On November 3, 2023 Genialis, the RNA-biomarker company, reported new data detailing how RNA sequencing data can help elucidate tumor biologies that may be amenable to immunotherapies and targeted agents (Press release, Genialis, NOV 3, 2023, View Source [SID1234636934]). The information was presented in two posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting.

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In the first poster with Exact Sciences, Genialis found the Xerna TME Panel, an RNA-based pan-tumor biomarker previously shown to be predictive of responses to multiple immune-targeted cancer therapies, identified 49.4 percent of colorectal cancer patients (N = 336) as having immune biological features that may benefit from immunotherapy. By contrast, only 11 percent and 9 percent were TMB- or MSI-High, respectively. Many of these patients also harbor genetic alterations that have associated targeted therapy options, opening up the opportunity for novel combined therapeutic approaches.

In a second presentation, Genialis introduced its ResponderID MSI program, demonstrating how a machine learning-based classifier of microsatellite instability (MSI) from RNA sequencing data performs comparably to state of the art IHC- and PCR-based MSI detection methods. The Genialis model yielded a mean AUC ROC of 0.96, with all but one validation dataset >0.94. The MSI classifier is tumor-type agnostic, and does not require matched normal samples, as is the case for some PCR-based methods. The Genialis RNA-Seq pipeline solves the need for a fast, accurate, and accessible NGS-based method for MSI detection, aiding in the identification of patients that may benefit from immune checkpoint inhibitor therapy.

"RNA biomarkers provide more comprehensive and dynamic insights into cellular states and regulatory processes compared with DNA or protein biomarkers. And in the case of these two posters, Genialis is showing how using an RNA-based approach helps identify subsets of patients who may benefit from immunotherapy treatment," said Mark Uhlik, Ph.D., VP of Biomarker Discovery. "Genialis has been successful in developing RNA-based biomarkers for myriad cancer types and drug targets, and we are committed to apply our use of cutting-edge technology to aid in the development of potentially life-saving therapies."

Genialis is expert at developing RNA-based patient classifiers, a largely underutilized analyte in clinical diagnostics. Genialis ResponderID draws on multimodal datasets, including RNA-seq data, and employs ML/artificial intelligence (AI) to analyze changes in tens or hundreds of genes relevant to disease pathology. The proprietary algorithms built into ResponderID then identify patterns of RNA transcription that characterize the underlying biology of disease states and the patient’s likely response to therapeutics. By probing the interactions of the underlying disease biologies, ResponderID biomarkers reflect complex disease phenotypes.

Genialis Abstract #219, "Prevalence of genomic alterations in Xerna tumor microenvironment subtypes in colorectal cancer patients," and Abstract #179, "Profiling microsatellite instability using RNA sequencing data" will be on display at the San Diego Convention Center during SITC (Free SITC Whitepaper) 2023. For more information on ResponderID or to make an appointment with Genialis to learn more, please visit www.genialis.com

On November 3, 2023 TriSalus Life Sciences Inc., (Nasdaq: TLSI), an oncology company integrating its novel delivery technology with immunotherapy to transform treatment for patients with liver and pancreatic tumors, reported initial positive safety and feasibility data from a Phase 1 trial at the Society of Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) 2023 Annual Meeting (Press release, TriSalus Life Sciences, NOV 3, 2023, View Source [SID1234636933]).

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TriSalus is studying an investigational class C toll-like receptor-9 (TLR9) agonist, SD-101, delivered intravascularly using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials (periotrial.com). In PERIO-03, SD-101 is delivered via PEDD with the TriSalus Infusion System using a retrograde venous approach, leveraging established interventional radiology access techniques.

The TriSalus Infusion System has an expandable SmartValve and can interface with standard invasive blood pressure transducers for continuous pressure monitoring during infusion of a therapeutic. During infusion, the device blocks retrograde flow and modulates pressure in the vessel, resulting in the perfusion of the venous and capillary network isolated by the device.

