On April 9, 2024 NeoImmuneTech, Inc. (NIT), a global leader in T-cell-based immunotherapy, reported a poster on a pre-clinical study that opens a new field of potential applications for NT-I7 (efineptakin alfa) (Press release, NeoImmuneTech, APR 9, 2024, View Source [SID1234641958]). The poster was presented at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (April 5-10, 2024, San Diego, CA).

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The study explored the efficacy of NT-I7 (efineptakin alfa) in combination with FOLFOX (a combination of 5-fluorouracil, leucovorin, and oxaliplatin), a first-line standard of care (SoC) for colorectal cancer, in an animal model of colorectal cancer (MC38, C57BL/6 mice).

The study’s findings suggest a significant improvement in treatment outcomes when NT-I7 is used alongside FOLFOX, demonstrating a 69% reduction in tumor size compared to the administration of FOLFOX alone. While the overall Absolute Lymphocyte Count (ALC) in the blood was reduced by FOLFOX treatment, the number of anti-cancer specific T cells in the tumor was significantly increased in the combination group compared to FOLFOX alone.

Dr. Luke Oh, President and CEO of NeoImmuneTech said: "We are very excited by results that shows NT-I7 might be effective in combination with cytotoxic chemotherapeutic agents. As chemotherapeutic agents are still the standard of care for most early-stage cancer indications, combining NT-I7 with various chemotherapeutic agents might bring new hope to patients in situations where immuno-oncology is not used."

About Colorectal Cancer
Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer affects more than 150,000 people in the US and 1.8 million people worldwide each year. Despite progress in treatment in the last decade, the 5-year survival rate is still only 63% overall and a meager 13% for patients with metastatic disease.

About NT-I7 (efineptakin alfa) (rhIL-7-hyFc)
NT-I7 (efineptakin alfa) is the only clinical-stage long-acting human IL-7, and is being developed in oncologic and immunologic indications, where T cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naïve and memory T cell development and for sustaining immune response to chronic antigens (as in cancer) or foreign antigens (as in infectious diseases). NT-I7 exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. NT-I7 is being studied in multiple clinical trials in solid tumors and as vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors and other immunology-focused indications.

On April 9, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the latest findings of GFH547, an oral panRAS (ON) inhibitor, in a late-breaking research abstract at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, GenFleet Therapeutics, APR 9, 2024, View Source [SID1234641957]).

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GFH547 is developed with novel mechanism of action by reshaping and repurposing intracellular cyclophilin A (CypA) protein to target active RAS proteins across most wild/mutant subtypes. Preclinical data demonstrated profound panRAS inhibitory activity of GFH547 and it holds the potential to overcome adaptive and acquired resistance against SIIP (switch II pocket)-based KRAS inhibitors.

"Secondary mutations detected among subjects in clinical studies of KRAS inhibitors have paved the way for the development of future therapies, and GFH547 is anticipated as a new-generation inhibitor to combat the drug resistance. GenFleet’s KRAS G12C inhibitor (GFH925) has had its New Drug Application accepted with Priority Review Designation in China. From the first-generation KRAS inhibitor to a new-generation pan-RAS inhibitor, the continuous achievements underscore GenFleet’s insight into the development of RAS pathway targeted therapies. The top-tier development also showcases the depth of GenFleet’s cutting-edge pipeline and its value potential." stated Fusheng Zhou, Ph.D., Vice President of GenFleet’s Drug Discovery Department.

Abstract Title: GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS (ON) inhibitor with broad spectrum anti-tumor activities
Abstract No.: LB165/11

The GFH547-Cyp A-RAS tripartite complex inhibits most wild/mutant subtypes of active, GTP-bound RAS proteins
GFH547 has demonstrated preliminary efficacy to inhibit RAS proteins across most subtypes including the KRAS mutant proteins commonly found in human tumors (especially harboring G12C, G12D and G12V mutations). Compared with targeting RAS proteins or the RAS-RAF complex alone, the recruitment of CypA into the tripartite complex induces more profound inhibition of RAS pathway (including the RAS proteins and their downstream interaction with RAF).

