On November 6, 2023 Imugene Limited (ASX: IMU), a clinical stage immuno-oncology company, reported a clinical trial update of its Phase 1 MAST (Metastatic Advanced Solid Tumours) trial evaluating the safety and efficacy of novel cancer-killing virus CF33-hNIS (VAXINIA) (Press release, Imugene, NOV 6, 2023, https://mcusercontent.com/e38c43331936a9627acb6427c/files/44c8291a-171d-e510-504e-2691967778cb/Phase_1_CF33_VAXINIA_Study_Update_Positive_Early_Signals.pdf [SID1234636976]).

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As announced last week, the trial has now cleared cohort 4 of the intravenous (IV) arm of the monotherapy dose escalation study, as well as IV cohort 2 of the combination study where VAXINIA is administered with checkpoint inhibitor drug pembrolizumab (KEYTRUDA). Cohort 5 of the IV arm for the monotherapy dose escalation is now open as is IV cohort 3 of the combination study.

As of 31 October 2023, 34 patients have been dosed with VAXINIA during the continuing dose escalation phase comprised of 16 patients intratumorally and 18 patients intravenously as either monotherapy or in combination with pembrolizumab. Twenty-five patients were evaluable (received at least their first scan at day 42) and seven patients have their first scan still pending. Of the evaluable patients the BOR (best overall response) are 1 Complete Response (CR), 1 Partial Response (PR), 16 Stable Disease (SD), showing patients had control and stability of their cancer and 8 progressive disease (PD) as measured by iRECIST and RECIST criteria
Importantly early results from 6 patients with gastrointestinal cancers who received CF33-hNIS alone including 2 colorectal cancer, 2 bile duct, 1 pancreatic and 1 liver cancer showed positive treatment effects, with a disease control rate (all CR, PR and SD) of 75%
Trial expansion is planned for 10 patients with bile duct cancers

Imugene MD & CEO Leslie Chong said: "Phase 1 trials are generally designed to look for safety, tolerability and early response signals to determine the optimal dose for further development. The early positive response data we are seeing at the mid-dose level in hard-to-treat bile duct cancer suggests that VAXINIA may be a potent anti-cancer drug as we interrogate higher dose levels. With no adverse safety signals, thus allowing us to dose higher, VAXINIA will have a very high therapeutic window which is valuable in oncology drug development."

Notably one patient with bile duct cancer, treated IT with mid-dose level displayed pseudoprogression (see below) with a 49% increase in tumour burden after two cycles of therapy. However, by the 4th cycle they achieved a Complete Response (iCR) with no known recurrence in over 200 days. A second patient with bile duct cancer, who previously progressed on prior drug therapies, achieved Stable Disease (SD) for > 4 months upon receiving IV-administered CF33-hNIS.

Bile duct cancers are difficult to treat and typically respond poorly to immunotherapy drugs. Pseudoprogression is a phenomenon in which the cancer initially appears to be growing, largely due to the cancer cells being infected by the virus then followed by infiltration of cancer fighting immune cells. However, it is usually followed by a decrease in tumour burden when the therapy takes effect. This phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false impression the cancer is growing.

The multicenter Phase 1 MAST trial commenced by delivering a low dose of VAXINIA to patients with metastatic or advanced solid tumours who have had at least two prior lines of standard of care treatment. The City of Hope-developed oncolytic virus has been shown to shrink colon, lung, breast, ovarian and pancreatic cancer tumours in preclinical laboratory and animal models. Overall, the study aims to recruit cancer patients across approximately 10 trial sites in the United States and Australia.

The clinical trial is titled "A Phase I, Dose Escalation Safety and Tolerability Study of VAXINIA (CF33- hNIS), Administered Intratumorally or Intravenously as a Monotherapy or in Combination with Pembrolizumab in Adult Patients with Metastatic or Advanced Solid Tumours (MAST)." The trial commenced in May 2022 and is anticipated to run for approximately 24 months while being funded from existing budgets and resources.

Full study details can also be found on clinicaltrials.gov under study ID: NCT05346484.

On November 5, 2023 Elpiscience Biopharmaceuticals, Inc. ("Elpiscience"), a clinical-stage biopharmaceutical company focused on developing next-generation immunotherapies to benefit cancer patients worldwide, reported studies for its innovative immunotherapeutic molecules at the SITC (Free SITC Whitepaper) 2023 Annual Meeting, including KG2A/NKG2C dual-targeting antibody ES015-2, a high affinity LILRB1 specific blocking antibody ES008-a, and the first-in-class anti-CD39/TGF-βRII bifunctional fusion protein ES014 (Press release, Elpiscience, NOV 5, 2023, View Source [SID1234636979]).

