On November 3, 2023 Immunitas Therapeutics ("Immunitas"), a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated therapeutics for patients with cancer, reported the first proof-of-concept data on its second program, a myeloid and B cell modulating anti CLEC2D-Toll-like receptor 9 (TLR9) agonist conjugate, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 38th Annual Meeting (SITC 2023), held November 1-5 in San Diego, California (Press release, Immunitas Therapeutics, NOV 3, 2023, https://www.prnewswire.com/news-releases/immunitas-therapeutics-presents-new-data-for-tlr9-agonist-conjugate-at-the-society-for-immunotherapy-of-cancer-2023-annual-meeting-301976730.html [SID1234636918]).

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CLEC2D is a C-type lectin-like protein that is broadly expressed on a subset of immune cells and is naturally internalized by myeloid and B cells. Upon internalization, it can act as a vehicle to deliver histone/DNA complexes to endosomal TLR9, stimulating inflammatory responses. Harnessing this CLEC2D-mediated internalization offers a compelling immunotherapy approach of delivering CpG to TLR9 that can stimulate inflammatory responses with the potential to improve recruitment of functional T and NK cells into tumor tissues.

"The inability to induce adequate responses in tumors with poor T and NK cell infiltration has limited the clinical impact of existing immunotherapies. At Immunitas, we prioritize targeting novel biological pathways with first-in-class molecules that have potential to show monotherapy efficacy in early clinical development. This program leverages our specialized knowledge of the CD161-CLEC2D pathway, and we are excited to be progressing a therapeutic with demonstrated potential to address the challenge of poor T and NK cell infiltration and truly benefit patients who lack immunotherapy options," said Amanda Wagner, President and Chief Executive Officer of Immunitas Therapeutics. "We are pleased to have our team present this data demonstrating in vitro proof-of-concept for our anti-CLEC2D antibody conjugated to a CpG oligonucleotide."

The presented data showed that treatment with Immunitas’ anti CLEC2D-TLR9 agonist immune stimulating antibody complex (ISAC) induced pro-inflammatory responses in THP1-TLR9 reporter cell lines and dramatically increased production of IFN-α, a critical cytokine for induction of anti-tumor T cells, in human plasmacytoid dendritic cells. Treatment of CLEC2D-expressing B cells with the ISAC molecule resulted in sustained B cell proliferation and upregulation of co-stimulatory molecules, enabling stronger induction of T cell immune responses.

The results further confirmed that CLEC2D is expressed on tumor-associated macrophages (TAMs)—macrophages that strongly contribute to the immunosuppression in tumor microenvironments and can also directly promote tumor cell growth. Treatment of TAMs with Immunitas’ anti CLEC2D-TLR9 agonist ISAC reversed TAM-mediated suppression of T cell proliferation and activation, indicating that TLR9 agonism can reprogram TAMs towards an inflammatory state. Studies in human peripheral blood mononuclear cells (PBMCs) has demonstrated that treatment with the anti CLEC2D-TLR9 agonist ISAC did not trigger release of inflammatory cytokines, providing a preliminary indication of safety.

The presentation will be available on the Immunitas website following the meeting.

Presentation Details for SITC (Free SITC Whitepaper) 2023
Title: Anti CLEC2D-TLR9 agonist conjugate binds to and internalizes CLEC2D on myeloid cells, plasmacytoid DCs and B cells leading to robust TLR pathway activation and inflammatory cytokine production
Abstract Number: 1131
Date/Time: Friday, November 3, 2023, 9:00am – 7:00pm PDT

About CLEC2D
CLEC2D is a C-type lectin-like protein broadly expressed on a subset of immune cells and tumor cells. It is also the ligand for CD161, target for Immunitas’ lead investigational candidate, IMT-009. Additionally, CLEC2D naturally internalizes in TLR9 expressing myeloid and B cells. Building on this biology, Immunitas is developing a novel anti CLEC2D-TLR9 agonist immune stimulating antibody complex (ISAC) comprising a fully human anti-CLEC2D antibody conjugated to a CpG oligonucleotide. This CLEC2D-TLR9-ISAC molecule is capable of triggering TLR9 pathway activation in myeloid cells, B cells, and plasmacytoid dendritic cells and enabling induction of sustained T cell immunity. Harnessing this biology offers a compelling immunotherapy approach that stimulates inflammatory responses that may improve recruitment of functional T and NK cells in tumors with otherwise poor T cell infiltration.

