On November 9, 2024 Marengo Therapeutics, Inc., a clinical-stage biotechnology company pioneering novel approaches for precision T cell activation, reported encouraging initial Phase 1 clinical data from its lead program, invikafusp alfa (STAR0602), during a late-breaking oral presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting taking place in Houston, Texas (Press release, Marengo Therapeutics, NOV 9, 2024, View Source [SID1234648062]).

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This is the first public disclosure of results from the ongoing STARt-001 Phase 1/2 trial (NCT05592626), evaluating invikafusp alfa as monotherapy in biomarker-enriched (TMB-H, MSI-H/dMMR or virally associated) patients with advanced anti-PD-1 resistant, or refractory solid tumors.

Phase 1 data from STARt-001 trial demonstrate early anti-tumor activity, including initial signals of clinical benefit in heavily pre-treated, anti-PD-1 resistant cancer patients. Invikafusp alfa also showed a manageable safety profile consistent with its novel mechanism of action, further supporting its potential as a treatment option across a range of high tumor mutational burden (TMB-H) cancers or virally associated malignancies.

"Having completed Phase 1 and commenced the Phase 2 dose expansion cohorts of STARt-001, Marengo is thrilled to share initial clinical findings that validate our novel selective dual T cell agonist platform," said Zhen Su, M.D., MBA, Chief Executive Officer of Marengo Therapeutics. "The single agent activity observed in Phase 1, especially in PD-1 resistant cold tumors such as colorectal cancer is a critical milestone, and we look forward to further exploring the potential of STAR0602 to become a next-generation backbone IO therapy across a range of tumor types."

Additional highlights from the Phase 1 findings include:

Sustained and selective in vivo expansion of TCRVβ6/Vβ10 T cells was achieved across all 6 dose levels with up to ~500% peak increase post invikafusp alfa treatment

Disease Control Rate (PR + SD) was reported in 50% of 28 patients from all dose escalation cohorts with 32% of patients experienced tumor shrinkage across six tumor types

At the optimal biological dose range (0.08 mg/kg and 0.12 mg/kg), invikafusp alfa had single agent clinical activity with 63% Disease control rate, 50% of patients experienced tumor shrinkage and 25% ORR reported in TMB-H, anti-PD-1 resistant patients

Safety profile was consistent with the T cell activation/expansion mechanism of action (MOA) without corticosteroid or tocilizumab pretreatment. The most common treatment-related adverse events (TRAEs) were mainly transient grade 1 & 2 CRS during first and second infusion without any grade 4 adverse events (AEs) or immune effector cell-associated neurotoxicity syndrome (ICANS)

Recommended Phase 2 dose (RP2D) of 0.08 mg/kg was selected for Phase 2 dose expansion studies based on safety, PK/PD data and preliminary anti-tumor activity
"The first-in-human data suggest that this novel approach to selectively activate and expand Vβ T cell subsets may hold promise for treating patients with advanced solid tumors," said Dr. James L. Gulley, Co-Director of the Center for Immuno-Oncology and Clinical Director of the National Cancer Institute. "The observed unique Vβ T cell biology in humans and selective expansion of Vβ6/Vβ10 across a range of solid tumors, combined with the initial anti-tumor activity, particularly in heavily pre-treated anti-PD-1 resistant cancer patients with TMB-H colorectal cancer, are encouraging signs. The differentiated clinical profile supports further investigation of this unique mechanism of action in the next phase of clinical trials for high unmet medical needs in anti-PD-1 resistant tumors."

Taken together, the data presented from the STARt-001 study underscore invikafusp alfa’s potential as a novel therapeutic option for patients with advanced, PD-1-resistant solid tumors. Marengo has initiated the Phase 2 dose expansion and expects to share initial results in 2H 2025.

Late-breaking oral presentation details:

Title: A Phase 1/2 study of Invikafusp alfa (STAR0602), a first-in-class TCR β chain-targeted bispecific antibody, as monotherapy in patients with antigen-rich solid tumors resistant to anti-PD(L)1.
Conference: 39th SITC (Free SITC Whitepaper) Annual Meeting.
Abstract Number: LBA-1470.
Session Title: Late-Breaking Abstract Session 2.
Session Date and Time: Saturday, November 9, 2024, 11:45 AM – 12:15 PM.
Presenter: James L. Gulley, M.D., Ph.D. (National Cancer Institute, Bethesda, Maryland, USA).

