater anti-tumor effect was seen in humanized compared to non-humanized mice, demonstrating that immune cells play a role in the effects of the NPRL2 nanoparticle therapy. Study findings suggest that NPRL2 gene therapy induces anti-tumor activity against KRAS/STK11mt tumors through dendritic cell-mediated antigen presentation and cytotoxic immune cell activation. The Company believes this data could support the potential for a new drug candidate in its pipeline, and it also provides further evidence for the Company’s belief that the ONCOPREX Delivery System has the ability to be successful using genes other than the TUSC2 gene the Company is already using in clinical trials with REQORSA.

In the third poster, entitled, "Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells" researchers reported that TUSC2-deficient cancer cells consistently exhibited decreased glycolytic rates and mitochondrial ATP production, leaving these cells without enough energy to support their vital functions. By comparison, when Beas2B, a normal human bronchial epithelial cell line with normal levels of TUSC2, was transfected with a TUSC2 containing plasmid, the glycolytic rate and mitochondrial metabolism was increased. This suggests the mechanism by which REQORSA treatment affects immune and other non-cancerous cells that leads to increased immune response against tumors. The study further suggested that REQORSA may play an important role as a cancer treatment to target and disrupt the metabolism of cancer cells, leading to a decrease in the rate of glycolysis.

These AACR (Free AACR Whitepaper) posters have been made available on Genprex’s website at www.genprex.com.

Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells
About Reqorsa Therapy
REQORSA (quaratusugene ozeplasmid) for NSCLC and small cell lung cancer (SCLC) consists of the TUSC2 gene expressing plasmid encapsulated in non-viral nanoparticles made from lipid molecules (Genprex’s ONCOPREX Delivery System) with a positive electrical charge. REQORSA is injected intravenously and specifically targets cancer cells, which generally have a negative electrical charge. REQORSA is designed to deliver the functioning TUSC2 gene to cancer cells while minimizing their uptake by normal tissue. REQORSA has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer cells, re-establishes pathways for programmed cell death, or apoptosis, in cancer cells, and modulates the immune response against cancer cells.

Genprex’s strategy is to develop REQORSA in combination with currently approved therapies and believes that REQORSA’s unique attributes position it to provide treatments that improve on these current therapies for patients with NSCLC, SCLC, and possibly other cancers.

About The Oncoprex Delivery System

Genprex’s ONCOPREX Delivery System is a novel non-viral approach that utilizes lipid-based nanoparticles in a lipoplex form to deliver tumor suppressor genes deleted during the course of cancer development. The platform allows for the intravenous delivery of various tumor suppressor genes, and potentially other genes, to achieve a therapeutic affect without the risk of toxicity often associated with viral delivery systems. Genprex believes this system allows for delivery of a number of cancer-fighting genes, alone or in combination with other cancer therapies, to combat multiple types of cancer.

On April 9, 2024 Gennao Bio, a privately held genetic medicines company developing first-in-class, targeted nucleic acid therapeutics, reported new preclinical results on the application of its non-viral, cell penetrating gene monoclonal antibody (GMAB) platform technology as an antibody-drug conjugate (ADC) for the treatment of solid tumors (Press release, Gennao, APR 9, 2024, View Source [SID1234641933]). The data were presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024.

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Exploratory research evaluating GMAB’s ability to deliver conjugated cytotoxic payloads was conducted through Gennao’s ongoing collaboration with the laboratory of Peter M. Glazer, M.D., Ph.D., Chair of the Department of Therapeutic Radiology, Professor of Genetics and Robert E. Hunter Professor of Therapeutic Radiology at the Yale School of Medicine and co-founder of Gennao. In preclinical studies, our GMAB technology demonstrated selective delivery of payloads into tumors by targeting ENT2, a nucleoside transporter that is highly overexpressed in many tumors. ENT2 overexpression on both the plasma and nuclear membranes allows GMAB targeted therapies to internalize directly into the cytoplasm of tumor cells avoiding the endocytic pathway and traffic directly into the nucleus. In vitro studies of the GMAB ADC conjugated to exatecan, a potent topoisomerase I inhibitor, exhibited nuclear localization and activation of the DNA damage response pathway leading to tumor cell death.

"The safe targeted delivery of cytotoxic drugs continues to be a challenge for the development of new ADCs. Leveraging GMAB as an ADC represents a highly differentiated approach to the delivery of drugs exclusively to tumors while avoiding harmful impact to healthy tissue. In preclinical studies, chronic treatment of the GMAB ADC demonstrated significant tumor regression and was well tolerated, providing support for the continued investigation of this novel delivery platform as an ADC," said Dr. Glazer.

In a preclinical study utilizing the DLD1 BRCA2 gene knockout xenograft mouse model of colorectal cancer, two aggressive systemic dosing regimens of the GMAB ADC were compared to exatecan alone and control. The GMAB ADC demonstrated durable tumor regression and a significant survival benefit compared to control and exatecan alone. Safety analyses showed no change in body weight throughout treatment and no change in blood chemistry markers indicative of no kidney or liver toxicity. Further, since ENT2 is also expressed in skeletal muscle, serum chemistry and analysis of muscle tissue sections demonstrated no indication of tissue damage to muscle.

"These preclinical results reinforce the versatility of the GMAB platform and its ability to deliver therapeutic payloads beyond genetic medicine to targeted tissue," Chris Duke, chief executive officer of Gennao. "Additional in vivo studies are planned through our collaboration with Yale to further optimize the GMAB ADC approach. The ability to leverage a novel antigen target, combined with GMAB’s unique biology, offers the potential to create promising novel, first-in-class treatment options for individuals living with cancer."