Early safety and feasibility data from the PERIO-03 locally advanced pancreatic adenocarcinoma trial revealed that in three patients who received SD-101 via retrograde venous infusion PEDD at the lowest dose level (0.5 mg), there were no serious grade 3/4 adverse events related to treatment. This is a first-in-human experience for use of PEDD and retrograde venous infusion for delivery of an immunologic agent into pancreatic tumors. Immune signals pointed to a decrease in myeloid derived suppressor cells (MDSC) activity in the treated pancreatic tumors, with declines in MDSC associated genes, including arginase-1, nitric oxide synthetase-2, and S100A9 (n=3). Signals associated with T cell activation were also noted in pancreatic tumor biopsy specimens.

"There is a critical need for novel treatments and approaches in locally advanced pancreatic cancer. The PERIO-03 trial is a highly innovative and multidisciplinary approach of delivery of a novel immunotherapy into the pancreas through pancreatic retrograde venous infusion," stated Michael S. Lee, M.D., associate professor of Gastrointestinal (GI) Medical Oncology at The University of Texas MD Anderson Cancer Center. "The treatments have been well tolerated and the translational studies show intriguing changes in immune markers. We are excited to continue enrolling patients in this study."

"These data offer additional validation of our innovative immunotherapy approach for pancreatic tumors. SD-101 was selected based on its mechanism of action, which has the potential to reverse immunosuppression in the pancreas through depletion of MDSC in concert with broad stimulation of immune cells in the tumor microenvironment," said Steven C. Katz, M.D., FACS, Chief Medical Officer at TriSalus. "TriSalus delivery systems, which use the PEDD method, are designed to overcome mechanical barriers to immunotherapy success, which may be underappreciated factors in limiting performance of TLR agonists in liver and pancreas tumors. Pancreatic tumors in particular contain very dense stromal tissue, which may accentuate the mechanical barriers to effective drug delivery in these patients."

Overall, the data emerging from PERIO-03 trials indicate immunologic changes are occurring within the pancreas, with a favorable safety profile. Additionally, pre-clinical data presented by TriSalus at SITC (Free SITC Whitepaper) indicates that SD-101 administered via PEDD can enable both intravenously and subcutaneously administered checkpoint inhibitors.

TriSalus will also present data from its PERIO-01 trial for uveal melanoma liver metastases at a SITC (Free SITC Whitepaper) late breaker session on Saturday, November 4 at 11:25 am PT. All TriSalus presentations from SITC (Free SITC Whitepaper) are available here following their respective sessions.

About Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials

The Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials are studying an investigational class C toll-like receptor-9 agonist, SD-101, delivered intravascularly by TriSalus’ TriNav Infusion System (TriNav) using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials.

The PERIO-01 Phase 1 clinical study for uveal melanoma with liver metastases (UMLM), is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-02 Phase 1b clinical study for hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-03 Phase 1 clinical study for locally advanced pancreatic adenocarcinoma, is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

On November 3, 2023 AbCellera (Nasdaq: ABCL) reported new data on its T-cell engager (TCE) programs in two poster presentations at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting (Press release, AbCellera, NOV 3, 2023, View Source [SID1234636932]). The data illustrate how AbCellera is leveraging its TCE platform to discover and develop immuno-oncology therapeutics for multiple tumor targets.

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In its first poster, AbCellera presented data demonstrating that TCE function is determined by multiple factors, including—but not limited to—CD3-binding affinity. Based on these findings, AbCellera developed a high-throughput process that prioritizes TCE function to streamline the selection of diverse CD3-binding antibodies for different tumor targets. AbCellera is currently leveraging its integrated platform to discover and develop TCEs for multiple programs. The poster included data from two of these programs targeting prostate-specific membrane antigen (PSMA) and melanoma-associated antigen 4 (MAGE-A4).

"Altering the affinity of either a small set of CD3-binding antibodies, or an antibody such as SP34-2, is a frequently used strategy to reduce risk of cytokine release syndrome by TCEs. However, we have demonstrated that CD3 affinity alone is not sufficient to optimize TCE function," said Bo Barnhart, Ph.D., VP of Translational Research at AbCellera. "By pairing functionally diverse CD3-binders with a wide range of tumor-binding arms, our TCE platform has identified promising bispecific molecules."

In its second poster, AbCellera presented additional data on its MAGE-A4 x CD3 program, which targets MAGE-A4, a challenging peptide-MHC target. AbCellera used its bispecific platform, OrthoMabTM, to engineer more than 200 bispecific TCEs. Results from high-throughput assessment of these molecules demonstrate that the platform can generate high-quality TCEs for further development.

