Search

Terese Catherine Hammond,1,2 Raymond C Lee,1,3 Bryan Oronsky,4 Tony R Reid,4 Scott Caroen,4 Tiffany M Juarez,2 Jaya Gill,5 Annie Heng,2 Santosh Kesari1,2,5 1Providence St. Johns Health Center, Santa Monica, CA, USA; 2John Wayne Cancer Institute, Santa Monica, CA, USA; 3Cardiovascular Thoracic Institute, Keck School of Medicine of USC, Los Angeles, CA, USA; 4EpicentRx, Inc., La Jolla, CA, USA; 5Pacific Neuroscience Institute, Santa Monica, CA, USACorrespondence: Bryan Oronsky, EpicentRx, Inc, 11099 North Torrey Pines Road, La Jolla, CA, 92037, USA, Tel +1 858 947-6635, Fax +1 858 724-3080, Email boronsky@epicentrx.comAbstract: Two critically ill COVID-19 infected patients, who had exhausted all available treatment options, were treated with the small-molecule RRx-001 with subsequent improvement. RRx-001, a first-in-class small molecule with anti-inflammatory, vascular normalizing and macrophage-repolarizing properties, has been safely administered 300+ patients in clinical trials. This is the first report of RRx-001 treatment of COVID-19.Keywords: COVID-19, SARS-CoV-2, critical care, ARDS, RRx-001, nitric oxide, viral diseases

Background: RRx-001 is a novel broad-spectrum anticancer agent that triply inhibits DNA methyltransferases (DNA MTases), Histone Deacetylases (HDAC), and Lysine Demethylases. In the first-in-human, Phase I trial, 5/5 patients who progressed on RRx-001 treatment were resensitized to previously refractory irinotecan therapy, hinting at a generalized resensitization effect. A randomized open-label multi-part, multi-center phase II trial of RRx-001 versus regorafenib (ROCKET) is underway to explore the resensitization and/or ‘episensitization’ potential in irinotecan refractory tumors and its impact on overall survival. Methods: Patients with irinotecan-refractory metastatic colorectal cancer with an ECOG PS 0–1 who progressed on oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab are randomized 2:1 to receive RRx-001 16.5 mg/m2 IV 1x/week or regorafenib 160 mg orally 21 of 28 days until progression or unacceptable toxicity followed by treatment with refractory irinotecan-based therapies. Results: To date, 23 patients have been randomized with 10 patients evaluable for resensitization. Post RRx-001 patients demonstrated marked decreases in CEA in all 6 patients as compared to 4 patients receiving regorafenib who were too systemically unwell to proceed to subsequent treatment. Progression free survival (ongoing) for RRx-001 + irinotecan is 5.9 months compared 0.92 months on Regorafenib + irinotecan. Combined Disease Control Rate (SD + PR) for the combination of RRx-001 and reintroduction of Irinotecan based therapy is currently 100%, whereas no patients to date randomized to the regorafenib arm have been able to start irinotecan based therapy secondary to decreasing performance status. Conclusions: Early results in the ROCKET study suggest that RRx-001-mediated resensitization to previously refractory therapies may have a generalized effect, independent of KRAS or p53 status. These early results are intriguing and may be a major advancement in epigenetic therapy. RRx-001 is a novel pan-epigenetic inhibitor that may potentially offer improved QOL and overall survival over currently approved therapy in the chemotherapy refractory colorectal cancer. [ABSTRACT FROM AUTHOR]

The expression "lost at sea" means to be confused or perplexed. By extension, lost at SCLC references the current confusion about how to circumvent the chemoresistance, particularly platinum resistance, which so plagues the treatment of extensive-stage small cell lung cancer (ES-SCLC) that in 2012 the US National Cancer Institute (NCI) designated it a "recalcitrant cancer." Over a decade later, despite the approval of immune checkpoint inhibitors and the conditional approval of lurbinectedin, the prognosis for ES-SCLC, and especially platinum-resistant ES-SCLC, has scarcely improved. The focus of this review, which briefly summarizes current treatment options for ES-SCLC, is on five clinical-stage therapies with the potential to successfully reverse the platinum resistance that is perhaps the biggest obstacle to better clinical outcomes., Competing Interests: Declarations Conflict of interest BO, SC, TR are employed by EpicentRx LM, YS, XW, LZ, and NA are employed by SciClone Pharmaceuticals NA has no competing interests to declare., (© 2024. The Author(s).)