On November 3, 2023 Plus Therapeutics, Inc. (Nasdaq: PSTV) (the "Company"), a clinical-stage pharmaceutical company developing targeted radiotherapeutics with advanced platform technologies for central nervous system cancers, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to rhenium (186Re) obisbemeda for the treatment of breast cancer with leptomeningeal metastases (LM) (Press release, PLUS THERAPEUTICS, NOV 3, 2023, View Source [SID1234636917]).

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ODD status is granted by the FDA to an investigational drug or biological product intended to prevent, diagnose or treat a rare diseases or condition affecting fewer than 200,000 people in the United States. Companies granted ODD are eligible for certain benefits, including assistance in the drug development process, tax credits for clinical costs, exemptions from certain FDA fees and 7 years of post-approval marketing exclusivity.

"Receiving Orphan Drug Designation from the FDA is important validation of our radiotherapeutic candidate for breast cancer patients with LM who currently have no FDA-approved treatment options," said Marc H. Hedrick M.D., President and Chief Executive Officer of Plus Therapeutics. "LM is a rapidly progressing and fatal complication of several cancers, including breast cancer, and incidence continues to rise. ODD status, together with the previously granted Fast Track designation, underscores the significant and urgent need for new treatment options for LM. We believe rhenium (186Re) obisbemeda has the potential to address this unmet need, and we look forward to continued progress of our ReSPECT-LM program."

Rhenium (186Re) obisbemeda is currently being evaluated in the ReSPECT-LM Phase 1/2a dose escalation clinical trial. Cohort 4 of the ReSPECT-LM trial recently completed enrollment, and the Company anticipates moving into Cohort 5 following standard safety review. Updates on the ReSPECT-LM trial will be presented at the Society for Neuro-Oncology Annual Meeting November 15-19, 2023. In addition to ODD, the FDA previously granted rhenium (186Re) obisbemeda Fast Track designation for the treatment of LM.

About Leptomeningeal Metastases (LM)

LM is a rare complication of cancer in which the primary cancer spreads to the cerebrospinal fluid (CSF) and leptomeninges surrounding the brain and spinal cord. All malignancies originating from solid tumors, primary brain tumors, or hematological malignancies have this LM complication potential with breast cancer as the most common cancer linked to LM, with 3-5% of breast cancer patients developing LM. Additionally, lung cancer, GI cancers and melanoma can also spread to the CSF and result in LM. LM occurs in approximately 5% of people with cancer and is usually terminal with 1-year and 2-year survival of just 7% and 3%, respectively. The incidence of LM is on the rise, partly because cancer patients are living longer and partly because many standard chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells, yet there are no FDA-approved therapies specifically for LM patients, who often succumb to this complication within weeks to several months, if untreated.

About Rhenium (186Re) obisbemeda

Rhenium (186Re) obisbemeda is a novel injectable radiotherapy specifically formulated to deliver highly targeted high dose radiation in CNS tumors in a safe, effective and convenient manner to optimize patient outcomes. Rhenium (186Re) obisbemeda has the potential to reduce risks and improve outcomes for CNS cancer patients, versus currently approved therapies, with a more targeted and potent radiation dose. Rhenium-186 is an ideal radioisotope for CNS therapeutic applications due to its short half-life, beta energy for destroying cancerous tissue and gamma energy for live imaging. Rhenium (186Re) obisbemeda is being evaluated for the treatment of recurrent glioblastoma and leptomeningeal metastases in the ReSPECT-GBM and ReSPECT-LM clinical trials. ReSPECT-GBM is supported by an award from the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), and ReSPECT-LM is funded by a three-year $17.6M grant by the Cancer Prevention & Research Institute of Texas (CPRIT).

On November 3, 2023 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported that it will present additional positive data from its Phase 1 study of MP0317 in patients with advanced solid tumors at the 2023 Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), being held November 1–5 in San Diego, California (Press release, Molecular Partners, NOV 3, 2023, View Source [SID1234636916]). MP0317 is a CD40 agonist designed to activate immune cells specifically within the tumor microenvironment (TME) by anchoring to fibroblast activation protein (FAP).

