TGF-β trap of AdAPT-001 turns up the heat on tumors and turns down checkpoint blocker resistance.

At the ASCO 2024 meeting, Anthony P Conley, coauthor on this editorial, presented promising data from the phase 1/2 clinical trial called BETA PRIME (ClinicalTrials.gov NCT04673942) with AdAPT-001 plus a checkpoint inhibitor (CI). All participants gave informed consent to participate in BETA PRIME before taking part.

CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency.

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.

Lost at SCLC: a review of potential platinum sensitizers.

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.

Hypothesis: AdAPT-001 and pseudoprogression - when seeing is not necessarily believing.

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.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

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.

Commentary on oncolytic viruses: past, present, and future.

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), 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.

Data Management 101 for drug developers: A peek behind the curtain.

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.

A Local and Abscopal Effect Observed with Liposomal Encapsulation of Intratumorally Injected Oncolytic Adenoviral Therapy.

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.

A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma.

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.

RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist.

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.

Case Report of AdAPT-001-Mediated Sensitization to a Previously Failed Checkpoint Inhibitor in a Metastatic Chordoma Patient.

Chordoma is a rare, but aggressive bone tumor with a high recurrence rate that primarily arises at the cranial and caudal ends of the axial skeleton. Systemic chemotherapies are not effective against the tumor, and outside of surgical resection and radiation, no approved options are available. Prognosis depends on the extent of surgical resection, with the more the better, and adjuvant radiotherapy.

Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME).

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 Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.

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.

PREVLAR: Phase 2a Randomized Trial to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Head and Neck Chemoradiotherapy.

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.

Patent and Marketing Exclusivities 101 for Drug Developers.

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.

Clinical Course of Two Patients with COVID-19 Respiratory Failure After Administration of the Anticancer Small Molecule, RRx-001.

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.

ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer.

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.

What Exactly Is Inflammation (and What Is It Not?).

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.

Full Remission of CAR-Deficient Tumors by DOTAP-Folate Liposome Encapsulation of Adenovirus.

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.

Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes.

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.

RRx-001 and the "Right stuff": Protection and treatment in outer space.

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.

Superficial Venous-Associated Inflammation from Direct IV Administration of RRx-001 in Rats.

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.