On April 12, 2021 Treovir, an immuno-oncology company that is developing and plans to commercialize G207 for recurrent glioblastoma in children, reported that G207, an oncolytic HSV immunotherapy, was well tolerated with evidence of clinical effectiveness in a phase 1 study of 12 pediatric patients with recurrent high-grade glioma (Press release, Treovir, APR 12, 2021, View Source [SID1234577943]). Data from the phase 1 study (NCT02457845) are being presented by Gregory Friedman, M.D., professor in the Department of Pediatrics at the University of Alabama at Birmingham, during Week 1 of the virtual AACR (Free AACR Whitepaper) Annual Meeting 2021, held April 10-15. Data from this trial have been published in the New England Journal of Medicine.

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In the Phase 1 dose-escalation study, 12 pediatric patients 7 to 18 years of age with progressive high-grade glioma received an infusion of G207 alone or G207 in combination with radiation. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators and only 20 grade 1 adverse events were possibly related to G207. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4). The overall survival rate was more than double the typical survival rate for children with high-grade glioma. Some 36 percent of the patients thus far have survived longer than 18 months, surpassing the expected survival for newly diagnosed children with high-grade glioma. Additionally, G207 markedly increased the number of tumor-infiltrating lymphocytes for at least nine months after infusion effectively turning immunologically "cold" tumors "hot".

Gregory Friedman, M.D., Principal Investigator of the study, said, "This is the first study utilizing delivery of a viral immunotherapy directly into brain tumors in children and the results indicate that G207 can be delivered safely into tumors located in all areas of the cerebrum in children. The key findings thus far are that the approach is safe and well tolerated, and the preliminary evidence of efficacy is very promising."

G207 is an oncolytic HSV engineered to infect only tumor cells. When infused into a tumor, the virus enters the tumor cells and replicates and kills the cells. In the process, G207 releases viral progeny that infect and kill nearby tumor cells. Furthermore, as demonstrated in the Phase 1 study for the first time, G207 induces a strong local immune response to harness the body’s immune system to further fight against the tumor cells.

"We are enthusiastic that the Phase 1 results appear to support the use of G207 as a safe and potentially effective therapy to treat pediatric high-grade gliomas," said Michael Christini, CEO of Treovir. "There are no approved therapies to treat these types of lethal tumors and it is our goal to develop G207 for glioma and other childhood brain cancers."

In collaboration with Dr. Friedman and the Pediatric Brain Tumor Consortium, Treovir is in the late stages of planning its Phase 2 clinical trial for G207 in recurrent high grade glioma (NCT 04482933). The Phase 2 trial is expected to start later in 2021. Additionally, G207 is being studied at UAB and Children’s of Alabama in recurrent pediatric brain tumors, including medulloblastoma, which arise in the cerebellum, the most common location for pediatric tumors to arise. (NCT 03911388)

"It is our goal that the Phase 2 study will support market approval of G207 to treat pediatric recurrent high-grade gliomas and our company’s mission is clear: We want to commercialize G207 and provide hope to the children and families who currently have no effective therapeutic options," stated Mr. Christini.

Brain tumors are the most common solid tumor in children, and aggressive types like glioblastoma have an extremely low survival rate: as low as 10% five years after diagnosis. Malignant high-grade glioma accounts for 8 to 10% of pediatric brain tumors and survival rates have not improved in 30 years. The median life expectancy of recurrent high-grade glioma is only 5.6 months.

The study was supported by the US FDA Orphan Products Clinical Trials Grants Program, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, and the Kaul Pediatric Research Institute. Dr. Friedman has no financial or equity interest in Treovir and was not paid by Treovir for the Phase 1 study.

On April 12, 2021 Flagship Biosciences, the leader in data-centric pathology and tissue analysis, and Leap Therapeutics (Nasdaq: LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported a partnership to use a clinically validated tumor expression assay utilizing RNAscope and tissue image analysis (Press release, Leap Therapeutics, APR 12, 2021, View Source [SID1234577942]). In a poster shared this week at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, the companies presented data on the validation of a Dickkopf-1 (DKK1) RNAscope chromogenic in situ hybridization (CISH) assay and digital image analysis solution.