On November 9, 2024 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to bringing a first-in-class pipeline of induced pluripotent stem cell (iPSC)-derived cellular immunotherapies to patients with cancer and autoimmune disorders, reported initial clinical and new preclinical data for FT825 / ONO-8250, a multiplexed-engineered, chimeric antigen receptor (CAR) T-cell product candidate targeting human epidermal growth factor receptor 2 (HER2), at the 2024 Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting being held in Houston, TX on November 6-10, 2024 (Press release, Fate Therapeutics, NOV 9, 2024, View Source [SID1234648059]). FT825 / ONO-8250 incorporates a novel H2CasMab-2 binding domain targeting HER2 that is designed to overcome on-target, off-tumor toxicity and to recognize variants associated with poor clinical outcomes and tumor escape. In an ongoing Phase 1 study in advanced solid tumors, three patients were treated with FT825 / ONO-8250 in the first low-dose cohort as monotherapy, and no dose-limiting toxicities (DLTs) and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) were observed. The multi-center, Phase 1 study is currently being conducted under a strategic collaboration with Ono Pharmaceutical Co., Ltd. (Ono).

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"FT825 / ONO-8250 integrates seven novel synthetic controls of CAR T-cell function designed to overcome multiple mechanisms that impede the safe and effective treatment of solid tumors. We are very pleased with initial Phase 1 clinical observations from the first low-dose cohort, which showed a favorable safety profile, product expansion, and maintenance of an activated CAR T-cell state," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition, new preclinical data for FT825 / ONO-8250 presented today at SITC (Free SITC Whitepaper) highlighted the cancer-selective recognition profile of its novel HER2 antigen binding domain, including its potential to target variants uniquely expressed on tumor cells. Under our collaboration with Ono, we are excited to further assess the potential of FT825 / ONO-8250 to benefit patients with hard-to-treat advanced solid tumors who currently have limited treatment options."

Initial Phase 1 Clinical Observations

The Phase 1 study is designed to assess the safety, pharmacokinetics, and activity of FT825 / ONO-8250 as monotherapy and in combination with monoclonal antibody (mAb) therapy in patients with advanced solid tumors (NCT06241456). Three heavily pre-treated patients, all of whom were previously treated with at least five prior lines of therapy including HER2-targeted therapy, were administered conditioning chemotherapy and FT825 / ONO-8250 at the first dose level of 100 million cells as monotherapy. In all three patients, peak CAR T-cell expansion was observed at Day 8 following treatment. In addition, phenotyping of FT825 / ONO-8250 sourced from the patients’ peripheral blood on Day 8 was indicative of an activated state (as evidenced by high levels of Granzyme B expression and maintenance of CAR expression) with no evidence of exhaustion (as evidenced by low levels of PD-1 and TIM3 expression). As of a data cutoff date of October 25, 2024, FT825 / ONO-8250 was well-tolerated with no DLTs and no events of any grade of CRS, ICANS, or GvHD. Enrollment is currently ongoing at the second dose level of 300 million cells as monotherapy and at the first dose level of 100 million cells in combination with epidermal growth factor receptor (EGFR)-targeted mAb therapy.

Preclinical Data

While HER2-directed therapies, such as trastuzumab (Herceptin) and trastuzumab deruxtecan (Enhertu), are effective in treating HER2-positive cancers, widespread HER2 expression in normal epithelial tissue can lead to significant off-tumor, on-target toxicities. At an oral presentation today at SITC (Free SITC Whitepaper) entitled "Preferential targeting of HER2-expressing cancer cells by FT825 / ONO-8250, an off-the-shelf iPSC-derived CAR-T cell incorporating novel synthetic mechanisms for enhanced solid tumor activity", scientists from the Company, Ono, Osaka University, and Tohoku University highlighted that FT825 / ONO-8250 demonstrated potent HER2-specific, anti-tumor activity in both in vitro and in vivo settings with limited cytolytic targeting of HER2+ normal cells. The on-tumor selectivity of FT825 / ONO-8250 was attributed to its incorporation of a novel HER2-targeted antigen binding domain, which was derived from a cancer-specific monoclonal antibody H2CasMab-2 (Kaneko et al., 2024), that was shown to differentially and preferentially recognize both locally misfolded HER2 and p95 truncation variants of HER2 as compared to trastuzumab. The scientists also presented preclinical data demonstrating that FT825 / ONO-8250 exhibits potent antibody-mediated cellular cytotoxicity (ADCC) through its high-affinity non-cleavable CD16 (hnCD16) Fc receptor, synergizing with trastuzumab to enhance clearance of HER2+ tumor cells and with cetuximab to enable multi-antigen targeting of HER2 and epidermal growth factor receptor (EGFR) expressed on cancer cells.