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"MP0317 continues to demonstrate its potential to overcome the limitations of existing CD40 agonists through its unique DARPin design that allows to activate immune cells directly within the TME, while avoiding eliciting systemic toxicities," said Philippe Legenne M.D, acting CMO of Molecular Partners. "The encouraging results presented at SITC (Free SITC Whitepaper) provide clinical evidence of MP0317-induced, tumor-targeted CD40 activation. The observed remodeling of the TME and MP0317’s favorable safety profile across all dosing cohorts, including the highest planned doses, support further investigation of MP0317 in later-stage clinical studies including combination trials."

Details of the poster presenting updated results from the ongoing MP0317 Phase 1 study at the SITC (Free SITC Whitepaper) 2023 Annual Meeting can be found below. The poster will be made available on Molecular Partners’ website after the presentation.

Title: Ongoing Phase 1 study of MP0317, a FAP-CD40 DARPin, shows a favorable safety profile and early evidence of tumor-localized CD40 activation in patients with advanced solid tumors
Poster number: 721
Location & Timing: Exhibit Hall B, Friday November 3, 2023, 9am – 7pm ET

This update, based on data from 46 patients, corroborates earlier reported findings of MP0317-induced CD40 activation and related remodeling of the TME. The detection of MP0317 in tumor biopsies is associated with an increase in CD40-mediated re-programming of immune cells illustrated by IFNg production and dendritic cell (DC) maturation within the TME. Elevation of serum levels of CXCL10, an effector chemokine downstream of IFNg signaling, and changes in soluble biomarkers (sFAP & sCD40) post-MP0317 treatment support these findings. To date, one patient achieved a partial response and stable disease was observed in eight additional patients.

MP0317 continues to display a favorable safety profile across all dosing cohorts (0.03–10 mg/kg, Q3W & Q1W), with limited systemic inflammation-related adverse reactions compared to other CD40 agonists. Dose-limiting toxicity was reported in only one patient to date (transient asymptomatic Grade 3 elevation of liver enzymes), at the highest planned MP0317 dose of 10 mg/kg administered Q3W.

The positive results of this fully enrolled Phase 1 study in patients with refractory/relapsed tumors support continued clinical evaluation of MP0317 and potential investigation in combination studies. The Company expects to share final results of this study in 2024. For further information please see clinicaltrials.gov (NCT05098405).

This ongoing first-in-human Phase 1, open-label, dose-escalation study assesses the safety and tolerability as well as pharmacokinetics/pharmacodynamics and preliminary antitumor activity of MP0317 monotherapy in patients with advanced solid tumors known to express FAP and CD40 (NCT05098405). Recruitment for the dose-escalation portion of the study is complete, with 46 patients enrolled in the Netherlands and France across nine dosing cohorts. Patients received MP0317 at doses of 0.03–10 mg/kg in every-3-weeks (Q3W) or weekly (Q1W) schedules (data cut-off 10 October 2023).

About MP0317
MP0317 targets both the FAP and the immunostimulatory protein CD40 to enable tumor-localized immune activation. Through this proposed mechanism of action, MP0317 is designed to activate immune cells specifically within the tumor microenvironment, potentially delivering greater efficacy with fewer side effects compared to systemic CD40-targeting therapies.

On November 3, 2023 Omeros Corporation (Nasdaq: OMER) reported online publication of a report detailing treatment with narsoplimab of 15 adult and pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), 14 of whom had "high-risk" TA-TMA (Press release, Omeros, NOV 3, 2023, View Source [SID1234636915]). Narsoplimab is Omeros’ investigational antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system. The report was authored by an external group of investigators involved in the treatment of these patients with narsoplimab provided under Omeros’ compassionate use program.

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The report will be featured as a poster presentation at the 65th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), to be held December 9-12, 2023 in San Diego. The abstract (#3543) is available on the ASH (Free ASH Whitepaper) website at www.hematology.org or by clicking here.

