anti-OX40 (CD134) / AstraZeneca - LARVOL DELTA

The NFκB/COX2 Pathway Mediates the Inhibition of CAR-T Cell Proliferation and Function By Bone Marrow Stroma (ASH 2024) - "We used a CAR-T cell consisting of a CD33 binder and CD28z-OX40 costimulatory moiety...The addition of celecoxib at the time of infusion of apoMSC, restored the ability of CAR-T cell to expand in vivo and control leukemic cell increase in the peripheral blood. We conclude that BM-MSC can be induced to acquire immunosuppressive properties by activated CAR-T cells through 2 different but overlapping mechanisms, both dependent on NF-κB and COX2 signalling pathway. Our work provides critical information to overcome resistance to CAR-T cell treatment by neutralising the negative effects of the stromal microenvironment."

CAR T-Cell Therapy • Stroma • Oncology • ANXA5 • CCL8 • CD33 • CXCL10 • CXCL8 • CXCL9 • IL6 • PACERR • PD-L1 • PTGS2 • STAT1

NF-κB Inducing Kinase Is a Therapeutic Target for Autoimmune Diseases by Orchestrating Both B Cell and T Follicular Helper Cell Responses (ACR Convergence 2024) - "NF-κB inducing kinase (NIK) regulates immune cell signaling downstream of a subset of the tumor necrosis factor superfamily receptors including BAFFR, CD40, OX40, lymphotoxin receptor and RANK... Our findings indicate that NIK-mediated signaling events play an intrinsic role in both Tfh and B cells to regulate immune responses. Targeting NIK may therefore have potential in the treatment of autoimmune diseases."

Immunology • Oncology • Rheumatology • Targeted Protein Degradation • CD27 • CD40LG • CD70 • CXCR5 • ICOS • IL21 • PD-1 • TNFA

Bone Marrow Stroma Impairs CAR-T Cell Proliferation and Function: Mechanistic Insights (ASH 2023) - "We used a CAR-T cell consisting of a CD33 binder and CD28z-OX40 costimulatory moiety...2). Our work provides critical information to overcome resistance to CAR-T cell treatment by neutralising the negative effects of the stromal microenvironment."

CAR T-Cell Therapy • Stroma • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CCL8 • CD33 • CXCL10 • CXCL8 • CXCL9 • IL6 • PACERR • PD-L1 • PTGS2 • STAT1

Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and impact response to immuno-oncology treatments. (PubMed, Front Immunol) - "We hypothesized that these differences may contribute to impaired anti-cancer immune responses in aged mice and therefore assessed the anti-tumor efficacy of different IO therapies in aged mice, including both co-stimulation (using an anti-OX40 antibody) and immune checkpoint blockade (using anti-PD-L1 and anti-CTLA-4 antibodies). Whilst aged mice retained the capacity to generate anti-tumor immune responses, these were significantly attenuated when compared to the responses observed in young mice. These differences highlight the importance of age-related immunological changes in assessing and refining the translational insights gained from preclinical mouse models."

Immuno-oncology • Journal • Oncology • CD8

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review. (PubMed, J Asthma Allergy) - "Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study)...Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified...These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma."

Journal • Review • Allergy • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. (ASCO 2020) - P1 | "Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Research Funding: AstraZeneca"

Clinical • Combination therapy • Dermatology • Fatigue • Oncology • Pruritus • Renal Disease • Solid Tumor • TNFRSF4

Safety and tolerability of MEDI0562, an OX40 agonist monoclonal antibody, in combination with durvalumab or tremelimumab in adult patients with advanced solid tumors. (PubMed, Clin Cancer Res) - "Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated."

Combination therapy • Journal • Immunology • Oncology • Solid Tumor • CD4 • CD8 • FOXP3

Effect of Biologics on Allergic Response and Airway Hyperresponsiveness: A Systematic Literature Review (ATS 2022) - "Mepolizumab had no effect on EAR or LAR (1/1 study) or AHR (3/3 studies). In one study each, IMA-638, lebrikizumab and tralokinumab had no effect on AHR. Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR in one study. Benralizumab had no effect on LAR (1/1 study), and no studies were identified assessing AHR. In one study each, efalizumab, tocilizumab, Ro-24-7472 and anti-OX40 ligand had no effect on AHR...No published studies were identified for dupilumab or reslizumab.CONCLUSIONSAcross multiple biologics studied, reductions in both EAR and LAR to allergens were observed with omalizumab and tezepelumab. Tezepelumab also consistently attenuated nonspecific AHR to methacholine or mannitol. These findings provide further insight into the mechanisms of AHR and the clinical benefits of asthma biologics and suggest that tezepelumab may broadly target mediators or cells involved in asthma inflammation."

Review • Allergy • Asthma • Inflammation • Pulmonary Disease • Respiratory Diseases

MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody (AACR 2018) - "Combining MEKi with OX40 agonist antibody significantly enhanced anti-OX40 antitumor effect. These data highlight the ability of pharmacologic MEK inhibition in inducing TSCM, which can be used ex vivo to enhance the potency of T-cell therapies and in vivo in combination immune therapy."

IO Biomarker • Solid Tumor

Quantitative modeling as a systematic approach for drug combination evaluation in immuno-oncology (IO) (AACR 2018) - "This work provides a quantitative modeling framework to comparatively predict responses to IO combinations, based on realistic baseline conditions prevailing in the TME, while revealing mechanistic interactions underlying such responses in IO combinations."

IO Biomarker • PD(L)-1 Biomarker • Oncology

OX40 agonists for cancer treatment: a patent review. (PubMed, Expert Opin Ther Pat) - "United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists."

Journal • Immune Modulation • Inflammation • Oncology

Anti-OX40 Antibody (MEDI6469) in Patients With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1; N=44; Recruiting; Sponsor: Providence Health & Services

New P1 trial • Biosimilar • Colorectal Cancer • Oncology

"AstraZeneca drops an OX40 cancer drug candidate in Q4 pipeline cleanup https://t.co/MMyDeAYEdE" (@endpts)