Under the terms of its partnership with Ono for FT825 / ONO-8250, Fate and Ono are jointly responsible for development and commercialization in the U.S. and Europe, and Ono maintains exclusive development and commercialization rights in the rest of the world. The parties are also conducting preclinical development of an additional solid tumor program targeting an undisclosed tumor-associated antigen.

On November 09, 2024 Replimune Group, Inc. (NASDAQ: REPL), a clinical stage biotechnology company pioneering the development of novel oncolytic immunotherapies, reported that the primary analysis data from the IGNYTE clinical trial, including initial biomarker analyses, was presented as a late-breaking abstract during an oral session at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2024) in Houston, Texas (Press release, Replimune, NOV 9, 2024, View Source [SID1234648057]). In addition, data from the ARTACUS clinical trial evaluating RP1 monotherapy in solid organ transplant patients with advanced cutaneous malignancies was also shared in an encore poster presentation during the meeting.

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"The initial biomarker analyses included in the SITC (Free SITC Whitepaper) presentation which demonstrate increases in tumor CD8+ T cell infiltration and PD-L1 expression along with the induction of an immune inflammatory gene signature after treatment, further support the intended mechanism of RP1 in combination with nivolumab, including its ability to induce a systemic response after progression on prior anti-PD1 therapy," said Kostas Xynos, MD, PhD, MBA, Chief Medical Officer of Replimune. "We believe that the systemic activity of RP1 and nivolumab is in particular demonstrated by the similar level of responses seen in both injected and non-injected lesions, including hard to treat visceral lesions, and by the durability of the responses seen."

IGNYTE Clinical Trial Data at SITC (Free SITC Whitepaper)
The IGNYTE clinical trial cohort in anti-PD-1 failed melanoma included 140 patients who received RP1 plus nivolumab after confirmed progression while being treated for at least 8 weeks with anti-PD-1 based therapy, with or without anti-CTLA-4. The primary analysis by blinded independent central review was triggered once all patients had been followed for at least 12 months. The median follow-up at the time of the primary analysis was 15.4 months (0.5-47.6 months).

Data from the IGNYTE trial presented at SITC (Free SITC Whitepaper) 2024 show:

One-third of patients experienced a confirmed response, with an overall response rate (ORR) of 33.6% by modified RECIST (mRECIST) v1.1 criteria, the primary endpoint in the trial protocol, and 32.9% by RECIST v1.1 criteria, an additional analysis requested by the FDA. The complete response (CR) rate by mRECIST v1.1 was 15%. In patients who had prior anti-PD1 and anti-CTLA-4, the ORR was 27.7% and for those who had primary resistance to anti-PD1, the ORR was 35.9% by mRECIST v1.1.
The median duration of response from response initiation was 21.6 months.
Most injected and non-injected lesions (85%) in responders had a 30% or greater reduction in size. RP1 plus nivolumab induced deep responses in non-injected lesions in visceral organs, including those distant from the injection site.
Median overall survival for the trial has not been reached, however, one-, two-, and three-year survival rates were 75.3%, 63.3%, and 54.8%, respectively. 12-month progression free survival (PFS) was 32.8% and median PFS was 3.7 months.
Initial biomarker data included in the SITC (Free SITC Whitepaper) presentation show:

Tumor inflammation signature (TIS) and nano string analysis revealed an increase in the expression of genes associated with CD8+ T cells and inflammatory cytokines. These markers highlight the potential of RP1 plus nivolumab to generate a potent anti-tumor immune response. TIS is an investigational use only assay consisting of 18 genes that assesses the presence of an adaptive immune response, and which is associated with responsiveness to anti-PD1 therapy1.
Immunohistochemistry (IHC) images demonstrate that RP1 plus nivolumab may stimulate tumors to a more immune inflamed state, further highlighting the potential of RP1 plus nivolumab to reverse mechanisms of resistance to anti-PD1 therapy.
As previously reported, RP1 combined with nivolumab continues to be well-tolerated. Treatment-related adverse events associated with RP1 in combination with nivolumab were predominantly Grade 1-2 constitutional type events (> 5% of patients), including fatigue, chills, pyrexia, nausea, influenza-like illness, injection-site pain, diarrhea, vomiting, headache, pruritis, asthenia, arthralgia, myalgia, decreased appetite, and rash, with a low incidence (12.8% of patients) of Grade 3-4 events, which were predominantly Grade 3. Grade 4 events were one each of lipase increased, cytokine release syndrome, myocarditis, hepatic cytolysis, and splenic rupture. There were no Grade 5 events.