Background: Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed., Methods: To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC., Results: We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines., Conclusion: The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial (NCT04673942) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-β), which sequesters TGF-β, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer. Pseudoprogression (PsP) or progression prior to response or stabilization, has been widely recognized with radiotherapy for primary brain tumors and immune checkpoint inhibitors (ICIs). PsP has also been described and documented in the context of oncolytic virotherapy but perhaps to a lesser extent. However, repeated intratumoral injections with these immunostimulatory agents may induce a more intense immune response and release more antigenic epitopes than with ICIs, for example, which are strictly T-cell directed rather than also tumor-directed like AdAPT-001., Competing Interests: Competing interests: Coauthors CL, SC, BO, MS, and TRR declare that EpicentRx, which owns and develops AdAPT- 001, is their employer. AC declares no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 10 11 , 5.0 × 10 11 , 1.0 × 10 12 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 10 12  vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 10 12  vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling., (© 2023. The Author(s).)

Whither oncolytic viruses? From the peak of their popularity in the early 2000s, when the ONYX-015 adenovirus had just entered the clinic, and then again in 2015 when the Food and Drug Administration-approved talimogene laherparepvec (also known as OncoVEX GM-CSF ), which briefly revived interest, oncolytic viruses (OVs) have mostly fallen out of favor despite the many pharmaceutical companies with OVs in development.This commentary enumerates and addresses the core conceptions, perceptions, and misconceptions that characterize the current 'trough of disillusionment' in which the field of anticancer virotherapy finds itself and suggests reasons for optimism., Competing Interests: Competing interests: All authors are employed by EpicentRx, which develops the transforming growth factor-beta trap armed oncolytic virus, AdAPT-001, mentioned here., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In drug development a frequently used phrase is "data-driven". Just as high-test gas fuels a car, so drug development "runs on" high-quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States. It is intended to demystify CDM, which means nothing more esoteric than the collection, organization, maintenance, and analysis of data for clinical trials. The review is written with those who are new to drug development in mind and assumes only a passing familiarity with the terms and concepts that are introduced. However, its relevance may also extend to experienced professionals that feel the need to brush up on the basics. For added color and context, the review includes real-world examples with RRx-001, a new molecular entity in phase III and with fast-track status in head and neck cancer, and AdAPT-001, an oncolytic adenovirus armed with a transforming growth factor-beta (TGF-β) trap in a phase I/II clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this review is also included for easy reference., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study., Methods and Materials: This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria., Results: Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient., Conclusions: Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.

Introduction: The current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma., Methods: In this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response., Results: A total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 - NA). PFS median was 8 months (95% CI: 5 - NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16)., Conclusions: The addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study., Competing Interests: Authors BO, TR, and SC are employed by the company EpicentRx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fine, Reid, Caroen, Oronsky, Abrouk and Butowski.)

RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or "engineered" as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a "targeting" moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This "payload", which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide "linker" attached to a binding site, which correlates with the F ab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues., Competing Interests: Authors BO, TR, and SC are employees of EpicentRx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oronsky, Takahashi, Gordon, Cabrales, Caroen and Reid.)

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology., (© 2023. The Author(s).)

Background: Bromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options., Methods: This single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03., Results: Twelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination., Conclusions: The combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted., Clinical Trial Registration: ClinicalTrials.gov identifier, NCT02518958., Competing Interests: Authors SC, BO, MQ, JW are employed by EpicentRx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Reid, Oronsky, Caroen, Quinn, Williams, Cabrales and Abrouk.)