The poster will be presented by Dr. Marta Castelli, Department of Oncology and Hematology, University of Milan and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. Details of the presentation are as follows:

Clinical Safety and Efficacy of Narsoplimab in Pediatric and Adult Patients with Transplant-Associated Thrombotic Microangiopathy: A Real-World Experience (Abstract #3543)
Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster II
Date: Sunday, December 10, 2023
Presentation Time: 6:00 p.m. – 8:00 p.m. PT
Location: San Diego Convention Center, Halls G-H

About Narsoplimab

Narsoplimab, also known as "OMS721," is an investigational fully human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a novel pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. Importantly, inhibition of MASP-2 has been demonstrated to leave intact the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. A biologics license application (BLA) is pending before the U.S. FDA for use of narsoplimab in the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), and Omeros expects to resubmit the BLA to include additional information supporting approval of narsoplimab in this indication. Narsoplimab is also in clinical development programs focused on other complement-mediated disorders, including COVID-19. FDA has granted narsoplimab breakthrough therapy and orphan drug designations for TA-TMA and orphan drug status for the prevention (inhibition) of complement-mediated thrombotic microangiopathies as well as for the treatment of TA-TMA. The European Medicines Agency has granted orphan drug designation to narsoplimab for treatment in hematopoietic stem-cell transplant.

On November 3, 2023 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company developing a novel class of T cell engagers to selectively modulate tumor-specific T cells, reported the presentation of new positive data from its ongoing fully enrolled Phase 1 trials evaluating its lead interleukin-2 (IL-2)-based T cell engager, CUE-101, as a monotherapy and in combination with KEYTRUDA (pembrolizumab) for patients with recurrent/metastatic HPV+ head and neck squamous cell carcinoma (HNSCC) (Press release, Cue Biopharma, NOV 3, 2023, View Source [SID1234636914]). New clinical data will also be reported from the company’s ongoing Phase 1 trial evaluating its second candidate, CUE-102, for the treatment of Wilms’ Tumor 1 positive (WT1+) recurrent/metastatic cancers.

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The data will be presented in two posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 38th Anniversary Annual Meeting (SITC 2023) being held in San Diego, California and virtually November 1-5.

"I am pleased to observe the clinical benefit patients are deriving and encouraged by the positive enhancement of data from the CUE-101 clinical trials," said Christine Chung, M.D., Chair, Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, and a principal investigator participating in the clinical trial. "The notable prolongation in overall survival to over 20 months in monotherapy represents a significant advancement of clinical benefit compared to the current standard of care for this population with advanced and refractory disease. Similarly, the reported enhanced overall response rate to date in combination with pembrolizumab, compared to the historical response rate for pembrolizumab alone, is very promising for first line patients. I look forward to evaluating the trial results as they continue to mature and remain highly encouraged by the observations to date. There is a significant unmet medical need for more efficacious and less toxic treatment options for patients with recurrent/metastatic head and neck cancer, and these results from the CUE-101 trial demonstrate the potential to address this need."

Key data highlights from the fully enrolled CUE-101 combination expansion portion of the trial evaluating CUE-101 at the recommended Phase 2 dose (RP2D) of 4mg/kg plus pembrolizumab, as of data cutoff of September 27 with 17 evaluable patients, include:

DCR of 65% and ORR of 47%, demonstrating evidence of clinical activity in comparison to the 19% ORR observed with pembrolizumab treatment alone in the KEYNOTE-040 trial 1,2- This includes one complete response (CR) and seven partial responses (PR), in addition to three durable stable diseases (DSD) of ≥ 12 weeks.
56% ORR in patients with combined positive score (CPS) 1-19, in comparison to the 14% with pembrolizumab monotherapy in the KEYNOTE-040 trial 1,2, with five of the eight responses in tumors with low PD-L1 expression (CPS less than 20).
21 of the 22 patients treated with CUE-101 and pembrolizumab remain alive at time of data cutoff, including eight patients living beyond 12 months.
No unanticipated, significant safety concerns have emerged, and adverse events have been readily managed with appropriate medical care.
Key data highlights from the CUE-101 expansion portion of the Phase 1b trial evaluating CUE-101 at the RP2D as monotherapy to date with 19 evaluable patients, include:

