On April 8, 2024 Ichnos Glenmark Innovation (IGI), an alliance between Ichnos Sciences Inc., a global fully-integrated clinical-stage biotech company developing multispecifics in oncology, and Glenmark Pharmaceuticals Ltd., reported preclinical data for its oncology asset ISB 2001 during the oral presentation at the annual American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2024 (Press release, Ichnos Glenmark Innovation, APR 8, 2024, View Source [SID1234641894]). ISB 2001 is currently being tested in a Phase I clinical trial in r/r MM.

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The oral presentation showcased the results of ISB 2001 anti-myeloma activity in bone marrow aspirates from patients who were either newly diagnosed or suffer from r/r MM following multiples lines of treatment, including patients relapsing after CD38 and BCMA targeted therapies. This pre-clinical study shows the promise of ISB 2001 trispecific antibody targeting BCMA and CD38 against multiple myeloma, and CD3 on T cells. It illustrates IGI’s support in the fight against r/r MM.

"We are thrilled to present our preclinical findings for ISB 2001 at AACR (Free AACR Whitepaper)," said Lida Pacaud, MD, Chief Medical Officer of Ichnos Glenmark Innovation. "The development of ISB 2001 holds special significance for us as it is crafted utilizing our cutting-edge BEAT antibody engineering platform, a cornerstone of our pioneering approach to create innovative multispecific treatments for blood cancers and solid tumors."

ISB 2001 – Mechanism of Action

ISB 2001 is the first T cell-engaging antibody that simultaneously targets BCMA and CD38 on MM cells. It is a trispecific antibody based on BEAT (Bispecific Engagement by Antibodies based on the TCR) technology, a proprietary platform allowing maximal flexibility and manufacturability of full length multispecific antibodies. ISB 2001 combines three proprietary antigen-binding arms, each targeting a different antigen, with one arm binding to the epsilon chain of CD3 on T cells, and the other two binding BCMA and CD38 on MM cells. Its fragment crystallizable (Fc) domain was fully silenced to suppress Fc effector functions. ISB 2001 redirects CD3+ T lymphocytes to kill tumor cells expressing low to high levels of both BCMA and CD38. With two different tumor-associated antigens instead of one, ISB 2001 has increased binding specificity to MM cells due to enhanced avidity-based binding.

Other Impactful Preclinical Results

The oral presentation summarized the preclinical characterization of ISB 2001, while focusing on the features that enable ISB 2001 to overcome escape mechanisms.

ISB 2001 showed superior cytotoxicity in comparison with teclistamab, alnuctamab and EM-801 across cell lines with variable expression levels of both BCMA and CD38.
ISB 2001 showed minimal cytotoxicity reduction by soluble factors (sCD38, sBCMA, APRIL) compared to teclistamab, alnuctamab and EM-801, which exhibited cytotoxicity reduction to a much eater degree.
Superior tumor growth inhibition in MM xenograft models relative to teclistamab + daratumumab combination.
Maintained cytotoxicity against MM cell in bone marrow aspirates from two patients relapsing from CD38 or BCMA targeted therapies as well as demonstrated superior cytotoxicity against MM cells over teclistamab in newly diagnosed or r/r patients (as well as smoldering MM and Plasma Cell Leukemia patients).
In relapsed/refractory (r/r) MM patients, who received CD38 targeted therapy, daratumumab cytotoxicity was substantially reduced due to low CD38 expression, while ISB 2001 was still effective.

Teclistamab is considered the next line of treatment in such patients. However, ISB 2001 consistently demonstrated increased cytotoxicity compared to teclistamab in bone marrow aspirates from both newly diagnosed and r/r patients, as well as in two patients with smoldering MM and plasma cell leukemia. Remarkably, ISB 2001 also induced stronger cytotoxic response in one patient relapsing after BCMA targeted therapy, suggesting that the dual targeting by ISB 2001 TCE can overcome the escape mechanisms.

The oral presentation and corresponding data are available for review here. More information about ISB 2001, and the rest of Ichnos’ pipeline can be found here.

On April 8, 2024 Edison Oncology Holding Corp. ("Edison Oncology"), a privately held biopharmaceutical company, reported the presentation of positive interim data from the company’s ongoing multicenter Phase 1/2a clinical trial of Orotecan (oral irinotecan HCL, VAL-413) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Press release, Edison Oncology, APR 8, 2024, View Source [SID1234641893]).

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"Intravenous irinotecan is a standard treatment for various pediatric cancers, but current intravenous regimens confine children to hospital infusion centers for 30-50% of their days during treatment, robbing them of their childhood experiences," explained Jeffrey Bacha, CEO of Edison Oncology.