Introduction: RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan., Patients and Methods: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month "primer" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m 2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m 2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis., Results: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI., Conclusion: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed "signal" accompanied by a sufficient safety profile., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Persistent post-COVID syndrome, also referred to as long COVID, is a pathologic entity, which involves persistent physical, medical, and cognitive sequelae following COVID-19, including persistent immunosuppression as well as pulmonary, cardiac, and vascular fibrosis. Pathologic fibrosis of organs and vasculature leads to increased mortality and severely worsened quality of life. Inhibiting transforming growth factor beta (TGF-β), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients' families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Despite an ever-increasing need for newer, safer, more effective, and more affordable therapies to treat a multitude of diseases and conditions, drug development takes too long, costs too much, and is too uncertain to be undertaken without the conferment of exclusionary rights or entry barriers to motivate and sustain investment in it. These entry barriers take the form of patents that protect intellectual property and marketing exclusivity provisions that are provided by statute. This review focuses on the basic ins and outs of regulatory and patent exclusivities for which new chemical entities (NCEs), referring to never-before approved drugs with an entirely new active ingredient, are eligible and uses RRx-001, a small molecule aerospace-derived NCE in development for the treatment of cancer, radiation toxicity, and diseases of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, as a "real world" example. This is intended as a '101-type' of primer; its aim is to help developers of original pharmaceuticals navigate the maze of patents, other IP regulations, and statutory exclusivities in major markets so that they can make proper use of them., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Adenovirus (Ad)-based vectors have shown considerable promise for gene therapy. However, Ad requires the coxsackievirus and adenovirus receptor (CAR) to enter cells efficiently and low CAR expression is found in many human cancers, which hinder adenoviral gene therapies. Here, cationic 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-folate liposomes (Df) encapsulating replication-deficient Ad were synthesized, which showed improved transfection efficiency in various CAR-deficient cell lines, including epithelial and hematopoietic cell types. When encapsulating replication-competent oncolytic Ad (TAV255) in DOTAP-folate liposome (TAV255-Df), the adenoviral structural protein, hexon, was readily produced in CAR-deficient cells, and the tumor cell killing ability was 5× higher than that of the non-encapsulated Ad. In CAR-deficient CT26 colon carcinoma murine models, replication-competent TAV255-Df treatment of subcutaneous tumors by intratumoral injection resulted in 67% full tumor remission, prolonged survival, and anti-cancer immunity when mice were rechallenged with cancer cells with no further treatment. The preclinical data shows that DOTAP-folate liposomes could significantly enhance the transfection efficiency of Ad in CAR-deficient cells and, therefore, could be a feasible strategy for applications in cancer treatment.

In medicine, inflammation is a fuzzy, overused word first coined by the Romans, the intended meaning and precise definition of which varies according to the person and the clinical context. It tends to carry a negative connotation as a response gone awry, like a raging, out-of-control wildfire that requires immediate control and containment lest it destroy all in its path; however, frequently overlooked or lost in the shuffle is the primordial importance of inflammation to health and survival. The precise definition of inflammation matters for several reasons, not least because of the over-liberal use of anti-inflammatory drugs to inhibit inflammation, which may, contrary to prevailing dogma that all inflammation is harmful, act counterproductively to prevent restitutio ad integrum. Using fire as a central analogy, this overview attempts to define inflammation, the better to determine how to manage it, i.e., whether to fan its flames, let it burn out, or suppress it entirely.

From antibiotics to aspirin to antimalarials and to anticancer agents, about half of the world's best-selling drugs are derived from nature. However, accelerating climatic disruption, habitat destruction, pollution, and biodiversity loss all negatively impact the potential of natural sources to continue to serve as repositories of novel pharmaceuticals. On that basis, the final frontier for drug development is perhaps not the rainforests, coral reefs, and other natural habitats but rather the aerospace industry with its virtually unlimited and inexhaustible man-made 'library' of potentially bioactive compounds. The first aerospace-sourced therapeutic to reach the clinic is RRx-001, an inhibitor of the NOD-like receptor - Nucleotide-binding oligomerization domain with Leucine rich Repeat and Pyrin domain (NLRP3) inflammasome in a Phase 3 trial for the treatment of small cell lung cancer (SCLC) and in a soon-to-start Phase 3 trial for protection against chemoradiotherapy-induced severe oral mucositis in first line head and neck cancer. As manned missions to the Moon, Mars, and asteroids as well as space tourism beckon, it is perhaps fitting that a compound like RRx-001, which is derived from 1,3,3-Trinitroazetidine (TNAZ), an explosive propellant for rockets, is a potential "all purpose" option to mitigate the major biomedical effects of space radiation exposures including cancer development and other tissue degenerations both within mission and after mission. This article highlights the promise of RRx-001 to attenuate the acute and late effects of radiation exposure on astronauts including the development of cancer., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022. Published by Elsevier B.V.)

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad ( p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.

Oncolytic viruses, colloquially referred to as "living drugs", amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruses to prime and augment their activity. This review focuses on adenoviruses, the most clinically investigated of all the oncolytic viruses. It covers specific design features of clinical adenoviral candidates and highlights their potential both alone and in combination with checkpoint inhibitors in clinical trials to turn immunologically "cold" and unresponsive tumors into "hotter" and more responsive ones through a domino effect. Finally, a "mix-and-match" combination of therapies based on the paradigm of the cancer-immunity cycle is proposed to augment the immune responses of oncolytic adenoviruses., Competing Interests: B.O., S.C. and T.R. are employees of EpicentRx.

