On April 12, 2021 ONCURIOUS NV, a Belgium-based biotech company focused on developing innovative oncology treatments, reported that encouraging data from a Phase 1 dose escalation study of TB-403 in pediatric subjects with relapsed or refractory medulloblastoma (MB), was presented at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Oncurious, APR 12, 2021, View Source [SID1234577915]).

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The data was presented by Dr. Giselle Sholler, Director, Isabella Santos Foundation Solid and Rare Tumor Program, Chair at Beat Childhood Cancer Research Consortium, and Professor, Paediatric Oncology at the Levine Children’s Hospital in Charlotte, NC.

The Phase 1 trial (ONC-403-001) was an open–label, multi-center, dose escalation study of TB–403 in a total of 15 pediatric subjects – 11 with relapsed or refractory MB, 2 with Ewing Sarcoma (ES) and 2 with alveolar rhabdomyosarcoma (ARMS). The study was conducted in conjunction with the Beat Childhood Cancer Research Consortium, Massachusetts General Hospital and Atrium Health Levine Children’s Hospital.

The study evaluated 4 dose levels of TB-403: 20 mg/kg, 50 mg/kg, 100 mg/kg, and 175 mg/kg. The dose limiting toxicity (DLT) assessment cycle for the study was 28 days with subjects receiving 2 doses of TB-403 at Day 1 and Day 15 respectively. After the DLT period, temozolomide or etoposide could be added to the subject’s treatment regimen.

Evaluations for the response to TB-403 were made at the end of cycle 1 and every 2 cycles thereafter.

The key safety findings from the study were as follows:

TB-403 was safe and well tolerated at all dose levels: no maximum tolerated dose (MTD) was reached
TB-403 exposure of children is in accordance with the exposure of the drug in adults
TB-403 exposure and concentration increased dose-proportionally over the dose range of 20-175 mg/kg

The key response findings were as follows:

At the 3 highest dose levels of TB-403, 7 out of 8 of medulloblastoma patients had stable disease
4 medulloblastoma patients had prolonged stabilization of disease > 100 days
Exploratory biomarker analysis showed a decrease in plasma levels of free placental growth factor (PlGF) to undetectable levels at all doses of TB-403, with no apparent changes in other angiogenic or inflammatory factors.

The results of the Phase 1 study warrant further evaluation of TB-403 in pediatric subjects with relapsed or refractory medulloblastoma (MB).

Dr. Giselle Sholler, Chair at Beat Childhood Cancer Research Consortium, commented: "I am pleased that the Beat Childhood Cancer Research Consortium has been able to play a key role in this important study. The encouraging data that I presented at AACR (Free AACR Whitepaper) show that treatment with TB-403 can produce a clinically meaningful response in a significant number of children with relapsed and refractory medulloblastoma. The encouraging results, in what is a very difficult to treat patient population, warrant further clinical investigation, and we at the Beat Childhood Cancer Research Consortium would be happy to play our role in any such effort."

TB-403 is a humanized monoclonal antibody against PlGF which is expressed in several types of cancer, including medulloblastoma. A paper in Cell (Cell, 152, 1065-76, 2013), highlighted that PlGF plays a role in the growth of medulloblastoma. The paper was based on preclinical research conducted by Prof Rakesh Jain from the Massachusetts General Hospital at Harvard (Boston) and the team of Prof Dr. Peter Carmeliet from the VIB/ KU Leuven.

Prof Dr. Peter Carmeliet from the VIB/ KU Leuven, added, "I am pleased that our preclinical research showing that PlGF plays a key role in the growth of medulloblastoma has been confirmed in this Phase 1 clinical study with TB-403. I look forward to following the further clinical development of this novel PIGF inhibitor and am confident that it has the potential to benefit children suffering from this devastating brain cancer."

Dr. Patrik De Haes, Executive Chairman of Oncurious said, "I would like to thank everyone who has taken part in the execution of this successful study with TB-403, especially the patients and their families. The data that has been generated show that TB-403 could expand the treatment options for children with relapsed and refractory medulloblastoma. Meanwhile, Oncurious’ international patent application, published with a positive indication on the patentability of the combination of TB-403 with etoposide or temozolomide, and expiring as late as 2040, puts Oncurious in a good position to evaluate potential partnering options for future development and manufacturing of TB-403."

On April 12, 2021 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 collaborators presented positive preclinical data for the combination of TUSC2 immunogene therapy (REQORSA) in combination with chemotherapy and immunotherapies for the treatment of non-small cell lung cancer (NSCLC) (Press release, Genprex, APR 12, 2021, View Source [SID1234577913]). Collaborators also presented positive preclinical data for the use of REQORSA in combination with targeted therapies for the treatment of NSCLC. These data were presented in two presentations at the 2021 American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting. The TUSC2 gene is a tumor suppressor gene and is the active agent in REQORSA.