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Study Highlights:

Title: Selective delivery of TGFβ "trap" to CD39-expressing immune and stroma cells reshapes tumor microenvironment and rejuvenates antitumor immunity
Abstract Number: 453

CD39-Adenosine and TGFβ are two key immune suppressive pathways within the tumor microenvironment (TME). TGFβ, in contrast to its biphasic effects on tumor cells, acts on stromal cells and immune cells in the TME, which commonly express high levels of CD39, to promote tumor progression. CD39-targeted TGFβ "trap" is thus more likely to effectively inhibit tumor progression. Our study showed that ES014, a bifunctional antibody–ligand trap which comprises an antibody targeting CD39 fused to a TGFβ receptor II ectodomain, can inhibit TGFβ activity and lead to cancer killing in ex vivo models.

A phase I clinical study is ongoing to primarily investigate the safety, tolerability, and preliminary clinical activity of ES014 in patients with advanced solid tumors.

Highlights:

ES014 binds and neutralizes both CD39 and TGFβ.
ES014 promoted killing of tumors from NSCLC patients in ex vivo MPE model.
ES014 inhibits Treg differentiation and TGFβ-induced CD39 expression on T cells.
ES014 promotes T cell survival.
Title: ES015-2, a first-in-class NKG2A and NKG2C dual-targeting antibody, demonstrated potent anti-tumor immune response
Abstract Number: 498

The inhibitory receptor NKG2A and the activating receptor NKG2C modulate the function of NK and CD8 T cells by recognizing the same ligand HLA-E. NKG2A is selectively expressed on lymphocytes with cytolytic function, and the NKG2C "engager" has the potential to generate a strong antitumor response against various tumors. Inhibiting NKG2A and HLA-E alone was not as effective as had been expected in both mouse tumor models and in clinical trials. Our NKG2A/NKG2C dual targeting antibody ES015-2 can inhibit NKG2A function yet promoting NKG2C action, leading to superior anti-tumor response.

Highlights:

ES015-2 is a NKG2A/NKG2C dual targeting antibody.
ES015-2 can completely block the interaction of NKG2A/CD94 with HLA-E, thereby inhibits HLA-E-induced NKG2A inhibitory signaling.
Ligation of ES015-2 effectively potentiates the activation of NKG2C+ NK cells and T cells.
Title: ES008-a, a high affinity LILRB1 specific blocking antibody activates multiple immune cells to fight cancers
Abstract Number: 510

LILRB1 is the most broadly expressed member of LILRB family on various immune cells. Blocking LILRB1 augments macrophage phagocytosis of tumor cells, restores cytotoxic function of NK cells, and enhances tumor cell killing by effector CD8+ T cells. The high affinity LILRB1 specific blocking antibody ES008-a can activate multiple immune cells to fight cancers.

Highlights:

ES008-a is a high affinity LILRB1-specific blocker that can completely block HLA-G/LILRB1 and HLA-A2/LILRB1 interactions.
ES008-a promotes NK cell-mediated destruction of tumor cells.
ES008-a synergizes with CD47/SIRPα inhibitors in enhancing macrophage phagocytosis of tumor cells.

On November 4, 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 additional Phase 1 clinical data during the late-breaker oral presentation session at the Society of Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) 2023 Annual Meeting (Press release, TriSalus Life Sciences, NOV 4, 2023, View Source [SID1234636980]).

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The PERIO-01 Phase 1 study for uveal melanoma with liver metastases (UMLM), studied SD-101 delivered via PEDD with the TriNav Infusion System in combination with intravenous checkpoint inhibitors. The data presented today at SITC (Free SITC Whitepaper) demonstrate that SD-101 is well tolerated when given by the PEDD method and is associated with immunologic effects both within the liver and systemically, which may enable better outcomes with systemic checkpoint inhibition. The Progression-Free Survival (PFS), Disease Control Rate (DCR), and ctDNA molecular response data in PERIO-01 patients in combination with nivolumab are encouraging for UMLM and for other indications under development. At the optimal biologic dose of SD-101 (2 mg) in combination with nivolumab (n=7), the median PFS was 11.7 months with an 81% DCR.

"We are encouraged to see that SD-101 is well tolerated when given by PEDD, in association with immunologic effects within the liver and systemically, which may enable better outcomes with systemic checkpoint inhibition," said Steven C. Katz, M.D., FACS, Chief Medical Officer at TriSalus. "The PFS and ctDNA molecular response data in PERIO-01 patients in combination with nivolumab are promising for UMLM and as well as for other indications that we are pursuing."