RRx-001 is a small molecule NLRP3 inflammasome inhibitor with anti-CD47 and antiangiogenic/vascular normalization properties in a Phase 3 clinical trial that has been designated as a drug-device combination by the FDA. In the Phase 1 first-in-man dose escalation clinical trial, where RRx-001 was given by direct intravenous (IV) infusion, the main adverse event was a sterile painful infusion phlebitis (IP). Less pain was experienced when RRx-001 was infused at a slower rate over multiple hours which was impractical on an outpatient basis. In Phase 2, for reasons of convenience and safety, RRx-001 was co-administered with an aliquot of autologous blood from an ex-vivo device called the eLOOP on the premise that RRx-001 binds to hemoglobin on red blood cells (RBCs), making it unavailable to directly interact with venous nociceptors. Phlebitis has the potential to progress to deep venous thrombosis or septic thrombophlebitis or post-thrombotic syndrome in hypercoagulable and immunosuppressed cancer patients. In this 13-week toxicology study of once weekly IV RRx-001 administration to Wistar Han rats followed by a recovery period of 28 days. The main observed toxicity was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis observed in man. Due to this development, direct IV infusion of RRx-001 is relatively contraindicated in favor of co-administration with autologous blood., Competing Interests: Competing Interests: The authors declare that EpicentRx Inc. funds research of RRx-001., (© The author(s).)

RRx-001, a CD47 antagonist via its inhibition of MYC and the γ-subtype of the peroxisome proliferator-activated receptor (PPAR) has been associated to date with minimal toxicity. The aim of this post-hoc analysis was to evaluate the toxicity and efficacy of RRx-001 in Asian patients since RRx-001, in the context of multiple Phase 3 studies, will be administered in China and Chinese territories as well as potentially throughout the rest of Asia. Patients received 4 mg of RRx-001 in three different antitumor clinical trials with chemotherapy and/or radiation and a retrospective subset efficacy and toxicity analysis was conducted for patients with Asian ancestry in comparison to patients with other ethnic backgrounds. The toxicity and efficacy data from these studies were similar between Asians and the rest of the treated patients. While the sample sizes are too small to draw definitive conclusions, at a dose of 4 mg, when RRx-001 is combined with chemotherapy, no apparent differences in terms of safety and efficacy are observed in cancer patients with Asian ancestry., Competing Interests: EpicentRx Inc is the sponsor of these clinical trials featuring RRx-001., (AJCR Copyright © 2022.)

Multiple new variants of the SARS-CoV-2 virus have emerged globally, due to viral mutation. The majority of COVID-19 vaccines contain SARS-CoV-2 spike protein, which is susceptible to mutation. It is known that protection against COVID-19 after two doses of mRNA vaccine continuously wanes over time. If viral variants contain mutated spike protein, current vaccines may not provide robust protection. This perspective suggests the inclusion of SARS-CoV-2 nucleocapsid protein in future COVID-19 vaccines and boosters, as nucleocapsid is much less vulnerable to mutation and may provide stronger immunity to novel viral variants., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-β receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-β. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8 + T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.

For close to 40 years small-cell lung cancer (SCLC) was adrift, as listless, and as idle as a painted ship on a painted ocean, with nary a breeze to blow in the direction of clinical progress or change. The preferred decades-old first line regimen was etoposide-platinum, to which ≥50% of patients respond, followed by decades-old, tired topotecan in second line for platinum sensitive patients, full stop, because there were no approved therapeutic options (nor generally any compelling experimental ones) in third line or beyond. In 2012 SCLC was designated by the U.S. Congress as a "recalcitrant" tumor type and for good reason: because most patients relapse, after the generally favorable response in first line, respond poorly, if at all to subsequent therapies, and rarely survive beyond 1 year. A significant sea change occurred in 2018 with the approval of nivolumab followed by pembrolizumab and atezolizumab in 2019, durvalumab in 2020, accelerated approval for lurbinectedin in 2020 and trilaciclib in 2021 for myelosuppression. In 2021, the US indications for nivolumab and pembrolizumab were withdrawn. Suddenly, a tumor type, whose name was virtually synonymous with stalled progress and movement, and which was much less well studied and funded than its more prevalent cousin, non-small cell lung cancer (NSCLC), finds itself in the eye of the storm, that is, at the epicenter of an intense flurry and ferment of activity, not all of it positive. This review surveys approved drugs and select up-and-coming ones in development for extensive stage SCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Monoclonal antibodies targeting the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) axes have permanently changed the therapeutic landscape for multiple tumor types previously associated with a dismal prognosis such as melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma. However, only a subset of patients initially benefits from these inhibitors, and increasing clinical experience indicates that in a substantial proportion of initial responders, lethal secondary resistance ultimately develops months or years later. In this paper we evaluated combination therapy with a Phase 1 oncolytic adenovirus called AdAPT-001, armed with a TGF-β "trap" that binds to and neutralizes the immunosuppressive cytokine, TGF-β, and a checkpoint inhibitor, anti-PD-L1, in PD-L1 resistant tumors. The study, which was performed in an immunocompetent syngeneic ADS-12 mouse model, demonstrated that the combination of AdAPT-001 with PD-L1 blockade reversed PD-L1 resistance, potentially representing a future paradigm shift for patients that are primarily or secondarily resistant to checkpoint inhibitors., Competing Interests: None., (AJCR Copyright © 2022.)