mOS of 20.8 months in 2L+ patients (majority 3L+) treated with CUE-101 monotherapy, notably longer than the historical mOS of 7.5 and 8.4 months reported from third-party clinical trials with checkpoint inhibitors in 2L R/M HNSCC in CheckMate 1411 and KEYNOTE-040, respectively.3
DCR of 37% in late stage, refractory patients, including one confirmed PR of > 36 weeks duration and six DSD of ≥ 12 weeks. Of note, one patient has maintained stable disease (SD) for over 22 months with no detectable evidence of HPV cell-free DNA (cfDNA) in their blood after starting CUE-101 treatment and this patient recently demonstrated an unconfirmed partial response (uPR).
Key data highlights from the CUE-102 Phase 1 clinical trial to date include:

No DLTs reported to date in patients treated during the dose escalation phase at doses ranging between 1–8mg/kg of CUE-102 intravenously every 3 weeks; a MTD has not been reached.
Two patients at the 2mg/kg dose, one with gastric cancer and one with ovarian cancer have demonstrated reduction in tumor burden.
Matteo Levisetti, M.D., chief medical officer of Cue Biopharma added, "It is highly gratifying to share the positive results from the ongoing Phase 1 trial of CUE-101, highlighting its clinical activity in combination with pembrolizumab in 1L patients and the prolonged survival observed in 2L+ patients treated with CUE-101 monotherapy. The promising data further supports our confidence in defining registrational trials for CUE-101, capitalizing on the previously granted Fast Track Designation. Concurrently, the unveiling of positive findings from the ongoing CUE-102 trial have provided early evidence of tolerability and clinical activity, including reductions in tumor burden. These observations are highly encouraging, suggesting that we may have opened up a path for immunotherapy in treating multiple cancers historically resistant to check point inhibitors. The cancers overexpressing WT1 represent substantial patient populations that may benefit from CUE-102 treatment. To date, the CUE-102 trial has been enrolling patients at a rapid pace, reflecting the significant and pressing unmet medical need in these indications."

Dan Passeri, chief executive officer of Cue Biopharma, added, "The clinical data generated to date, from both our CUE-101 monotherapy and combination trials in HPV+ R/M HNSCC, as well as the early data observed in our ongoing WT1-specific CUE-102 dose escalation trial, demonstrate what we believe to be a best-in-class approach to immune modulation, and a clear path forward to realizing the full potential of activating the patient’s own immune system against cancer. We are pleased with our accomplishments to date and look forward to ongoing progress across our platform as we continue developing promising therapies for cancer patients with high, unmet medical needs."

Presentation Details
Title: A phase 1 dose-escalation and expansion study of CUE-101, given as monotherapy in 3L and in combination with pembrolizumab in 1L recurrent/metastatic HPV16+ head and neck cancer patients
Abstract Number: 674
Presenter: Christine Chung, M.D., H. Lee Moffitt Cancer Center, Tampa, Fla. USA
Date: Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m.–8:30 p.m. PDT

Title: A phase 1 trial of CUE-102, a novel WT1-pHLA-IL2-Fc fusion protein in HLA-A*0201 positive patients with WT1-positive recurrent/metastatic cancers
Abstract Number: 750
Presenter: Jennifer Eva Selfridge, M.D., Ph.D., University Hospitals Cleveland Medical Center, Cleveland, OH, USA
Date: Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m.–8:30 p.m. PDT

All posters will be available to conference attendees as virtual e-posters on the virtual meeting platform November 3, 2023 at 9 a.m. PDT/12 p.m. EDT through January 12, 2024. Cue Biopharma’s posters will also be available on November 3, 2023 in the Investors & Media section of the Company’s website at www.cuebiopharma.com, under Scientific Publications and Presentations.

References:
1Harrington, K. J., et al. (Feb 2023). Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Journal of clinical oncology, DOI: View Source

2Burtness, B., et al. (Mar 2022) Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. Journal of clinical oncology, DOI: View Source

3Cohen, EW E. (Nov 2018) Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomized, open-label, phase 3 study. The Lancet, DOI: View Source(18)31999-8

About the CUE-100 Series
The CUE-100 series consists of Fc-fusion biologics that incorporate peptide-MHC (pMHC) molecules along with rationally engineered IL-2 molecules. This singular biologic is anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing the potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.