"The results of PERIO-01 highlight the importance of getting the biology right and not just pushing a drug to its maximum tolerated dose. The biological effects of SD-101 are best at the lowest dose tested, revealing tumor microenvironment reprogramming and inflammatory cell trafficking from normal to metastatic liver tumors," said Sapna Patel, M.D., director of the uveal melanoma program at The University of Texas MD Anderson Cancer Center. "This is not seen at higher doses of SD-101, and these findings ensure we are entering the next phase with the optimal dose in combination with checkpoint inhibition, for patients with metastatic uveal melanoma."

PERIO-01 is an open-label, first-in-human Phase 1 trial of SD-101, administered by hepatic arterial infusion with TriNav using PEDD in UMLM. The study consists of dose-escalation cohorts of SD-101 (2, 4, or 8 mg) alone or with immune checkpoint inhibition. At the data cutoff as of September 29, 2023, 56 patients were enrolled, with each having received at least one dose of SD-101. Of the patients with available data, 16 patients (29%) were treatment-naïve and 40 (71%) had failed at least one prior line of therapy, including 8 patients (14%) on 3rd or greater line of treatment. SD-101 infused via PEDD in combination with systemic checkpoint inhibition was well tolerated, with an overall serious grade 3/4 adverse event rate related to treatment of 11% (n=56), and no such events at the optimal SD-101 dose level of 2 mg in combination with nivolumab (n=7). The most common adverse events overall were gastrointestinal (41%), fatigue (30%), and skin toxicity (27%), with the majority being minor.

Encouraging early efficacy signals were noted in the UMLM patients treated in PERIO-01. Overall, the ctDNA molecular response rate was 65% using specified time points (n=20), and 82% when analyzing the best on-treatment response (n=26). Clearance of ctDNA was noted in 59% of subjects when assessing the best on-treatment response. There was an 81% disease control rate at 2 mg SD-101 via PEDD with nivolumab (n=7). Across all subjects, two partial responses (≥30% decrease) and five minor responses (10-29% decrease) were documented as the best on-treatment response. The median progression free survival at the optimal dose of SD-101 via PEDD (2 mg) in combination with nivolumab was 11.7 months with a 1-year overall survival rate of 86% (n=7).

Among PERIO-01 patients who received SD-101 via PEDD in combination with intravenous nivolumab, there was evidence of increases in CD8+ T cells, CD4+ T cells, and natural killer cells within their liver metastases. Gene expression analysis by Nanostring revealed increased TLR signaling, interferon signaling, cytokine signaling, Th1 T cell activation, and lymphocyte activation. At the optimal SD-101 dose of 2 mg in combination with nivolumab, decreases in monocytic myeloid derived suppressor cells (MDSC), M2 macrophages, and regulatory T cells were found in liver metastases. Along with predicted immune changes within liver metastases, encouraging peripheral immune signals were detected. Increases in IFNγ, soluble IL2-receptor, IL-15, IL-18, T cell activation, and NK cell proliferation were found in the blood.

Dr. Katz added, "These data reflect additional validation of our innovative immunotherapy approach for liver and pancreas tumors. SD-101 was selected based on its mechanism of action, which has the potential to reverse immunosuppression in the liver and pancreas through depletion of MDSC in concert with broad stimulation of immune cells in the tumor microenvironment. 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."

Overall, the data emerging from the PERIO-01 and PERIO-03 also presented at SITC (Free SITC Whitepaper) indicate immunologic changes are occurring within the liver and pancreas, with favorable safety profiles. Patients with liver metastases in the PERIO-01 study have had favorable outcomes despite pre-treatment.

All TriSalus presentations from SITC (Free SITC Whitepaper) is 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 the TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-02 trial is evaluating whether this same platform approach (PERIO-01) with SD-101 and PEDD can improve the performance of systemic checkpoint inhibitors in treating patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma.

The PERIO-03 study is an open-label, Phase 1/1b study of the pressure-enabled intrapancreatic infusion of SD-101, a TLR 9 agonist, alone or in combination with intravenous checkpoint blockade in adults with locally advanced pancreatic cancer.

On November 4, 2023 KangaBio reported that the U.S. FDA has granted official approval for their independent R&D clinical trial application (IND) for KGX101 (Press release, KangaBio, NOV 4, 2023, View Source [SID1234636978]). KGX101 is a recombinant IL-12 Fc fusion protein designed for intravenous injection. The KGX101 clinical trials will be carried out simultaneously in both United States and Australia. These trials will primarily focus on late-stage solid tumors and the effectiveness will either be evaluated as a standalone therapy or in combination with anti-PD-L1 antibodies. Several research centers in Australia have already commenced patient screening for participation in these clinical trials.