On April 9, 2024 Fusion Pharmaceuticals Inc. (the "Company") reported a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 which showed interim efficacy and safety data from the Phase 2 TATCIST open-label clinical trial evaluating FPI-2265, an actinium-225 based PSMA-I&T targeting radioconjugate ("RC") for the treatment of metastatic castration-resistant prostate cancer ("mCRPC") (Press release, Fusion Pharma, APR 9, 2024, View Source [SID1234641932]). Results demonstrate that FPI-2265 is active in heavily pretreated patients with progressive mCRPC, including patients who received prior lutetium-based RCs. Safety, tolerability and clinical activity data were generally consistent with other published studies of small molecule-based 225Ac-PSMA RCs.

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As of the March 1, 2024 data cutoff, 35 patients received at least one dose of FPI-2265, with 25 patients having at least 12 weeks of follow-up. The analysis included 25 patients for safety evaluation and 20 patients for assessing prostate-specific antigen ("PSA") response. Four participants were identified as superscan patients and were excluded from the efficacy analyses and reported separately in the safety analysis. One participant was not included in the efficacy analysis due to uninterpretable PSA response. Patients in the study were pretreated with a median of four prior lines of anticancer therapy, with 20 out of 25 (80%) receiving prior chemotherapy, including 10 patients who received at least two prior lines of taxanes. Nine out of 25 patients received a prior 177Lu-based PSMA RC.

From the efficacy-evaluable patient population, PSA50 (≥50% decline in PSA by 12 weeks after first treatment) response was achieved in 10 out of 20 patients (50%) regardless of prior lutetium treatment. PSA50 was achieved in 61% of lutetium-naïve participants and 42% of lutetium-treated participants. In an exploratory subset analysis of 13 patients, including six patients who received prior 177Lu-based PSMA RC treatment, with baseline PSMA Mean Standardized Uptake Value (SUVmean) >6, PSA50 response was observed in nine patients (69%).

FPI-2265 demonstrated meaningful improvement in secondary endpoints which include maximum % PSA decline, and independent reviewer-assessed response rates based on RECIST v1.1 criteria, and the rate of disease progression in bone per Prostate Cancer Working Group 3 (PCWG3) criteria.

FPI-2265 was generally well tolerated and in line with prior published data, with predominantly Grade 1-2 treatment related adverse events ("TRAEs") observed, including xerostomia (dry mouth), thrombocytopenia, anemia, fatigue and dry eye. Xerostomia, the most common TRAE, was primarily Grade 1 with all incidences being Grade 1-2 (62% Grade 1 and 24% Grade 2). One treatment-related death due to cerebral hemorrhage was reported in a superscan patient. Three out of 25 participants discontinued treatment due to TRAEs, including two participants in the superscan group, however there were no discontinuations due to xerostomia.

On April 9, 2024 FORE Biotherapeutics reported new nonclinical data related to plixorafenib (FORE8394; formerly PLX8394), the company’s novel, investigational, small-molecule, next-generation, orally available selective inhibitor of BRAF alterations, will be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2024, taking place April 5-10, 2024, in San Diego and virtually (Press release, Fore Biotherapeutics, APR 9, 2024, View Source [SID1234641931]). The data show nonclinical synergistic activity of plixorafenib when combined with MEK inhibition across all BRAF alterations tested. In cells with BRAF V600 or non-V600 mutations or BRAF fusions, the combination of plixorafenib and binimetinib is most potent of the BRAF and pan-RAF inhibitors tested. In plixorafenib resistant cells, these cells can be resensitized with the addition of binimetinib. To date, plixorafenib has demonstrated encouraging efficacy and safety data from the phase 1/2a study; these nonclinical data help build the foundation for potential future development of plixorafenib in combination with a MEK inhibitor.

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Poster
Abstract number: 4609
Poster Title: The paradox-breaker BRAF inhibitor plixorafenib (PLX8394; FORE8394) synergizes with MEK inhibitors (MEKi) in BRAF V600 and non-V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi
Presentation Session Date/Time: April 9, 2024, 9:00 AM – 12:30 PM Poster Session

About Plixorafenib

Plixorafenib is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF alterations while sparing wild-type forms of RAF. Nonclinical and clinical studies have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAF V600 monomers targeted by first- and second-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants and others. Unlike earlier-generation BRAF inhibitors, plixorafenib does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker", plixorafenib could therefore address acquired resistance to current RAF inhibitors and, additionally, may yield improved safety and more durable efficacy than first-generation RAF inhibitors.

Plixorafenib is currently being evaluated in two clinical trials in patients with advanced solid tumors with activating BRAF alterations. Interim clinical data from a Phase 1/2a trial presented at ESMO (Free ESMO Whitepaper) 2022, ASCO (Free ASCO Whitepaper) 2023 and SNO 2023 provided evidence of durable anti-tumor activity in patients with BRAF-mutated cancers with a 42% overall response rate and a median duration of response of 17.8 months in MAPK inhibitor-naïve participants with V600-mutated advanced solid tumors. Of the 9 patients with primary central nervous system tumors, 6 had confirmed response (ORR 67%) with a median duration of response of 13.9 months. In addition to the Phase 1/2a trial, plixorafenib is currently being investigated in the ongoing, potentially registrational Phase 2 FORTE study.