"We’re delighted to share encouraging interim findings from our ongoing clinical trial. These results bolster the promise of Orotecan as an oral alternative to intravenous therapy. By enabling at home treatment, Orotecan holds the potential to significantly enhance quality of life and reduce treatment expenses for both pediatric and adult cancers."

Irinotecan (intravenous, i.v.) is a topoisomerase-I inhibitor approved by the FDA for the treatment of colorectal cancer and used ‘off label’ in the treatment of a several types of cancer including gastric cancers, neuroendocrine and adrenal tumors, pancreatic cancer, small cell lung cancer, cervical cancer, ovarian cancer, esophageal cancer, soft tissue sarcomas and bone cancer. Demonstration of clinical benefit across a range of tumors has made i.v. irinotecan a key component of many standard treatment protocols. However, for recurrent pediatric cancers, patients receiving irinotecan endure daily infusions for five to ten days every two weeks, exacerbating non-adherence to treatment schedules, negatively impacting their quality of life and driving up healthcare costs.

Efforts to develop oral regimens using the intravenous formulation have yielded promising results in terms of tumor response in prior clinical studies. Nonetheless, the poor taste of the intravenous formulation has resulted in reduced patient compliance and limited widespread adoption of oral irinotecan regimens.

Orotecan (oral irinotecan HCL, VAL-413) is a novel, patented, oral liquid formulation of irinotecan hydrochloride designed to deliver the drug orally with improved tolerability.

The current clinical trial is designed to evaluate safety, tolerability and efficacy of Orotecan given with oral temozolomide for treatment of recurrent pediatric solid tumors including but not limited to neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, hepatoblastoma and medulloblastoma.

Patients up to 30 years of age with recurrent pediatric solid tumors may be eligible. During the first cycle of treatment, each patient receives four daily doses of Orotecan and one daily dose of the "off-the-shelf" i.v. preparation of irinotecan taken orally (IRN-IVPO) to allow for pharmacokinetic comparison. During all subsequent cycles patients receive Orotecan once daily in 5-day courses administered every 21 days.

The Company reported the following interim observations from the clinical trial:

The trial is currently enrolling the highest dose (110mg/m2/day) cohort, with no dose-limiting toxicity observed in the lower dose (90mg/m2/day) cohort. The 90mg/m2/day dose matches the dose of unformulated irinotecan i.v. given orally to more than two hundred patients across multiple published investigator-initiated pediatric cancer trials conducted over several years with promising outcome results.

Initial pharmacokinetic observations support equivalency between the Orotecan formulation and unformulated i.v. irinotecan given orally for both the parent compound and active metabolites SN-38 and SN-38 glucuronide.

Preliminary data suggests Orotecan oral formulation is palatable and suitable for protracted out-patient (at home) dosing for adolescent patients representing a potential significant improvement in quality of life and reduced cost of treatment vs. i.v. irinotecan. The longest treatment duration to date is twelve cycles of once-per-day oral dosing at home.
"We are grateful to the investigators, patients and families who have participated in this trial to date. These interim results are highly encouraging," said Mr. Bacha. "With the 90mg/m2/day Orotecan dose aligning with prior successful trials of unformulated i.v. irinotecan given orally coupled with pharmacokinetic equivalence and a palatable formulation suitable for outpatient dosing, we believe Orotecan holds immense potential to enhance the quality of life for patients while reducing treatment costs. These findings mark a significant advancement in our mission to improve outcomes for patients battling cancer."

On April 8, 2024 Serum Detect, Inc., a cancer diagnostics company advancing new technologies for early detection of cancer, reported the presentation of new data at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA (Press release, Serum Detect, APR 8, 2024, View Source [SID1234641892]). The new data suggests that, when combined with circulating tumor DNA (ctDNA) and cancer-related protein biomarkers, Serum Detect’s TCR-based approach may significantly improve sensitivity for the detection of early-stage cancer.

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Poster Highlights:

New study demonstrates the potential of Serum Detect’s TCR repertoire liquid biopsy to complement ctDNA approaches.

Presented a novel approach for discovery of lung cancer-associated circulating TCR repertoire functional units (RFUs), which are computationally derived sets of TCRs with similar sequences that may recognize shared tumor antigens.
A machine learning model for lung cancer status prediction using TCR RFUs detected nearly 50% of stage I lung cancers at a specificity of 80%.
The TCR RFU model score could distinguish lung cancer from non-cancerous lung conditions such as benign nodules and chronic obstructive pulmonary disease (COPD).
The TCR RFU model achieved a substantial gain in sensitivity for stage I cancer when the scores were added to plasma ctDNA mutation and lung cancer-related protein biomarker analysis, with an approximately 20%-point increase seen at the ~90% target specificity commonly used for cancer screening tests.
"The primary way to achieve cancer cures is through early detection," said Roman Yelensky, PhD, Serum Detect’s founder and CEO. "While liquid biopsy is promising, it is still failing to detect many early-stage cancers and pre-cancerous growths. Our first data on immune-based cancer early detection point to a potentially exciting complementary approach. We are grateful for the opportunity to share these findings with the research community and look forward to discussing our results with attendees at AACR (Free AACR Whitepaper) and collaborating to develop this technology into clinically impactful liquid biopsy tests."