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Sanyou Bio congratulates our partner, KangaBio on reaching this significant milestone. This achievement strengthens our 2022 strategic partnership, which is dedicated to advancing the development and innovation of antibody-based drugs. Sanyou Bio is pleased to have played a role in KangaBio’s preclinical efficacy evaluations for KGX101, revealing promising in vivo anti-tumor efficacy and safety outcomes. We are looking forward to gaining more insights into its performance during the clinical stage.

KGX101 is a prodrug of Interleukin-12 (IL-12) created using KangaBio’s proprotein technology platform. KGX101 has a prolonged half-life due to the use of the antibody Fc region. KGX101 becomes active specifically in tumors by fusing the protease-cleavable linker that targets tumors. This minimizes systemic cytokine toxicity when the linker is cleaved by tumor-specific matrix metalloproteinases in the tumor microenvironment, KGX101, similar to IL-12, activates immune cells within the tumor, reshaping the tumor microenvironment for therapeutic benefits.

On November 4, 2023 Candel Therapeutics, Inc. (the Company or Candel) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing viral immunotherapies to help patients fight cancer, reported that it will present two posters during the 2023 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in San Diego focused on the enLIGHTEN Discovery Platform (Press release, Candel Therapeutics, NOV 4, 2023, View Source [SID1234636975]).

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"We aim to leverage artificial intelligence and machine learning to expedite various aspects of drug discovery and development," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel. "Combined with our strong focus on human biology for drug discovery and our deep experience with herpes simplex virus as therapeutic vectors, Candel is poised to expand its portfolio of promising viral immunotherapy candidates and create value through discovery partnerships."

The first poster titled ‘Development of enLIGHTEN Alpha-201 herpes simplex viral vectors encoding payloads targeting the tumor microenvironment’ reports preclinical characterization of the enLIGHTEN viral chassis Alpha-201. Profiling of biological responses to Alpha-201 unveiled its potential to orchestrate changes in the tumor microenvironment, supportive of effective anti-tumor immune responses to immune checkpoint inhibitor (ICI) treatment. In preclinical models, Alpha-201 displayed enhanced peripheral blood mononuclear cell-mediated cancer cell killing and immune activation when armed with certain immunostimulatory payload combinations which was predicted in silico using the enLIGHTEN Advanced Analytics suite. These data validate Candel’s novel approach for in silico prediction of payload combinations and selection of indication-specific payloads with anti-tumoral activity using human datasets as a tool to accelerate, improve and de-risk certain aspects of the development of transformative viral immunotherapies.

"Tumor resistance to immunotherapy is driven by multiple mechanisms, which are heterogeneous in nature," said Francesca Barone, MD, PhD, Chief Scientific Officer at Candel. "By interrogating human datasets and generating predictions on tumor-specific mechanisms of progression, enLIGHTEN provides a unique opportunity to predict optimal gene payload combinations to arm viral vectors, enabling the design of multimodal therapeutics with greater potential to overcome tumor resistance."

The second poster titled ‘A novel viral immunotherapeutic targeting the CD47/SIRPα axis demonstrates potent anti-tumor effects’ describes the design of the first experimental agent based on the enLIGHTEN Discovery Platform, Alpha-201-macro1. This investigational agent is comprised of an immunostimulatory and oncolytic engineered viral chassis armed with a novel gene payload that is designed to interfere with the CD47/SIRPα pathway.

"Therapies targeting the CD47/SIRPα pathway have shown promising clinical results in solid and hematological malignancies; however, efficacy is often hindered by systemic toxicity," said Anne Diers, PhD, Senior Director of Research at Candel Therapeutics. "The Alpha-201-macro1 preclinical data presented today support the utility of local delivery of an immunologically active, multimodal agent as a potential alternative to systemic therapy. We are excited to leverage the enLIGHTEN Discovery Platform to optimize the immunostimulatory payload of this agent for activation of innate immune surveillance with the goal of maximizing its therapeutic potential."

Further details from the posters are available on the Candel website at: www.candeltx.com/media

About the enLIGHTEN Discovery Platform

Candel’s enLIGHTEN Discovery Platform is a systematic, iterative HSV-based discovery platform leveraging human biology and advanced analytics to create new viral immunotherapies for solid tumors. In October 2022, the Company announced a discovery collaboration with the University of Pennsylvania Center for Cellular Immunotherapies to identify how viral immunotherapy could enhance the efficacy of CAR-T cell therapy in solid tumors. The enLIGHTEN Discovery Platform is designed to deconvolute the complexity of the tumor microenvironment to identify druggable properties that correlate with clinical outcomes. These discoveries are translated into optimized multi-gene payloads of tumor modulators that are tailored for specific indications, disease stage, and rationally designed therapeutic combinations.