The presentation is available on the Company website under Events and Presentations.

The IGNYTE-3 confirmatory phase 3 trial evaluating RP1 plus nivolumab versus physician’s choice in patients with advanced melanoma who have progressed on anti-PD1 and anti-CTLA-4 or who are not candidates for anti-CTLA-4 therapy is currently recruiting. For additional information, visit View Source

On November 09, 2024 Corvus Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, reported new data highlighting the potential of ciforadenant, the Company’s adenosine A2A receptor antagonist, to overcome resistance to anti-PD1 immunotherapy in the treatment of metastatic castration resistant prostate cancer (mCRPC) (Press release, Corvus Pharmaceuticals, NOV 9, 2024, View Source [SID1234648056]).

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The data were presented today in an oral session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting by Aram Lyu, Ph.D., a postdoctoral fellow at Fred Hutch Cancer Center, University of California, San Francisco and Parker Scholar at the Parker Institute for Cancer Immunotherapy. Dr. Lyu’s abstract, titled "Identification and therapeutic target of myeloid-mediated mechanisms of immunotherapy resistance in prostate cancer" was selected as a Top 100 abstract by SITC (Free SITC Whitepaper).

"These studies reveal important details on the role of the adenosine pathway on the immunobiology of mCRPC, including the importance of myeloid cells and the adenosine gene signature," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "The mechanism is consistent with and builds on results from our clinical trials in renal cell cancer and prostate cancer, along with the potential for the adenosine gene signature to select patients most likely to respond. This could be an important advancement for patients with tumors that are resistant to checkpoint inhibitors, and is supportive of our ongoing clinical trial of ciforadenant in combination with ipilimumab and nivolumab in front line renal cell cancer."

SITC Oral Presentation Overview and Key Data
Previous studies have shown that mCRPC is resistant to therapy with immune checkpoint inhibitors. While tumor associated macrophages are known to contribute to immunosuppression with the tumor microenvironment, this study identified SPP1+ myeloid cells as a potential critical mediator of resistance to immunotherapy. The team led by Lawrence Fong, M.D. used single cell RNA expression profiling of tumor biopsies to measure levels of these cells in patients with early localized or metastatic hormone responsive prostate cancer compared to patients with mCRPC. The results showed that SPP1+ macrophages were more prevalent as cancer progresses to mCRPC patients.

Dr. Fong is the scientific director of the Immunotherapy Integrated Research Center at Fred Hutch, where he is also a professor in the Translational Sciences and Therapeutics Division and a Bezos Family Distinguished Scholar in Immunotherapy.

The researchers created a murine model that confirmed that SPP1+ macrophages were associated with suppressed immunity to prostate cancer and shortened overall survival. Further analysis of the related genetic pathways revealed involvement of adenosine signaling through the adenosine 2A receptor. The researchers utilized ciforadenant to inhibit adenosine signaling in this model and the key findings demonstrating its potential to overcome this resistance to immunotherapy include:

Ciforadenant treatment associated with reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy in the model
Ciforadenant treatment associated with reduced SPP1+ macrophage infiltration in the tumors, supporting a shift to a less immunosuppressive myeloid environment
The Adenosine Gene Signature, a biomarker that reflects adenosine induced immunosuppression in the tumor, was elevated in SPP1+ macrophages
Results from the model were consistent with data from the Phase 1b/2 clinical trial of ciforadenant in patients with mCRPC, which included data from 35 patients with advanced mCRPC, including 11 who received ciforadenant as a monotherapy (100 mg twice daily) and 24 that received ciforadenant (100 mg twice daily) in combination with atezolizumab (840 mg delivered intravenously every two weeks). 5 of 24 (21%) receiving combination therapy had PSA partial responses defined as PSA reductions >30%, compared to 1 of 11 (9%) receiving monotherapy.

About Ciforadenant
Ciforadenant (CPI-444) is an investigational small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine to immune cells present in the tumor microenvironment. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2a receptor present on immune cells and block their activity. Ciforadenant has been shown to block the immunosuppressive effects of myeloid cells present in tumors and preclinical studies published in 2018 demonstrated synergy with combinations of anti PD1 and anti-CTLA4 antibodies.

On November 8, 2024 Oncolys BioPharma reported non-consolidated Financial Results for the Nine Months Ended September 30, 2024 (Press release, Oncolys BioPharma, NOV 8, 2024, View Source [SID1234649625]).

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