On October 3, 2023 Akamis Bio, a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene (T-SIGn) therapy platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors, reported data from a Phase 1 study of its adenovirus vector technology in combination with radiotherapy that showed improved response rates relative to expectations for radiation alone in patients with locally advanced rectal cancer (Press release, Akamis Bio, OCT 3, 2023, View Source [SID1234635617]).

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The CEDAR study, sponsored by Cancer Research UK and Akamis Bio, found that Enadenotucirev (EnAd), a tumor selective, I.V.-administered oncolytic adenovirus (on which T-SIGn therapeutics are based), in combination with chemoradiotherapy, showed significantly higher response rates by MRI assessed tumor regression grade (mrTRG – 41.6%) and pCR/cCR (41.6%) than expected rates (~20%) for standard chemoradiation. In the two dose schedules with administration pre-CRT and post-CRT, mrTRG of 1 or 2 was observed in 5 out of 10 (50%) of the treated patients. Further, hexon staining of patient samples suggested EnAd localization in both the primary tumor and in metastatic sites. The combined therapy was well tolerated with an acceptable safety profile.

"These data are compelling given the higher-than-expected pCR/cCR rate, and the low adverse event rate highlights the ability to deliver the oncolytic virus concurrently with chemoradiation. This demonstrates the potential of a more reliable systemic administration compared to intratumoral injection," said Dr. Maria A. Hawkins, Chair of Radiation Oncology at University College in London and the principal investigator of the study. "We are further encouraged by the potential of this systemic treatment to reach micro-metastatic cancer sites and we believe this approach should be pursued in additional studies as we look to improve the efficacy of chemoradiation for a wide range of solid tumors."

EnAd is a group B adenovirus designed for the systemic treatment of metastatic or advanced epithelial tumors. It is a precursor to Akamis Bio’s clinical-stage Tumor-Specific Immuno-Gene (T-SIGn) therapeutics platform, which selectively delivers multiple transgene combinations, such as cytokines, chemokines, and antibodies for expression by tumor cells.

The primary objective of the Phase 1 CEDAR study was to determine the optimal dose and frequency that EnAd can be administered with chemoradiation for rectal cancer, with secondary objectives focused on demonstrating the ability to deliver EnAd with chemoradiation and to measure the local response rate to combined therapy compared to pre-treatment status.

"These results are very encouraging as they demonstrate the acceptable safety profile and potent efficacy achievable with our first-generation adenovirus vector, EnAd," said Dr. Oliver Rosen, Akamis Bio’s Chief Medical Officer. "As our T-SIGn therapeutics combine the EnAd backbone with an ability to selectively deliver transgenes to solid tumors, we look forward to building upon the clinical insights from the CEDAR study and demonstrating the potential of T-SIGn in conjunction with chemoradiation to positively impact the lives of patients living with rectal cancer and other solid tumors."

Data from the CEDAR study will be presented today at the 2023 American Society for Radiation Oncology Annual Meeting in San Diego, CA. Details of the presentation are as follows:

Poster Presentation Title: A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Cancer (CEDAR)
Poster Session: Gastrointestinal Cancer and Sarcoma
Date and Time: October 3 at 12:45 – 2:00 p.m. ET
Presenter: Dr Séan M. O’Cathail, MSc DPhil MRCPI FRCP FRCR, Senior Research Fellow, School of Cancer Sciences, University of Glasgow

About T-SIGn

Akamis Bio’s T-SIGn therapeutics are based on a replication competent, chimeric group B adenovirus backbone which has been adapted via directed evolution to home specifically to both primary and metastatic epithelial-derived solid tumor tissue following intravenous delivery. Once at the tumor site, T-SIGn therapeutics can drive the intratumoral expression of multiple transgene payloads, turning solid tumor cells into "drug factories" while leaving healthy tissue unaltered and intact. The intratumoral expression of immunologically active biomolecules and therapeutic proteins can result in the remodeling of the solid tumor microenvironment, triggering robust antitumor immune responses. T-SIGn therapeutics have the potential to be used in the monotherapy setting, as well as in combination with other immuno-oncology agents to target the key mechanisms that tumors use to evade the immune system.

On October 3, 2023 MAIA Biotechnology, Inc. (NYSE American: MAIA), a clinical stage company developing telomere-targeting immunotherapies for cancer, reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for THIO to be evaluated in the U.S. as part of THIO-101, the Company’s ongoing global phase 2 clinical study in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (Press release, MAIA Biotechnology, OCT 3, 2023, View Source [SID1234635616]). THIO is being tested in sequential combination with Regeneron’s anti PD-1 monoclonal antibody cemiplimab (Libtayo) to evaluate anti-tumor activity and immune response in NSCLC patients.