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"We are pleased to have these positive data that provide further support for the therapeutic potential of REQORSA in combination with immunotherapies and targeted therapies in NSCLC presented before an audience of the world’s leading cancer researchers. These data are particularly encouraging as we look to initiate our upcoming combination Acclaim-1 and Acclaim-2 clinical trials of REQORSA in NSCLC," said Rodney Varner, President and Chief Executive Officer of Genprex. "We know that many patients inevitably develop resistance to immune checkpoint blockade therapy or EGFR-TKI therapy. These data show that REQORSA in combination with immunotherapies and targeted therapies may provide enhanced efficacy in NSCLC that has become resistant to these regimens, offering hope to a large patient population who currently has limited treatment options."

Featured Genprex-supported posters presented at AACR (Free AACR Whitepaper) 21 include:

Oral Presentation:
Session: MS.IM02.02 – Overcoming Resistance in the Tumor Microenvironment: Novel Immunomodulatory Agents

Title: "TUSC2 immunogene therapy enhances efficacy of chemo-immune combination therapy and induces robust antitumor immunity in KRAS-LKB1 mutant NSCLC in humanized mice"

Poster Number/Channel: #76/Channel 03

Presentation Date/Time: April 10, 2021 from 2:50-3:00 p.m. ET

Presenters: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Feng Meng, Min Jin Ha, Elizabeth Shpall, Jack A. Roth. University of Texas MD Anderson Cancer Center, Houston, TX

Poster Presentation:
Session: PO.ET03.01 – Drug Resistance in Molecular Targeted Therapies

Title: "Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC"

Poster Number: #1105

Presentation Date/Time: April 10, 2021 from 8:30 a.m. – 11:59 p.m. ET

Presenters: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Lihui Gao, Meng Feng, Huiqin Chen, Min Jin Ha, Jack A Roth

The first presentation, entitled "TUSC2 immunogene therapy enhances efficacy of chemo-immune combination therapy and induces robust antitumor immunity in KRAS-LKB1 mutant NSCLC in humanized mice," showed that the triple combination of chemotherapy, immunotherapy (immune checkpoint blockade) and REQORSA demonstrated strong antitumor efficacy and induced robust antitumor immunity in KRAS-LKB1 (KL)-mutant NSCLC in clinically relevant humanized mice models.

In this study, researchers evaluated the antitumor immune response of a chemo-immunotherapy combination with REQORSA on highly metastatic KL-mutant human lung cancer in humanized mice. Humanized mice were first treated with REQORSA, immunotherapy nivolumab (Opdivo), or the combination. The results showed synergistic antitumor activity with the combination. Next, humanized mice were treated with REQORSA, immunotherapy pembrolizumab (Keytruda), or the combination. When REQORSA was added to the chemotherapy and immune checkpoint blockade combination, metastases regression was significantly greater than either REQORSA, REQORSA and pembrolizumab, or chemotherapy and pembrolizumab treatments.

"KRAS is a frequent genomic driver in lung adenocarcinoma,", said Michael Redman, Executive Vice President and Chief Operating Officer of Genprex. "LKB1 (also known as STK11) is a distinct subgroup of KRAS-mutants and is the most prevalent genomic driver of resistance to PD-1 blockade in KRAS-mutant lung cancer."

The second poster, entitled "Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR-mutant NSCLC," showed that REQORSA in combination with targeted therapy osimertinib (Tagrisso) demonstrated synergistic antitumor efficacy in EGFR mutant osimertinib resistant NSCLC tumors in H1975-OsiR isogenic tumors. Researchers also found that the upregulation of PDK1 was associated with osimertinib resistance.

In this study, researchers developed an osimertinib resistant H1975-OsiR isogenic cell line through continuous exposure to osimertinib. Xenograft tumors from both H1975-parental and H1975-OsiR cells were developed in NSG mice and were treated with osimertinib. Synergistic antitumor activity of REQORSA and osimertinib was found in H1975-OsiR tumors. The combinations showed a robust antitumor effect compared with single agent treatment groups. Reverse phase protein array (RPPA) data showed that PDK1 was significantly upregulated in the REQORSA and osimertinib group when compared with either control, osimertinib alone or REQORSA alone treated H1975-OsiR tumors, indicating that PDK1 may be associated with osimertinib resistance. No PDK1 inhibitor effect was found in the REQORSA treated group, implicating the specific role of PDK1 in osimertinib resistance.

On April 12, 2021 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, reported the presentation of two posters on the company’s clinical and preclinical oncology programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Alpine Immune Sciences, APR 12, 2021, View Source [SID1234577912]).