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DKK1 is a secreted modulator of Wnt signaling that is frequently overexpressed in tumors and associated with a poor prognosis for patients. DKN-01 is a humanized monoclonal therapeutic antibody that binds to and blocks the activity of DKK1 and has demonstrated clinical activity in gastric/gastroesophageal junction (G/GEJ) adenocarcinoma patients with elevated tumoral expression of DKK1 RNA. The companies have demonstrated that the DKK1 RNAscope assay and accompanying digital image analysis solution is specific, sensitive, accurate and reproducible according to Clinical Laboratory Improvement Amendments (CLIA) guidelines. The assay is currently being applied to prospectively identify G/GEJ patients with elevated tumoral expression of DKK1 for treatment with a DKN-01 plus tislelizumab combination (Leap Therapeutics; NCT04363801).

"CISH assays can be used for the interrogation of clinical samples when protein targets are not sufficient," said Flagship Biosciences CEO, Trevor Johnson. "However, reading these assays can be challenging for pathologists. At Flagship, our pathologist-driven image analysis generates unique cellular data profiles that allow for the kind of robust quantitative solution that Leap was looking for. Using our proprietary image analysis technology and patented, cell-based tissue analysis, we deliver the data-rich tissue interpretations to support therapeutic development."

"This is a robust laboratory developed test (LDT) that is superior to traditional DKK1 immunohistochemistry (IHC) by demonstrating improved specificity and sensitivity," said Michael Kagey, Ph.D., Senior Director of Translational Medicine. "Furthermore, the use of the digital image analysis algorithm to quantify DKK1 signal and support pathologist interpretation is a novel approach that reduces the risk of scoring bias."

To select patients for their clinical study, Leap Therapeutics sends samples from the United States and the Republic of Korea to Flagship’s centralized laboratory. Flagship conducts the RNAscope assay, image analysis, data analysis, and in-house pathologist review, providing the information needed to make clinical trial enrollment decisions.

"The DKK1 RNAscope LDT is an integral component of our clinical development strategy," said Douglas E. Onsi, President and CEO of Leap Therapeutics. "The rapid sample turnaround time from Flagship has allowed for the prospective screening of patients to support enrollment. We look forward to our continued partnership with Flagship."

On April 12, 2021 Jubilant Therapeutics Inc. , a biopharmaceutical company developing oral, small molecule modulators to meet unmet medical needs in oncology and autoimmune diseases, reported preclinical data from two programs investigating the company’s PRMT5 inhibitor and PD-L1 inhibitor as anticancer agents will be unveiled today in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, which will be held virtually from Nov. takes place until April 15 , 2021 (Press release, Jubilant Therapeutics, APR 12, 2021, View Source;pgid=1475&pressid=449 [SID1234577941]) .

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"We are pleased to announce these important data from our PRMT5 and PD-L1 programs that demonstrate efficacy and tolerability in preclinical models," said Syed Kazmi, President and Chief Executive Officer of Jubilant Therapeutics Inc. "Our oral PRMT5 inhibitor has good plasma and sustained brain exposure resulting in potent target inhibition, tumor growth delay, and a survival benefit in both xenografts and orthotopic brain models . Our shorter half-life oral anti-PDL1 immunotherapeutics are an attractive alternative to current intravenous antibody therapies, especially in the maintenance phase, with the potential to limit immune-mediated toxicities and side effects through innovative dosage approaches while maintaining class-based broad anti-tumor efficacy. We look forward to continuing our work on these programs as we see great potential for treating various types of cancer. "

A link to the e-posters listed below is available on the AACR (Free AACR Whitepaper) website.

Title: Novel Small Molecular Weight PRMT5 Inhibitors for the Treatment of Cancer
Poster Number: 1128
Date and Time: April 10 , 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Epigenetic Targets
Speaker: Dhanalakshmi Sivanandhan, et al.

Title: Novel Small Molecular Weight Inhibitors of PD-L1 / PD-1 Interaction
Poster Number: 1630
Date and Time: April 10 , 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Immune Checkpoints
Speaker (r ): Dhanalakshmi Sivanandhan, et al.

The overexpression of PRMT5, which has been demonstrated in various types of cancer such as lymphatic cancer, lung cancer, breast cancer, glioblastoma, gastric cancer, etc., is considered to be an important factor in tumorigenicity due to its repressive function on the expression of tumor suppressor genes. The most important highlights from an evaluation that examined the inhibition of tumor growth by the PRMT5 inhibitor JBI-778 in various cancer cell lines as well as in glioblastoma are as follows:

JBI-778 is a potent PRMT5 inhibitor that acts selectively against other PRMTs;
JBI-778 is a potent PRMT5 inhibitor that acts selectively against other PRMTs;
This orally administered small molecule demonstrated anti-tumor activity in a mantle cell lymphoma model with an ED50 of <10 mg / kg and complete inhibition of tumor growth (97%) at a dose of 50 mg / kg; and
JBI-778 demonstrated sustained exposure of the brain and significant inhibition of tumor growth in an orthotopic glioblastoma model, resulting in a significant survival benefit.
JBI-778 is currently being investigated for the treatment of a variety of cancers and IND-approved studies have begun.