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"We are extremely pleased to obtain clearance to extend our go-to-market THIO-101 trial to the U.S. and further develop THIO’s global reach," said Vlad Vitoc, MAIA’s Chief Executive Officer.

"The FDA IND clearance represents an essential milestone in the clinical development of THIO, as a first-in-class telomere targeting agent in clinical development for patients with advanced NSCLC," said Mihail Obrocea, M.D., MAIA’s Chief Medical Officer.

"We worked diligently with the FDA throughout the pre-IND/IND process to successfully align with their regulatory guidance and recommendations and we remain committed to developing novel, safe and effective treatments for patients with cancer," added K. Robinson Lewis, MAIA’s Head of Regulatory and Quality.

About Investigational New Drug Application

An Investigational New Drug (IND) application is a request for authorization from the U.S. Food and Drug Administration to administer an investigational drug or biological product to humans in the United States. Organizations can initiate a clinical trial in the U.S. with IND clearance from the FDA.

About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a first-in-class investigational telomere-targeting agent currently in clinical development to evaluate its activity in Non-Small Cell Lung Cancer (NSCLC). Telomeres, along with the enzyme telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies. The modified nucleotide 6-thio-2’-deoxyguanosine (THIO) induces telomerase-dependent telomeric DNA modification, DNA damage responses, and selective cancer cell death. THIO-damaged telomeric fragments accumulate in cytosolic micronuclei and activates both innate (cGAS/STING) and adaptive (T-cell) immune responses. The sequential treatment with THIO followed by PD-(L)1 inhibitors resulted in profound and persistent tumor regression in advanced, in vivo cancer models by induction of cancer type–specific immune memory. THIO is presently developed as a second or later line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

About THIO-101, Phase 2 Clinical Trial

THIO-101 is a multicenter, open-label, dose finding Phase 2 clinical trial. It is the first trial designed to evaluate THIO’s anti-tumor activity when followed by PD-(L)1 inhibition. The trial is testing the hypothesis that low doses of THIO administered prior to Regeneron’s anti-PD1 cemiplimab (Libtayo) will enhance and prolong immune response in patients with advanced NSCLC who previously did not respond or developed resistance and progressed after first-line treatment regimen containing another checkpoint inhibitor. The trial design has two primary objectives: (1) to evaluate the safety and tolerability of THIO administered as an anticancer compound and a priming immune activator and (2) to assess the clinical efficacy of THIO using Overall Response Rate (ORR) as the primary clinical endpoint. For more information on this Phase II trial, please visit ClinicalTrials.gov using the identifier NCT05208944.

On October 3, 2023 BostonGene, a leading provider of AI-based molecular and immune profiling solutions, reported a master agreement with Johns Hopkins University School of Medicine (JHUSOM) to collaborate on multiple clinical research projects (Press release, BostonGene, OCT 3, 2023, View Source [SID1234635615]). The agreement allows BostonGene and JHUSOM to further identify and validate novel precision medicine approaches.

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JHUSOM will work with BostonGene on the molecular characterization study of the patient’s tumor, microenvironment and immune system and its predictive value in response to treatment. BostonGene’s solution will provide JHUSOM with detailed analysis, interpretation and visualization of big data obtained from cancer patient’s genomic, transcriptomic, proteomic and imaging studies. This work hopes to identify significant somatic alterations, evaluate protein expression, compute tumor clonality, tumor heterogeneity, tumor microenvironment cell type composition, hereditary predisposition, viral infestation and pharmacogenomics and predict neoantigens for personalized vaccine development, among other molecular features. BostonGene will perform comprehensive bioinformatics to validate hypothesis-driven research to identify targetable molecular alterations.

"We’re honored to collaborate with JHUSOM to provide our AI-based molecular and immune profiling techniques that comprehensively analyze the tumor, microenvironment, and immune system to uncover treatable targets to personalize therapy for patients," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "This collaboration supports our mission to support doctors in finding the most effective strategy for personalized treatment options for their patients."

On October 3, 2023 Olatec Therapeutics LLC (Olatec), a leader in the developing class of oral selective NLRP3 inhibitors, reported a publication in Cancer Research Communications showing a reduction in tumor progression with dapansutrile as a monotherapy, resulting from inhibition of NLRP3/IL-1β pathway in mouse models of pancreatic ductal adenocarcinoma (PDAC) (Press release, Olatec Therapeutics, OCT 3, 2023, View Source [SID1234635614]). Additionally, the data show that dapansutrile, when administered in combination therapy with gemcitabine significantly increased efficacy of this chemotherapy.

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PDAC has been reported to constitute ninety percent of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. Long-term survival among PDAC patients remains poor due to a lack of effective screening methods, nonspecific symptoms, and limited treatment options. While there has been improvement in systemic chemotherapy, an urgent need still exists for an effective treatment.