The deep inhibition of KRAS pathway was observed following a single oral administration of GFH547 in KRAS mutant CDX tumors. GFH547 also demonstrates dose-dependent anti-tumor activity and drives tumor regression in KRAS mutant tumor models.

GFH547 is superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance
GFH547 is resistant to RTK activation by EGF stimulation which attenuates potency of current mainstream SIIP-based KRAS inhibitors. It is also effective to cells carrying secondary KRAS mutations causing acquired resistance to SIIP-based KRAS inhibitors. Overall, GFH547 demonstrates promising bioavailability, kinase selectivity and safety in the preclinical research.

About RAS and GFH457
RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK、PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.

GFH547 is a novel small-molecule panRAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH547 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH547 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance.

On April 9, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the latest research findings of GFH375, an oral KRAS G12D (ON/OFF) inhibitor, at the poster presentation of the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, GenFleet Therapeutics, APR 9, 2024, View Source [SID1234641956]).

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GFH375 (VS-7375) is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. With preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models, GFH375 also holds the potential for treating KRAS G12D mutant cancers with brain metastases.

"G12D mutation is the most prevalent KRAS mutation detected in human carcinomas, and no G12D-targeted therapies have been approved yet. Preliminary research has shown potent efficacy and safety of orally administered GFH375 in animal models. Additionally, GenFleet’s GFH925 (KRAS G12C inhibitor) has had its New Drug Application accepted with Priority Review Designation in China. GenFleet is well-positioned to rapidly deploy its proven expertise in developing RAS pathway inhibitors to deliver more cutting-edge innovative therapies. "stated Fusheng Zhou, Ph.D., Vice President of GenFleet’s Drug Discovery Department.

Preclinical research also demonstrated the combination of avutometinib (RAF/MEK clamp) and GFH375 confers enhanced anti-tumor efficacy relative to either agent alone, indicating potential for future clinical combination. Avutometinib in combination with defactinib (FAK inhibitor) is being developed by Verastem Oncology with clinical development across multiple indications and was granted breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status and after one more prior lines of therapy, including platinum-based chemotherapy. GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs, the first program selected is GFH375.

Abstract Title: GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy
Abstract No. : 3318

Original mechanism targets both active and inactive KRAS G12D
GFH375 inhibits GTP-bound KRAS G12D and its binding with downstream proteins such as RAF; the drug candidate also targets the GDP-GTP exchange to inhibit the activation of KRAS G12D.

Potent single agent anti-tumor efficacy of GFH375 and its potential for treating KRAS G12D mutant cancers with brain metastases
GFH375 potently and selectively inhibits phospho-ERK signaling and proliferation in KRAS G12D mutant tumor cells. GFH375 also accumulates in tumor tissue and elicits sustained inhibition of the protein following a single oral administration.

GFH375 induces tumor regression in multiple KRAS G12D CDX tumor models via oral administration. It also demonstrates potent anti-tumor activity in an intracranial CDX tumor model, which suggests the potential of GFH375 as a treatment for KRAS G12D mutant cancers with brain metastases.

Combination of GFH375 and avutometinib enhances anti-tumor efficacy while retaining favorable toxicity profile in vivo
The combination of GFH375 and avutometinib enhances anti-tumor efficacy and leads to more significant tumor regression over either drug candidate alone. Meanwhile, the results exhibit favorable toxicity profile of this combination.

About RAS and KRAS mutations

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.

About KRAS G12D and GFH375

Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitor holds promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alteration is the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.

GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain rights inside of mainland China, Hong Kong, Macau, and Taiwan.

On April 9, 2024 Jacobin Pharma (1167.HK), a clinical-stage oncology company focusing on undruggable targets, reported that the company will present the results of two preclinical evaluation of PARP7 inhibitor JAB-26766 and p53 Y220C reactivator JAB-30355 in form of the abstract during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (the "AACR 2024") from April 5 to 10, 2024 (Press release, Jacobio Pharmaceuticals, APR 9, 2024, View Source [SID1234641955]).