The findings are based on a large circulating TCR repertoire dataset of 922 lung cancer cases and control subjects in total. This proprietary TCR dataset was generated using a custom NGS assay on genomic DNA extracted from blood buffy coats, which is a specimen often collected but not typically used for early detection biomarker discovery. 197 lung cancer associated circulating TCR repertoire functional units were identified at a false discovery rate (FDR) ≤10%. These include 110 RFUs that were enriched in cancer patients and 87 RFUs that were enriched in non-cancer controls. Individual RFU statistical effect sizes were relatively small, highlighting the importance of signal aggregation across multiple TCRs and TCR repertoire functional units with Serum’s novel approach.

Poster presentation details:

Poster Title: Circulating T cell receptor repertoire analysis improves cancer early detection

Presentation Number: 2295

Presenters: Yilong Li, PhD; Michelle Nahas, PhD; Roman Yelensky, PhD

Session Title: Liquid Biopsy and Precision Oncology

Session Date and Time: Monday, Apr 8, 2024, 9:00am – 12:30pm PT

Location: Poster Section 36; Poster Board Number 6

Visit the poster session and follow Serum Detect on LinkedIn for more updates from #AACR24.

On April 8, 2024 Immunitas Therapeutics ("Immunitas"), a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated therapeutics for patients with cancer, reported preclinical data supporting the combination potential of IMT-009 with anti-PD1 immunotherapy at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR 2024) in San Diego, California (Press release, Immunitas Therapeutics, APR 8, 2024, View Source [SID1234641891]).

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"The need for new immuno-oncology approaches persists, with a significant proportion of patients unable to benefit from standard of care PD-1/PD-L1 checkpoint blockade treatment due to primary and acquired resistance. This need has fueled our work to develop IMT-009 as a differentiated cancer treatment option for patients," said Annalisa D’Andrea, Chief Scientific Officer at Immunitas. "The preclinical data presented at AACR (Free AACR Whitepaper) build upon this innovation, supporting potential for clinical benefit through combination approaches featuring IMT-009 and anti-PD-1 treatments."

Novel, anti-CD161 antibody IMT-009 has been shown to restore the anti-cancer activity of T and NK cells in preclinical studies by blocking interactions between CD161 and its ligand, CLEC2D, and is currently undergoing clinical evaluation for use in solid tumor and hematologic malignancies.

The data presented at AACR (Free AACR Whitepaper) 2024 build upon these preclinical data, reinforcing CD161 as a rational immunotherapy target with the potential to enhance T cell-mediated anti-tumor activity across a range of tumors. Single cell RNA sequencing analysis of published tumor datasets demonstrated the presence of CD161 expressing T cells in patients who have previously progressed on, or are refractory to, anti-PD-(L)1 therapy, indicating potential for benefit from treatment with IMT-009 as monotherapy or in combination with anti-PD-(L)1 therapy. In cancer cell models, combination of IMT-009 and anti-PD1 treatment significantly enhanced T cell mediated tumor killing. Transcriptomic changes upon treatment with IMT-009 also show robust T cell activation and cytotoxicity gene signatures which are further enriched in combination with anti-PD1 treatment. Together these data support clinical assessment of IMT-009 treatment in combination with anti-PD-(L)1 approaches in patients refractory to anti-PD-(L)1 treatment alone.

Presentation Details for AACR (Free AACR Whitepaper) 2024
Title: Abundance of KLRB1+ (CD161) T cells in anti-PD1 non responders coupled with enhanced tumor cytotoxicity of anti-CD161 (IMT-009) with anti-PD1 makes it a rational target for combination with anti-PD-(L)1 immunotherapy
Abstract Number: 1375
Date/Time: Monday, April 8, 2024, 9:00am – 12:30pm PT

About IMT-009
IMT-009 is a fully human, Fc-attenuated IgG1 monoclonal antibody that binds to CD161 and blocks its interaction with its ligand, CLEC2D. Preclinical data confirm that CD161 blockade with IMT-009 results in enhanced anti-tumor activity. IMT-009 is under evaluation in a Phase 1/2a clinical trial for use as a monotherapy and combination treatment for solid tumor and hematological malignancies. The Phase 1 study is designed to evaluate the safety, tolerability, pharmacodynamic biomarkers, and preliminary efficacy of IMT-009 as well as identify the Recommended Phase 2 Dose (RP2D).