PD-L1 expression is an immune evasion mechanism that is exploited by many cancers, including melanoma, non-small cell lung cancer, and breast cancer, that enables cancer to progress and metastasize. Key findings from the PD-L1 / PD-1 Study, which examined the ability of JBI-1527 to inhibit PD-L1 and restore T cell proliferation and function, included:

JBI- 1527 is a potent, selective inhibitor of PD-L1, which induces the dimerization of the protein and thereby reduces the PD-L1-induced suppression of T-cell activation;
The inhibitor shows a similar modulation of cytokines as pembrolizumab in the BioMAP assay and competes with the anti-PD-L1 blocking antibody, suggesting a similar binding site on PD-L1; and
In syngeneic CT-26 and MC38-hPD-L1 models, the small molecule showed a strong inhibition of tumor growth, comparable to anti-PD-L1 mAb / atezolizumab, and was well tolerated.
Studies to further evaluate JBI-1527 and other substances are ongoing.

On April 12, 2021 PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on the development of antibody therapeutics, reported that the company presented an e-poster featuring the non-clinical data of PMC-309 at American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually (Press release, PharmAbcine, APR 12, 2021, View Source [SID1234577940]).

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PMC-309, one of the company’s first immuno-oncology drug candidates, is a monoclonal IgG (Immunoglobulin G) that targets human VISTA (V-domain Ig Suppressor of T cell Activation), an immune checkpoint regulator. VISTA is found overexpressed on MDSC (Myeloid-Derived Suppressor Cells) and M2 macrophages both of which are immunosuppressive cells found abundantly around TME (Tumor Microenvironment).

The presentation highlighted that PMC-309 inhibits VISTA pathway on immunosuppressive cells and increases T cell activities in in vitro settings and shows potent anti-tumor effects in in vivo studies.

The in vitro studies confirmed that PMC-309 inhibits VISTA interaction and promotes T cell activation. PMC-309 blocked the VISTA pathway with its partner molecules such as VSIG3 (V-Set and Immunoglobulin domain containing 3), PSGL1 (P-selectin glycoprotein ligand-1) and other VISTA. In addition, there was a rise in the level of IFN-y, a pro-inflammatory cytokine, which indicates that PMC-309 enhanced T cell activities.

In in vivo studies, the test subjects administered with PMC-309 in both hPBMC (human Peripheral Blood Mononuclear Cell) engrafted mouse model and human VISTA Knock-In mouse model showed notable tumor growth inhibition. PMC-309 also showed a possible synergistic effect when used in combo with an anti-PD1 antibody because the combination of two antibodies demonstrated significantly improved tumor growth inhibition.

"Our non-clinical studies revealed PMC-309’s unique binding mechanism and its anti-tumor effect," said Dr. Jin-San Yoo, CEO of PharmAbcine. "The study results add to our confidence that PMC-309 can be a promising immunotherapeutic strategy in both mono and combo therapies for patients who do not respond to other immuno-oncology drugs."

Dr. Yoo also added, "We plan to initiate the IND (Investigational New Drug)-enabling studies and evaluate the potential toxicity risk this year. We expect PMC-309 to enter a clinical stage in 2022."

The e-poster presentation is currently available on the AACR (Free AACR Whitepaper) website. The details of the presentation are as follows:

Title: PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC)
Session category/title: Immunology/Immune Checkpoints
Abstract number: 1116
Poster number: 1626
Presentation Type: E-poster with audio presentation

On April 12, 2021 GT Biopharma, Inc. (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary NK cell engager (TriKE) protein biologic technology platform, reported additional interim results from its GTB-3550 TriKE first-in-human Phase I/II clinical trial for the treatment of high-risk myelodysplastic syndromes (MDS) and refractory/relapsed acute myeloid leukemia (AML) (Press release, GT Biopharma, APR 12, 2021, View Source [SID1234577939]).