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Dr. Andrea Wang-Gillam, Chief Medical Officer and Global Head of R&D of Jacobio Pharma, said: " The preclinical data of the two drugs are representatives of our continued efforts in developing drugs toward key oncogenic pathways. P53 Y220C is the first tumor suppressor gene to enter into clinical study and has the potential to be used in combination with chemotherapy or oncogenic protein inhibitors. As an important downstream target of the STING signaling pathway, PARP7 is expected to be used in combination with immunotherapy in the future. Jacobio is committed to developing both assets globally."

Details for the 2024 AACR (Free AACR Whitepaper) abstracts are as follows:

JAB-26766: a small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity
Poster Presentation: April 9, 2024, 9:00 AM – 12:30 PM (GMT-7)
Session: PO.ET09.01 – DNA Reactive Agents

JAB-26766 is a potent, orally bioavailable PARP7 inhibitor with >1800-fold selectivity on PARP7 over PARP2. JAB-26766 as a single agent shows potent in vivo anti-tumor activities, which can be further enhanced through combination with STING agonist or anti-PD-1 mAb.

JAB-30355: A highly potent, orally bioavailable p53 Y220C reactivator
Poster Presentation: April 9, 2024, 1:30 PM – 5:00 PM (GMT-7)
Session: PO.ET09.09 – Novel Antitumor Agents 4

JAB-30355 is a potent and selective p53 Y220C reactivator. JAB-30355 exhibited dose-dependent anti-tumor activity, inducing tumor stasis or regression in multiple CDX and PDX models of ovarian cancer, pancreatic cancer, gastric cancer, and small cell lung cancer, with overall good tolerability. A phase I/IIa clinical trial to evaluate the safety and efficacy of JAB-30355 in patients with advanced solid tumor is ongoing in U.S.

The 2024 AACR (Free AACR Whitepaper) Annual Meeting will be held in San Diego, California, U.S. from April 5th to April 10th. For more information, please visit the official website of the AACR (Free AACR Whitepaper): View Source

On April 9, 2024 Aadi Bioscience, Inc. (NASDAQ: AADI), a commercial-stage precision oncology company focused on developing and commercializing therapies for cancers with alterations in the mTOR pathway, reported it will present new non-clinical data that highlight the combinability of nab-sirolimus and its potential for synergy to enhance anti-cancer effects and overcome resistance (Press release, Aadi Bioscience, APR 9, 2024, View Source [SID1234641954]). These data will be presented during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA, taking place April 5-10, 2024.

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Poster presentation details and abstract highlights include:

Title: "Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines"
Presenting Author: Shihe Hou, PhD
Session Title: Reversal of Drug Resistance
Poster Number: Poster Section 25; Poster 6
Date/Time: Wednesday, April 10, 2024, 9:00 AM – 12:30 PM

Fulvestrant, the selective estrogen receptor degrader and PI3K inhibitors, such as alpelisib, have demonstrated efficacy in patients with HR+ PI3K-mutated breast cancer; however, resistance still occurs
nab-sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ breast cancer cells and PI3Ki in both HR+ and HR- breast cancer cells
The addition of nab-sirolimus to endocrine therapy or PI3K-AKT-mTOR pathway inhibitors may mutually overcome mechanisms of resistance induced by single-agent treatments
These data further support the combination of nab-sirolimus with endocrine therapy for hormone-driven cancers, as is currently being investigated in patients with advanced or recurrent endometrioid endometrial cancer in a Phase 2 study (NCT05997017)
Title: "Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors"
Presenting Author: Shihe Hou, PhD
Session Title: Targeting Kinase and ERK Pathways
Poster Number: Poster Section 46; Poster 3
Date/Time: Tuesday, April 9, 1:30 – 5:00 PM

Corresponding with greater antitumor activity, nab-sirolimus was associated with higher intratumoral drug concentration and stronger mTOR target suppression than everolimus when the agents were combined with KRAS G12C inhibitors
These findings suggest more efficient tumor-targeting with nab-sirolimus plus a KRAS G12C inhibitor may lead to improved target inhibition and improved clinical outcomes