"Since launching our TCE platform in 2021, we’ve gained a deeper understanding of TCE biology that we believe will enable us to rapidly bring best-in-class molecules to the clinic," said Neil Aubuchon, Chief Commercial Officer at AbCellera. "We look forward to applying these lessons to targets as we work towards bringing better cancer treatments to patients faster."

AbCellera’s poster presentations are available for download here.

About T-Cell Engagers

CD3 T-cell engagers are bispecific antibodies that guide the immune system to find and eliminate cancer cells by binding both cancer-killing T cells and tumor targets at the same time. Developing effective T-cell engagers requires two parental antibodies—a CD3-binding arm that fine-tunes T-cell activation and a tumor-binding arm with high specificity for cancer cells. The small number of available CD3-binding antibodies that can effectively fine-tune T-cell responses has been a barrier to T-cell engager development. To address this barrier, AbCellera developed a complete T-cell engager platform that includes fully human, developable CD3-binding antibodies with unique binding and functional properties. By combining these antibodies with OrthoMabTM, its clinically validated multispecific engineering platform, and its antibody discovery and development engine, AbCellera’s T-cell engager platform is designed to bring new cancer medicines to the clinic faster.

On November 3, 2023 Ankyra Therapeutics, an emerging clinical stage biotechnology company pioneering anchored immunotherapies to treat cancer, reported data from a preclinical study using ANK-101, an IL-12 anchored therapeutic, in combination with cytotoxic chemotherapy and immune checkpoint blockade, to treat head and neck squamous cell carcinoma, modeled by murine oral carcinoma (MOC1) (Press release, Ankyra Therapeutics, NOV 3, 2023, View Source [SID1234636931]). The study was conducted jointly by Ankyra Therapeutics and the Center for Immuno-Oncology, part of the National Institute of Health’s National Cancer Institute Center for Cancer Research. The findings are being presented during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023 in San Diego, CA.

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Following treatment with combinations of murine ANK-101, cisplatin (cis-platinum), and anti-PD-1 alone or together, tumor size and mouse survival were recorded. Data presented showed that a single dose of mANK-101 was associated with a significant delay in tumor growth in the MOC1 model, while anti-PD-1 and cisplatin alone, or in combination, had minimal impact on tumor growth. When mANK-101 was combined with either cisplatin or anti-PD-1, no further delay in tumor growth compared to monotherapy mANK-101 was observed; however, triple therapy (ANK-101, cisplatin, anti-PD-1) further delayed tumor growth and increased survival when compared to mANK-101 monotherapy.

"These are promising preclinical results for ANK-101, not only as a monotherapy but also in combination with chemotherapy and checkpoint inhibitors," said Howard L. Kaufman, M.D., President and CEO of Ankyra Therapeutics. "These data suggest that anchored IL-12 could improve the current standard of care in head and neck carcinoma while adding limited additional toxicity."

Ankyra Therapeutics is pioneering a new class of tumor-directed, anchored immuno-oncology agents, and its lead asset comprises IL-12 linked to aluminum hydroxide. The IL-12 complex is designed for local retention of functional IL-12 within the tumor microenvironment. Previous pre-clinical data demonstrated retention of IL-12 for up to 4 weeks without evidence of systemic toxicity, maximizing therapeutic potency while minimizing systemic exposure and on-target/off-tumor side effects. The U.S. Food and Drug Administration (FDA) and Health Canada have recently approved the company’s Investigational New Drug (IND) application for ANK-101: in early 2024, Ankyra plans to initiate a first-in-human Phase I clinical trial of ANK-101 as a single agent anchored immunotherapy in patients with advanced solid tumors who have failed standard of care treatments.

"As we prepare to enter the clinic, we are very encouraged by these results," said Leisha A. Emens, M.D., Ph.D., Senior Vice President of Translational Research of Ankyra Therapeutics. "In our preclinical studies, ANK-101 increases immune activity within the tumor microenvironment, priming the tumor for greater clinical benefit from the combination of chemotherapy and PD-1 blockade."

