Academic literature on the topic 'Multi-h Continuous Phase Modulation (CPM)'

BackgroundCRC remains the 2nd most common cause of cancer-related death in the US. Hepatic metastases develop in 20–50% of CRC patients.1 Median overall survival (OS) of patients with metastatic CRC is poor, even with the advent of biologics. A high density of CRC-infiltrating effector cytotoxic T lymphocytes (Teff; CTL) is known to predict long-term outcomes and the responsiveness of tumors to immune checkpoint inhibitors (ICI). In our ex vivo tumor explant models and CRC-bearing experimental animals, the combination of toll-like receptor-3 (TLR3) ligands with interferon (IFN)-α with cyclooxygenase (COX)-2 inhibitors resulted in increased production of Teff attracting chemokines CXCL10 and CCL5, along with suppression of regulatory T cells (Treg) attracting chemokine, CCL22 in the tumor microenvironment.2,3 A combination of all three factors was needed to uniformly elevate the desirable chemokines and counteract CCL22 induction. Based on these studies and on prior clinical safety data, we developed this phase IIa study combining IFNα2b, celecoxib (COX-2 inhibitor) and rintatolimod (selective TLR3 agonist) as a chemokine-modulating (CKM) regimen for CRC patients with unresectable liver-metastatic disease. We aim to study the immunological impact, potential clinical efficacy and safety of this CKM regimen in a non-randomized, single-arm prospective phase II trial.MethodsEligible patients have recurrent/metastatic unresectable CRC with hepatic metastases that are amenable to biopsy. Enrolled patients have prior treatment with or contra-indication to a fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF treatment, and an anti-EGFR targeted therapy (if RAS wt), as well as a PD-1 or PD-L1 targeted drug if MSI-H/dMMR. Patients receive celecoxib (200 mg orally PO BID), IFNα2b IV (20 million units/m2 IV QD), and rintatolimod (200 mg IV QD) on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Response assessment via liver biopsies (pre-treatment and on D20) and CT imaging (RECIST v1.1) on D46. If stable disease/response is demonstrated during repeat CT imaging, patients will continue to follow-up with CT imaging q8 weeks until progression, clinical deterioration, or withdrawal from the study. Primary endpoint assessment compares the change in CD8+ T-cells before treatment, with that seen post-treatment (measured by quantitative RT-PCR and expressed as a ratio of CD8α to a housekeeping gene). Secondary endpoints include objective response rate and safety profile. Subjects are monitored continuously for safety, based on Bayesian analysis. Exploratory endpoints include progression-free survival and overall survival. With a sample size of n=12 evaluable pts, the study design has a 90% power to detect a 0.77 standard deviation increase (pre- to post treatment) at a significance level of 0.1.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov Identifier: NCT03403634.Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center‘s Institutional Review Board, approval number: MOD00006722/I-52917.ConsentN/AReferencesLahr C.J, et al., A multifactorial analysis of prognostic factors in patients with liver metastases from colorectal carcinoma. J Clin Oncol, 1983. 1(11): p. 720–6.Muthuswamy R, et al. NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 2012;72(15):3735–3743.Obermajer N, et al. Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents. Nat Protoc13, 335–357 ( 2018).

Abstract Production of DF from native mammalian DNA involves heat controlled depolimerization of polymerized nucleic acids as a function of hyperchromicity measured at wavelengths of 260–280 nm as the ratio of Optical Density (OD) in (disorderly phase)/(OD) in (orderly phase). In double helix DNA this rearrangement can be of the order of 100%. DF is defined to represent a hyperchromicity ratio around 15%. Its structural formula is static: P1-5, (dAp)12–24, (dGp) 10–20, (dTp)13–26, (dCp)10–20. ASH Abstract #4086, 2004 reported sequence identities of the fragments at MW </=560 Da (the calculated MW of alkali Na-salt of ATP), using Reversed Phase- HPLC and (MALDI-TOF) (Oral, Lewis),to represent the capability of DF for 15% molecular rearrangement to include but not limited to: dC, dA, G, dGMP, AMP, dTTP, CTP, ATP, dGTP, CMP, cGMP, dAMP. 4 aptamers were sequenced from the PCR product of the double-stranded Defibrotide precursor (Schroer). We have analyzed Aptamer #4 of the sequence 5′ggtggtggttgtggt against the gag/pol region of HIV, and found 3 homology sites. Translation of the aptamer region in gag is a peptide “PEPTA”, and a pol gene fragment translates the same DNA sequence into TRANS. There is a conserved hairpin in the gag/pol region, just before the aptamer #4 homology. Other homologies of Aptamer #4 include but are not limited to the self-replicating portion of mitochondrial DNA (G.Gorilla, H.Sapiens), Candida tropicalis, but not Herpes, etc. T he reproducibility of these sequences in different batches of DF are still under study, and to be reported at the time of the ASH meeting. DF’s mechanism of efficacy as a dose dependent modulator of 2nd messengers, however, are based on a more universally reported data. Highlighted in the literature are the HIV induced loss of bi-directional phosphorilation between Gs GTP/Gs GDP in favor of unidirectional continuous activation of adenylate cyclase (AC) by Gs GTP and secondary uninhibited upregulation of cAMP production. This leads to a known intracellular imbalance between cAMP/cGMP favoring viral replication. Also known are Beta Adrenoreceptor coupling to AC by Gs GTP, and secondary upregulation of autocrine production of inflammatory cytokines of TNF-Alpha, IL6, IL2, IL1, as well as micelle and spore formation of Candida Albicans (Sabie). Similarly, HSV-1 Alpha0 Promoter isknown to contain a putative cAMP responsive element (CRE) via activating transcriptor protein ATP/cAMP CRE binding protein CREB, NF-kB via CA ((Danaher). Reported are upregulation of cAMP, ATP, NADH, gluthathione, 2–3 DPG, NADP /NADPH, and AC by DF, albeit as static events. We will report on an in-vivo dose system aiming at resetting the broken feedback loops of bi-directional phosphorilation reactions as a common denominator for DF’s mechanism of efficacy. The patient data dose-stratified from 40mg/kg/day to 300mg/kg/day using either approach are to be detailed at the time of the upcoming ASH meetings.