The multi-kinase inhibitor Regorafenib, approved for the treatment of metastatic colorectal cancer, is poorly tolerated with a Grade 3/4 drug related adverse event rate of 54% resulting in frequent dose reductions and discontinuations. RRx-001 is a minimally toxic NLRP3 inhibitor small molecule with macrophage-repolarizing properties in Phase 3 clinical trials. Studies have demonstrated the inhibitory impact of M2 macrophages on the activity of tyrosine kinases, suggesting that the repolarization of macrophages by RRx-001 may enhance the activity of TKIs. The purpose of these experiments was to determine whether RRx-001 demonstrated in vitro and in vivo synergy with regorafenib in colorectal cancer and whether RRx-001 attenuated the toxicity of regorafenib. Tumor-bearing mice were randomized into four cohorts: RRx-001 alone, regorafenib alone, RRx-001 + regorafenib and control. RRx-001 demonstrated in vitro and in vivo synergy with regorafenib with attenuation of toxicity in colorectal cancer cell lines. These results provide a rationale to treat colorectal cancer with RRx-001 plus another tyrosine kinase inhibitor like regorafenib., Competing Interests: None., (AJCR Copyright © 2022.)

Vascular normalisation refers to a 'remodeling' of the dysfunctional tumour capillary network, which regresses under the influence of anti-VEGF treatment, resulting in improved blood flow and oxygenation. RRx-001 is an anti-CD47-SIRPα small molecule with vascular normalising properties under investigation in clinical trials for the treatment of glioblastoma, brain metastases, lung cancer and colorectal cancer, with FDA Orphan Drug Designation in glioblastoma and other tumour types. This study investigated whether the improved oxygenation and perfusion that has been previously observed with RRx-001 both preclinically and clinically in the context of a brain metastasis trial was correlated with increased penetration and accumulation of the cytotoxic chemotherapies, irinotecan and temozolomide, in orthotopically implanted gliomas, priming tumours for improved response. The experiments demonstrate that administration of RRx-001 prior to temozolomide or irinotecan results in significantly increased uptake of irinotecan and temozolomide in orthotopic glioma tumours. Since the success of chemotherapy in the brain (and outside of it) is limited by subtherapeutic tumoral drug concentrations, vascular normalisation-enhanced delivery of standard cytotoxics as demonstrated with RRx-001 may mitigate or reverse clinical drug resistance and thereby improve the outcome of cancer therapy, particularly in the brain.

Transgene-enhanced oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. A Phase 1 clinical trial featuring AdAPT-001 is ongoing (NCT04673942). AdAPT-001, a type 5 adenovirus, which carries a TGF-β trap transgene that neutralizes the immunosuppressive cytokine, TGF-β, has been shown in an immunocompetent mouse model to eradicate both locally injected and non-injected tumors. Single dose biodistribution of the TGF-β trap transgene was also evaluated in tumor bearing mice, providing an explanation for systemic activity. The biodistribution and toxicity of a single administration of mouse AdAPT-001 (mAdAPT-001) in 129S1 immunocompetent mice bearing ADS-12 tumors (mouse lung carcinoma) were assessed. mAdAPT-001 was injected intratumorally and intravenously in groups of 25 mice each at varying dose levels. Soluble TGF-β trap was detected in the serum using ELISA. A single AdAPT-001 injection resulted in non-negligible long-term TGF-β trap persistence in the serum over the 14-day study after intravenous and intratumoral administration. No TGF-β-related toxicity was observed. At clinically relevant doses, AdAPT-001 was safe and well tolerated. Systemic levels of the TGF-β trap transgene were observed from both local and intravenous dosing., Competing Interests: None., (AJCR Copyright © 2021.)