About ANK-101

ANK-101 is an anchored drug complex composed of interleukin-12 (IL-12) linked to aluminum hydroxide. ANK-101 enables local delivery of functional IL-12 to the tumor microenvironment where it remains biologically active for several weeks but does not diffuse into the systemic circulation, thereby avoiding systemic toxicity. Treatment with ANK-101 in animal models has been associated with recruitment and retention of tumor-specific CD8+ T cells, NK cells and M1 macrophages activating innate and adaptive anti-tumor immunity. ANK-101 is being evaluated for the treatment of advanced solid tumors alone and in combination with anti-PD-1 agents.

On November 3, 2023 Scholar Rock (NASDAQ: SRRK), a Phase 3, clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported new data from its Phase 1 DRAGON proof-of-concept trial of SRK-181, a selective inhibitor of latent TGFβ1 activation being developed with the aim of overcoming resistance to checkpoint inhibitor therapy in patients with advanced cancer (Press release, Scholar Rock, NOV 3, 2023, View Source [SID1234636930]). These data will be presented in two poster presentations during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting & Pre-Conference being held November 1 – 5th in San Diego.

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The first poster focuses on the safety, efficacy, and preliminary biomarker data in patients with anti-PD-1 resistant clear cell renal cell carcinoma (ccRCC) in Part A2 (dose escalation) and Part B (dose expansion) of the Phase 1 DRAGON trial. The ccRCC cohort was the focus for that poster, as it was the fastest cohort to achieve enrollment goals. The second poster focuses on preliminary biomarker data from part B of the trial in patients with multiple tumor types.

Data presented continues to support proof of concept for SRK-181 in 28 heavily pretreated patients with ccRCC resistant to anti-PD-1. SRK-181 was generally well tolerated and showed promising anti-tumor activity in this patient population. Of 28 evaluable patients in the ccRCC cohort, six patients treated with SRK-181 in combination with pembrolizumab had confirmed partial responses (PRs) and achieved a best tumor reduction of 33% to 93%, with an objective response rate (ORR) of 21.4%. In the biomarker analysis for ccRCC, levels of circulating granulocytic myeloid-derived suppressor cells (gMDSC) correlated with clinical activity in ccRCC patients treated with SRK-181 in combination with pembrolizumab. The data cutoff for all analyses was August 29, 2023.

"The DRAGON trial has successfully delivered on its objective of demonstrating proof of concept for SRK-181 by showing promising anti-tumor activity. These data, along with biomarker results that support proof of mechanism, highlight the immunosuppressive role of TGFβ as a mechanism of anti-PD-1 resistance in patients," said Jay Backstrom, M.D., M.P.H., President and Chief Executive Officer of Scholar Rock. "We are particularly encouraged by the responses observed in patients with ccRCC who had been treated with multiple lines of therapy before receiving SRK-181."

Safety data from ccRCC cohort continue to show SRK-181 is generally well tolerated

Safety data from the ccRCC cohort (n=30 patients; part A2: 1 patient on 800mg q3w and 1 patient on 1600mg q3w and Part B: 28 patients on 1500 mg q3w) continue to show SRK-181 has been generally well tolerated when used in combination with pembrolizumab. No dose-limiting toxicities were observed at any dose level, including at 1500 mg q3w in combination with pembrolizumab, the recommended dose selected for Part B.

One Grade 4 treatment-related adverse event (AE) was observed, dermatitis exfoliative generalized. No Grade 5 treatment-related AEs occurred. Treatment-related serious adverse events were dermatitis exfoliative generalized (1 patient), pemphigoid and rash (both in 1 patient), immune-related hepatitis (1 patient), and diarrhea, nausea, and vomiting (all three in 1 patient).