On April 8, 2024 Nested Therapeutics, a biotechnology company pioneering a next-generation precision medicine platform to address hard-to-treat cancers, reported that preclinical data for the company’s lead program, NST-628, were featured in an oral presentation in the "New Drugs on the Horizon" series at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Nested Therapeutics, APR 8, 2024, View Source [SID1234641890]). The presentation, titled "NST-628 is a Novel, Potent, Fully Brain-Penetrant MAPK Pathway Molecular Glue that Inhibits RAS- and RAF-Driven Cancers," was given by Klaus Hoeflich, Ph.D., chief scientific officer and co-founder of Nested. The data were published concurrently online in the journal Cancer Discovery.

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"Dysregulation of RAS-MAPK pathway signaling is one of the most frequently occurring events in tumor development, impacting one in three newly diagnosed patients in the U.S. every year, the vast majority having no approved targeted treatment alternatives. While therapies have been developed for every node of the pathway, tolerability and durability of response continue to be challenging for patients with these difficult-to-treat cancers," said Dr. Hoeflich. "NST-628 was developed as a fully brain-penetrant, non-degrading molecular glue targeting the RAF and MEK nodes of the RAS-MAPK pathway. The preclinical data presented at AACR (Free AACR Whitepaper) show that NST-628 induces broad efficacy in tumor models and demonstrated the potential to overcome limitations of existing MEK and RAF inhibitors and RAS inhibitors in development. With a half-life and metabolic profile optimized to achieve a superior therapeutic index on a daily dosing schedule, as well as full intrinsic blood brain barrier penetrance, these data support NST-628’s potential as a best-in-class treatment for RAS- and RAF-driven cancers."

Preclinical data presented at AACR (Free AACR Whitepaper) and published in Cancer Discovery highlight the differentiated mechanism and drug-like properties of NST-628. Specifically:

In cellular and patient-derived tumor models harboring diverse KRAS, NRAS and BRAF alterations, NST-628 induced potent, deep and durable inhibition of the RAF-MEK signaling complex with broad efficacy without sacrificing tolerability at clinically achievable exposures over other MAPK-targeted compounds administered as either single agents or combinations.
With a predicted clinical half-life of 10-12 hours, the pharmacokinetic and metabolic profile of NST-628 has been optimized to broaden the therapeutic window and be clinically efficacious with once-daily oral dosing.
In mouse models with an intact blood brain barrier as well as central nervous system (CNS) models with RAS-MAPK alterations, NST-628 demonstrated full intrinsic CNS permeability. These data suggest NST-628 has the potential to treat brain metastases and primary CNS malignancies with MAPK pathway alterations. Approximately 40% of patients with metastatic cancer will develop symptomatic brain metastases, in particular in RAS-MAPK pathway dysregulated tumors such as lung, breast and melanoma.
Good laboratory practices (GLP) toxicology studies demonstrate significantly improved exposure margins when compared to other MEK inhibitors in non-clinical species.
Preclinical data support NST-628 as an ideal combination partner for upstream inhibitors including KRAS inhibitors by effectively preventing pathway reactivation.
In totality, the data validate NST-628’s potential to provide transformative clinical benefit as both a monotherapy or vertical combination anchor.
About the Phase 1 Study of NST-628
The ongoing Phase 1 open-label, single-arm, two-part study (NCT06326411) is intended to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of single agent NST-628 in adult patients with RAS-MAPK pathway mutated/dependent advanced solid tumors, especially diverse KRAS, NRAS and BRAF alternations, who have exhausted standard treatment options. The study includes two parts: dose escalation (Part A) followed by dose expansion (Part B). The primary objectives for Part A, which recently initiated, are delineating NST-628’s safety profile and establishing the recommended dose for Part B. For more information, visit clinicaltrials.gov.

About NST-628
NST-628 is a fully brain-penetrant, mechanistically novel non-degrading molecular glue that targets multiple nodes in the RAS/MAPK pathway. NST-628 was developed based on Nested’s proprietary structural insights of how signaling complexes form and function in cancer and addresses common pitfalls of other MAPK-targeted compounds, which remain unable to circumvent the risk of intrinsic resistance via signaling pathway reactivation. Preclinical data evaluating oncology biomarkers relevant to RAS/MAPK-driven cell and patient-derived models collectively demonstrate superior anti-tumor activity, including in RAS and central nervous system-implanted tumor models, and tolerability of NST-628 compared to other MAPK-targeted compounds administered as either single agents or in combination. With a half-life and metabolic profile optimized to achieve a superior therapeutic index on a daily dosing schedule, as well as full intrinsic blood brain barrier penetrance, these data support NST-628’s potential as a best-in-class treatment especially for KRAS, NRAS and BRAF-driven cancers.