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CT213: NEON-1: A First-in-Human Phase I Open-Label Study of ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, in Advanced Malignancies

Dr. Mark Voskoboynik from Nucleus Network and The Alfred Hospital in Melbourne, Australia, presented a Trials in Progress poster describing the ongoing first-in-human, phase 1 clinical trial involving monotherapy with ALPN-202, the company’s lead oncology program.
The trial, NEON-1, includes separate parts for dose escalation and expansion cohorts, and is enrolling patients with advanced solid tumors or lymphoma. Dose escalation continues to progress, with no dose-limiting toxicities to date.
P1740: Engineered Variant Domain Fusion Proteins Provide Checkpoint Inhibition and Tumor Antigen Dependent CD28 Costimulation Resulting in Potent Anti-Tumor Immunity

Alpine researchers demonstrated the use of directed evolution to engineer novel variant immunoglobulin domain (vIgD) Fc fusion proteins that enable tumor antigen-dependent CD28 costimulation.
The fusion proteins targeted the PD-L1 or HHLA2 tumor antigens, and demonstrated potent efficacy in antigen-positive tumor models in vitro and in vivo.
"Together, these presentations summarize the potential for an exciting, emerging CD28 costimulation portfolio," said Stanford Peng, MD, PhD, Alpine’s President and Head of Research and Development. "We look forward to the opportunity to present initial clinical data from NEON-1 at an upcoming scientific meeting and are optimistic about the potential to advance one or more of our preclinical programs toward the clinic in the near future."

Full abstracts are available on the AACR (Free AACR Whitepaper) Virtual Annual Meeting website and posters for both presentations are available on the Scientific Publications page of Alpine’s website.

About Alpine’s Directed Evolution Platform

Alpine’s directed evolution platform engineers native immune proteins, primarily of the immunoglobulin or tumor necrosis factor (receptor) superfamilies, into novel functional domains: variant immunoglobulin domains (vIgDs) and/or variant TNF domains (vTDs), respectively. These domains have acquired unique functional properties designed to benefit patients with cancer or inflammatory diseases.

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor with the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. NEON-1 (NCT04186637), a Phase 1 study of ALPN-202 in patients with advanced malignancies, is currently enrolling. Alpine is also targeting the initiation of NEON-2, a Phase 1 combination study of ALPN-202 and a PD-1 inhibitor, later this year.

On April 12, 2021 NuCana plc (NASDAQ: NCNA) reported the presentation of five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually April 9 to 14, 2021 (Press release, Nucana BioPharmaceuticals, APR 12, 2021, View Source [SID1234577911]). Data from all three of NuCana’s ProTides in clinical development were presented. Summaries of the posters are described below.

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NUC-3373

NuCana presented two posters on NUC-3373, its ProTide transformation of the active anti-cancer metabolite of 5-fluorouracil (5-FU), a very widely used anti-cancer drug. NUC-3373 has been designed to overcome the main challenges associated with 5-FU and capecitabine, including cancer-resistance mechanisms, the generation of toxic metabolites and unfavorable pharmacokinetic profile.

Poster Title: NUC-3373, a targeted inhibitor of thymidylate synthase, in patients with advanced colorectal cancer

This poster describes further encouraging interim data from 38 patients with metastatic colorectal cancer. In this difficult-to-treat group, who had received a median of four prior lines of therapy, NUC-3373, with or without leucovorin, demonstrated a 62% disease control rate (defined as stable disease lasting more than 8 weeks) in the efficacy-evaluable population. Three patients experienced reductions in their target lesions of 40%, 28% and 15% and several patients achieved a longer progression-free survival on NUC-3373 than they had on their prior therapy. NUC-3373 also continues to demonstrate a favorable safety profile with no FBAL or FUTP-associated Grade 3 or 4 toxicities, such as hand-foot syndrome, GI or hematological adverse events.

Poster Title: NUC-3373-induced DAMPs release in CRC cells promotes natural killer cell activation

The second NUC-3373 poster showed that NUC-3373-treated colon cancer cells are able to activate a natural killer (NK) cell response. NUC-3373 was shown to induce the release of damage associated molecular patterns (DAMPs) which may restore NK cell-mediated immune responses by reducing inhibitory signals. Thus, NUC-3373 has the potential to evoke immunogenic cell death and may enhance the clinical utility of immunotherapy agents.

NUC-7738

NuCana presented two posters on NUC-7738, a ProTide transformation of a novel nucleoside analog, 3’-deoxyadenosine or 3’-dA. NUC-7738, which has several potential anti-cancer mechanisms of action, is being evaluated in a Phase I study in patients with advanced solid tumors who have exhausted all standard therapies.

Poster Title: NUC-7738, a novel ProTide transformation of 3’-deoxyadenosine, in patients with advanced solid tumors

The first poster describes additional interim data from the ongoing Phase I study. These data demonstrate NUC-7738’s encouraging anti-cancer activity and favorable tolerability profile. Three case studies were described detailing patients who achieved tumor reductions and prolonged stable disease on NUC-7738.