Preliminary results of SRK-181 in ccRCC patients show promising anti-tumor activity

The response was assessed by principal investigators based on RECIST 1.1. Out of the 28 ccRCC patients with evaluable responses (defined as all enrolled patients except those who are still on study, but pending post-treatment radiographic evaluation):

Six patients had confirmed PRs (defined as at least a 30% tumor reduction), with best tumor reduction of 33% to 93%, and remained on study for 2.8+ to 16.3+ months (5 of the 6 patients remained on for over 6.5 months).
Ten patients had stable disease (SD) (defined as tumors with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). Five of these patients continued in the study.
The objective response rate (ORR), defined as the percentage of patients with a partial or complete response to therapy, was 21.4% and the disease control rate (DCR), defined as the percentage of patients whose disease shrinks or remains stable over a certain time period, was 57%. In this difficult to treat population, anti-PD-1 retreatment is generally associated with single-digit ORR or no response.1
Biomarker data support proof of mechanism in multiple tumor types

The biomarker strategy includes measuring effects of SRK-181 on both circulating and tumor immune cells, such as tumor infiltration by CD8+ T cells and reductions in myeloid-derived suppressor cell (MDSC) populations. The analysis included patients from Part B with ccRCC, melanoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC).

Following treatment with SRK-181 and pembrolizumab, circulating MDSC levels decreased below baseline in all patients with PRs (n=7), which included those in the ccRCC, melanoma, and UC cohorts. CD8+ T cells were measured in tumor types for which paired biopsy samples (i.e., samples before and after treatment for individual patients) of sufficient quality were available: UC, melanoma, and NSCLC. In those patients (n=8), SRK-181 treatment was associated with an increase in CD8+ T cell infiltration into tumors. These findings were consistent with preclinical data showing that treatment with SRK-181 and anti-PD-(L)1 therapy decreased circulating MDSC levels and increased CD8+ T cell infiltration into tumors, which correlated with tumor response and survival benefit.

The results will be presented at the SITC (Free SITC Whitepaper) 38th Annual Meeting in two poster presentations, details of which can be found below. The posters will be made available in the Publications & Posters section of Scholar Rock’s website following the conference.

Title: Establishing Proof of Mechanism in Patients: Preliminary Biomarker Data of SRK-181 (a latent TGFβ1 inhibitor) from DRAGON Study
Presentation Type: Poster 726
Presenter: Susan Henry, PhD, Senior Director, Translational Sciences, Scholar Rock, Inc.
Location: Exhibit Halls A and B1, San Diego Convention Center
Date/Time: November 4, 11:55 AM – 1:25 PM PST and 7 – 8:30 PM PST

Title: Safety, Efficacy, and Biomarker Results of SRK-181, a Latent TGFβ1 Inhibitor, in Anti-PD-1 Resistant Metastatic ccRCC Patients
Presentation Type: Poster 666
Presenter: Timothy Yap, MBBS, PhD, FRCP, Medical Oncologist and Physician-Scientist; and Associate Professor, Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center
Location: Exhibit Halls A and B1, San Diego Convention Center
Date/Time: November 4, 11:55 AM – 1:25 PM PST and 7 – 8:30 PM PST

For conference information, visit View Source

(1) Pal, et al. The Lancet. 2023; 15;402(10397):185-195.

About SRK-181

SRK-181 is a selective inhibitor of TGFβ1 activation being developed to overcome primary resistance to checkpoint inhibitor therapy, such as anti-PD-(L)1 antibodies, in advanced cancer. TGFβ1 is the predominant TGFβ isoform expressed in many human tumor types. Based on analyses of various human tumors that are resistant to anti-PD-(L)1 therapy, data suggest that TGFβ1 is a key contributor to the immunosuppressive tumor microenvironment, excluding and preventing entry of cytotoxic T cells into the tumor, thereby inhibiting anti-tumor immunity. (2) SRK-181 specifically targets the latent TGFβ1 isoform in a context-independent manner, designed to enable complete inhibition of TGFβ1 in all compartments within the tumor microenvironment. Scholar Rock believes that SRK-181 has the potential to overcome this immune cell exclusion and induce tumor regression when administered in combination with anti-PD-(L)1 therapy while potentially avoiding toxicities associated with non-selective TGFβ inhibition. The DRAGON Phase 1 proof-of-concept clinical trial (NCT04291079) in patients with locally advanced or metastatic solid tumors is ongoing. The trial is currently enrolling and dosing patients in multiple proof of concept cohorts conducted in parallel, including urothelial carcinoma (UC), cutaneous melanoma (MEL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and clear cell renal cell carcinoma (ccRCC). SRK-181 is an investigational product candidate and its efficacy and safety have not been established. SRK-181 has not been approved for any use by the FDA or any other regulatory agency.