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.

Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability. We next investigated the biomechanics of RBC adhesion in the context of local inflammatory cytokines after treatment with RRx-001 as a potential mechanism for preferential tumor aggregation. Human HEP-G2 and HT-29 tumor cells were subcutaneously implanted into nu/nu mice and were infused with RRx-001-treated and Technetium-99m ( 99m Tc)-labeled blood. RBC adhesion was quantified in an in vitro human umbilical vein endothelial cell (HUVEC) assay under both normoxic and hypoxic conditions with administration of either lipopolysaccharide (LPS) or Tumor necrosis alpha (TNFα) to mimic the known inflammation in the tumor microenvironment. One hour following administration of 99m Tc labeled RBCs treated with 10 mg/kg RRx-001, we observed an approximate 2.0-fold and 1.5-fold increase in 99m Tc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. Furthermore, we observed an approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001. To quantify RBC adhesive potential, we determined τ50, or the shear stress required for 50% disassociation of RBCs from HUVECs. After administration of TNF-α under normoxia, τ50 was determined to be 4.5 dynes/cm 2 (95% CI: 4.3-4.7 dynes/cm 2 ) for RBCs treated with 10 μM RRx-001, which was significantly different ( p < 0.05) from τ50 in the absence of treatment. Under hypoxic conditions, the difference of τ50 with (4.8 dynes/cm 2 ; 95% CI: 4.6-5.1 dynes/cm 2 ) and without (2.6 dynes/cm 2 ; 95% CI: 2.4-2.8 dynes/cm 2 ) 10 μM RRx-001 treatment was exacerbated ( p = 0.05). In conclusion, we demonstrated that RBCs treated with RRx-001 preferentially aggregate in HEP-G2 and HT-29 tumors, likely due to interactions between RRx-001 and cysteine residues within RBCs. Furthermore, RRx-001 treated RBCs demonstrated increased adhesive potential to endothelial cells upon introduction of TNF-α and hypoxia suggesting that RRx-001 may induce preferential adhesion in the tumor but not in other tissues with endothelial dysfunction due to conditions prevalent in older cancer patients such as heart disease or diabetic vasculopathy.

The present studies evaluate the in vivo prophylactic radioprotective effects of 1-bromoacetyl-3, 3-dinitroazetidine (RRx-001), a phase III anticancer agent that inhibits c-myc and downregulates CD-47, after total body irradiation (TBI), in lethally and sublethally irradiated CD2F1 male mice. A single dose of RRx-001 was administered by intraperitoneal (IP) injection 24 h prior to a lethal or sublethal radiation dose. When irradiated with 9.35 Gy, the dose lethal to 70% of untreated mice at 30 days (LD 70/30 ), only 33% of mice receiving RRx-001 (10 mg/kg) 24 h prior to total body irradiation (TBI) died by day 30, compared to 67% in vehicle-treated mice. The same pretreatment dose of RRx-001 resulted in a significant dose reduction factor of 1.07. In sublethally TBI mice, bone marrow cellularity was increased at day 14 in the RRx-001-treated mice compared to irradiated vehicle-treated animals. In addition, significantly higher numbers of lymphocytes, platelets, percent hematocrit and percent reticulocytes were observed on days 7 and/or 14 in RRx-001-treated mice. These experiments provide proof of principle that systemic administration of RRx-001 prior to TBI significantly improves overall survival and bone marrow regeneration., Competing Interests: BO and NA are employed by the company of EpicentRx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jurgensen, Skinner, Oronsky, Abrouk, Graff, Landes, Culp, Summers and Cary.)

Introduction : The CD47 and SIRPα checkpoint pathway has garnered much interest within the anti-cancer research community, with multiple experimental checkpoint inhibitors targeting CD47 and SIRPα in development. The use of such checkpoint inhibitors may however be limited by hematologic toxicity. Areas covered : We report on RRx-001, the first known small molecule downregulator of CD47 and SIRPα, which has shown a lack of hematologic toxicity in clinical trials. Expert opinion : RRx-001 is the first reported small molecule downregulator of CD47 and SIRPα and lacks any notable hematologic or systemic toxicity as demonstrated in clinical trials to date. Small molecule RRx-001 could be used in combination with or in place of CD47 targeting antibodies for anti-cancer treatment.