Poster Title: From bench to bedside: Using ProTide chemistry to transform 3’-deoxyadenosine into the novel anti-cancer agent NUC-7738

The second poster describes how NUC-7738 was designed to overcome the key cancer resistance mechanisms which have prevented the clinical development of 3’-dA. NUC-7738 was shown to efficiently generate high and prolonged intracellular levels of the active anti-cancer metabolite, 3’-dATP, and to cause cell death by activation of apoptotic pathways, as well as through inhibition of NFkB nuclear translocation.

Acelarin

Poster Title: NUC-1031 causes incorporation of fluorinated deoxycytidine into DNA, inducing persistent damage in biliary tract cancer cells

NuCana presented a poster that further demonstrated Acelarin’s activity in biliary tract cancer cells. Specifically, the poster described how Acelarin (NUC-1031) is converted to the active anti-cancer metabolite (dFdCTP) and demonstrated that it is incorporated into DNA, inducing persistent double-strand breaks. This leads to cell cycle arrest and DNA damage resulting in apoptosis in biliary tract cancer cells.

Abstracts and full session details can be found at www.aacr.org

On April 12, 2021 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of resistance in cancer, reported four preclinical poster presentations at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual annual meeting (Press release, ORIC Pharmaceuticals, APR 12, 2021, View Source [SID1234577910]).

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ORIC-101: Glucocorticoid Receptor (GR) Antagonist
ORIC-101 is a potent and selective GR antagonist, with two distinct mechanisms of action being evaluated in two Phase 1b trials in combination with: (1) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors and (2) Xtandi (enzalutamide) in metastatic prostate cancer.

Key findings of the presentation:

GR upregulation and activation, an established resistance mechanism for antiandrogens, may drive resistance when antiandrogens are combined with AKT inhibitors.
ORIC-101 was able to overcome this resistance and restore antitumor activity in preclinical prostate cancer cell lines.
Poster Presentation:

GR antagonist ORIC-101 overcomes GR-mediated resistance to the combination of AR and AKT inhibition in preclinical prostate cancer cell lines (Abstract 1420)
ORIC-533: CD73 Inhibitor
ORIC-533 is a highly potent, orally bioavailable CD73 inhibitor and has demonstrated greater potency in preclinical studies compared to an antibody approach and other small molecule CD73 inhibitors.

Key findings of the presentation:

Nanomolar concentrations of ORIC-533 efficiently rescued cytotoxic T-cell function in the presence of high AMP concentrations, reflective of levels observed in tumors.
Inhibitors of adenosine receptors A2A or A2A/B were only able to rescue CD8+ T-cell function in the context of low micromolar AMP, thus may be ineffective in tumors with moderate or high AMP and adenosine levels.
ORIC-533 has potential best-in-class properties in reversing immunosuppression in tumors.
Poster Presentation:

Blocking adenosine production with ORIC-533, a CD73 inhibitor with best-in-class properties, reverses immunosuppression in high-AMP environments (Abstract LB-163)
ORIC-944: PRC2 Inhibitor
ORIC-944 is a potent and selective allosteric inhibitor of polycomb repressive complex 2 (PRC2) and targets its regulatory embryonic ectoderm development (EED) subunit.

Key findings of the presentation:

ORIC-944 has potential best-in-class drug properties compared to first generation PRC2 inhibitors, including a clean CYP profile.
ORIC-944 demonstrated superior activity compared to an EZH2 inhibitor in an in vivo DLBCL model.
ORIC-944 demonstrated strong tumor growth inhibition as a single agent with once daily dosing in both enzalutamide-responsive and enzalutamide-resistant in vivo prostate cancer models.
Poster Presentation:

ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates robust in vivo activity in prostate cancer models (Abstract 1131).
ORIC-114: EGFR/HER2 Inhibitor
ORIC-114 is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations.

Key findings of the presentation:

ORIC-114 is highly selective for the EGFR family of receptors with superior kinome selectivity compared to other exon 20 inhibitors.
ORIC-114 demonstrated low nanomolar potency across exon 20 insertion variants in biochemical and cell-based assays.
Significant tumor regression was observed in multiple EGFR exon 20 patient-derived xenograft models using once daily oral administration of ORIC-114.
ORIC-114 displayed superior brain exposure relative to other compounds targeting exon 20 insertion mutations, and greater activity compared to other EGFR inhibitors in an intracranial NSCLC EGFR mutant xenograft model.
Poster Presentation:

ORIC-114, a brain penetrant, orally bioavailable, irreversible inhibitor selectively targets EGFR and HER2 exon20 insertion mutants and regresses intracranial NSCLC xenograft tumors (Abstract 1466).