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Additional results show GTB-3550 TriKE monotherapy is able to rescue the patient’s otherwise exhausted/inhibited/non-functional endogenous NK cell population and target direct killing of the patient’s AML and MDS cancer cells without the need for the co-administration addition of supplemental progenitor-derived or autologous/allogenic engineered NK cells.

GTB-3550 TriKE monotherapy has demonstrated clinical benefit in very hard to treat relapsed/refractory AML and high-risk MDS cancer patients by significantly reducing cancer cell (blast) levels and, in some cases, ending transfusion dependency with patients becoming eligible for bone marrow transplant.

The ability to use GTB-3550 in a monotherapy setting is a significant competitive and therapeutic advantage, and a major cost savings compared to the co-administration of drug/cell therapy combination regimens. GTB-3550 TriKE therapy requires no patient pre-treatment regimens such as myeloablative chemotherapy, and is well tolerated with no signs of cytokine release syndrome (CRS) or other toxicities suggesting GTB-3550 could be used to treat patients earlier in the disease process, whereas complicated and expensive combination drug/cell therapy regimens are expected to be used as late-stage or salvage therapies after all other therapeutic options have been exhausted.

Highlights from the first nine patients treated with GTB-3550 TriKE include:

Up to 63.7% Reduction in Bone Marrow Blast Levels Resulting in Clinical Benefit
Restores Patient’s Endogenous NK Cell Function, Proliferation and Immune Surveillance
No Progenitor-derived or Autologous/Allogenic Cell Therapy Required
No Cytokine Release Syndrome Observed
3 out of the last 5 Patients Treated Respond (25mcg/kg/day to 100mcg/kg/day therapeutic dose range)
"We believe GTB-3550 TriKE sets a new standard for NK cell engager therapies due to the incorporation of Interleukin 15 (IL-15) directly in the protein backbone. The flexibility and versatility of our TriKE platform allows us to change the cancer cell targeting moiety of TriKE to attack different cancers while maintaining the core NK cell activation, proliferation and persistence attributes of the molecule," said Anthony J. Cataldo, GT Biopharma’s Chairman and Chief Executive Officer. "The TriKE is a true monotherapy, unlike all other NK cell technologies in development. The novel TriKE uniquely does not need any outside NK cell manufacturing or combination drugs, to supplement or assist. Further, the TriKE does not require pre-conditioning of the patient’s immune system. These supplemental requirements of competitive technologies add tremendous cost to an already costly therapeutic approach. Everything the TriKE does happens with no outside assistance whatsoever. We believe the TriKE’s clinical data is demonstrating exactly that, opening the door to a significantly more cost-effective off-the-shelf therapeutic."

About High-Risk Myelodysplastic Syndromes
MDS is a rare form of bone marrow-related cancer caused by irregular blood cell production within the bone marrow. As a result of this irregular production, MDS patients do not have sufficient normal red blood cells, white blood cells and/or platelets in circulation. High-risk MDS is associated with poor prognosis, diminished quality of life, and a higher chance of transformation to acute myeloid leukemia. Approximately 40% of patients with high-risk MDS transform to AML, another aggressive cancer with poor outcomes.

About Acute Myeloid Leukemia
Acute myeloid leukemia is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. According to the National Cancer Institute (NCI), the five-year survival rate is about 35% in people under 60 years old, and 10% in people over 60 years old. Older people whose health is too poor for intensive chemotherapy have a typical survival of five to ten months. AML accounts for roughly 1.8% of cancer deaths in the United States.

About GTB-3550 TriKE
GTB-3550 is the Company’s first TriKE product candidate being initially developed for the treatment of AML and MDS, and other CD33+ hematologic cancers. GTB-3550 is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and anti-CD33 antibodies and a modified form of Interleukin 15 (IL-15). The natural killer (NK) cell-stimulating cytokine human IL-15 portion of the molecule provides a self-sustaining signal that activates NK cells and enhances their ability to kill. We intend to study GTB-3550 in CD33 positive leukemias such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and other CD33+ hematopoietic malignancies.

About GTB-3550 TriKE Clinical Trial
Patients with CD33+ malignancies (primary induction failure or relapsed AML with failure of one reinduction attempt or high-risk MDS progressed on two lines of therapy) age 18 and older are eligible (NCT03214666). The primary endpoint is to identify the maximum tolerated dose (MTD) of GTB-3550 TriKE. Correlative objectives include the number, phenotype, activation status and function of NK cells and T cells.