Inflammation in the tumor microenvironment (TME) in PDAC models caused by activation of the IL-1β pathway has been shown to promote PDAC cell proliferation, metastasis and to limit response to chemotherapy. Olatec’s preclinical studies advance this understanding by demonstrating that NLRP3 participates in the IL‑1β-mediated PDAC progression. Dr. Carlo Marchetti, the investigator in these studies, shows NLRP3 to be highly expressed in the tissue of pancreatic tumors when compared to normal pancreatic tissue. Dr. Marchetti further demonstrates that PDAC-bearing wild type mice treated with dapansutrile significantly reduce tumor growth and mass, which was confirmatory in his studies using mice with the NLRP3 genetic deletion. Advancing Olatec’s understanding of dapansutrile’s immunologic effect in cancer, the studies also show that inhibition of NLRP3 with dapansutrile result in intra-tumoral increase in IL-2, a reduction in T-helper (Th)2 response, and an augmented activation of CD8 T cells which resulted in a favorable change in the T Cell phenotype of the TME.

When asked about the implications of these findings, Charles Dinarello MD, Olatec SAB Chair, said: "the preclinical data we have generated using a well-established murine model of PDAC provide the rationale to advance dapansutrile into a PDAC clinical trial."

Olatec’s Founder and CEO, Damaris Skouras, commented: "There is an urgent unmet need for an effective treatment to extend patient survival with this pernicious form of pancreatic cancer. We believe patient outcomes could potentially be improved if the data from our preclinical studies translate in clinic trials."

About Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma has been reported to constitute 90% of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. The incidence rate for pancreatic cancer has increased by about 1% per year since the late 1990s in both men and women, according to American Cancer Society (Cancer Facts & Figures 2023). Lack of effective screening methods, nonspecific symptoms and limited treatment options are major limitations in the management of this disease that contribute to the extremely severe prognosis in pancreatic cancer patients. The 5-year survival reached approximately 11% for the first time in 2022. A combination of systemic therapy and surgery is needed to treat patients with PDAC in order to achieve the best chance at long-term outcomes. While there has been improvement in systemic chemotherapy, long-term survival among PDAC patients remains poor. Immunotherapy has increasingly become a treatment option of interest for many cancer types. The efficacy of immunotherapy to treat PDAC patients remains unclear, however, the PDAC tumor microenvironment may promote resistance to immunotherapy supporting the rationale for intervention with anti-inflammatory therapies.

About Dapansutrile

Dapansutrile (lab code: OLT1177) is an investigational small molecule, new chemical entity that specifically binds to and blocks NLRP3 (nucleotide-binding and oligomerization domain [NOD]‑, leucine rich repeat-, pyrin domain-containing 3), the sensor molecule integral in the formation of the NLRP3 inflammasome. Inflammasomes are multiprotein complexes involved in intracellular surveillance of danger signals that trigger an intense inflammatory response, via generation of bioactive IL-1β and IL-18 through caspase-1 activation. Dapansutrile has been shown to inhibit the formation of the NLRP3 inflammasome, which in turn inhibits the production of IL-1β and IL‑18. NLRP3 is one of the most characterized inflammasome sensors due to its involvement in a wide range of disorders, including sterile inflammation, infections, and rare genetic autoimmune syndromes. Dapansutrile has been well tolerated and shown to improve clinical outcomes in patients with acute gout flare (see The Lancet Rheumatology) and heart failure (see Journal of Cardiovascular Pharmacology). Dapansutrile has also been observed to have anti-inflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models including arthritis, asthma, acute myocardial infarction (AMI), heart failure, contact dermatitis, multiple sclerosis, melanoma, pancreatic and breast cancers, spinal cord injury (SCI), Parkinson’s and Alzheimer’s disease. For a complete list of Olatec’s original publications on dapansutrile in various preclinical and clinical disease areas, please refer to Olatec’s publication page, here.

On October 3, 2023 ImmPACT Bio USA, Inc. ("ImmPACT BIO"), a clinical-stage company developing transformative logic-gate-based chimeric antigen receptor (CAR) T-cell therapies for treating cancer and autoimmune diseases, reported that it will participate at the 2023 Cell & Gene Meeting on the Mesa, being held October 10-12, 2023 in Carlsbad, CA (Press release, ImmPACT-Bio, OCT 3, 2023, View Source;gene-meeting-on-the-mesa-301944692.html [SID1234635612]).

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Sumant Ramachandra, M.D., Ph.D., ImmPACT Bio’s president and chief executive officer, will present a corporate update and participate in a Q&A session on Wednesday, October 11, 2023 at 3:15 PM PT.