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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In recent years there has also been a resurgence of interest in ethnopharmacology (also known as ethnopharmacy or ethnobotany), the study of plant materials or other natural products that are used by local communities as a traditional cure for a particular disease. The assumption is that these materials may contain an active constituent that can be identified, purified, and obtained in large amounts (by extraction or synthesis) for further studies. One recent example of the success of this approach was the identification of a novel agent now used for the treatment of proliferative skin disorders, including nonmelanoma skin cancers. Researchers at the University of Birmingham (UK) and the company Peplin Ltd (Brisbane, Australia) discovered a new agent (initially known as PEP005 or 3-Angelate) in the sap of the weed Euphorbia peplus (also known as petty spurge or milk weed) which had a history of community use for the “folklore” treatment of corns, warts, and other skin lesions such as skin cancer. The researchers isolated ingenol as the active agent, and showed that it was 100 fold more cytotoxic toward certain tumor cells in vitro than healthy cells. Furthermore, evidence was obtained that it may work by activating the protein kinase C pathway, thus inducing the interleukin decoy receptors IL1R2 and IL13RA2 and triggering apoptosis. In 2004, two INDs were filed with the FDA for the clinical development of ingenol mebutate (PicatoTM) for solar keratoses and basal cell carcinoma. In 2009, Peplin Ltd was acquired by the pharmaceutical company Leo Pharma which specializes in dermatological products, and FDA approval for the topical treatment of actinic keratosis was obtained in 2012. Given this example of successful drug discovery and development, it is possible that more novel anticancer agent leads may be derived from natural product sources in the future.
Pharmacological treatments for eosinophilic esophagitis: current options and emerging therapies
Published in Expert Review of Clinical Immunology, 2020
RPC4046 was assessed as a second monoclonal antibody to block IL-13 from binding to subunits alpha 1 (IL13Ra1) and 2 (IL13Ra2) of the IL-13 receptor. In a recently published placebo-controlled RCT [45], 99 adult patients with EoE were assigned to either RPC4046 10 mg/kg IV loading dose followed by 360 mg SC once a week, 5 mg/kg IV loading dose + 180 mg SC once a week, or placebo in a 1:1:1 ratio for 16 weeks of therapy, with an optional open-label phase with the higher dose. After the double-blind period of 16 weeks, a statistically significant reduction in mean eosinophil count was observed in both RPC4046 groups compared with placebo. Peak esophageal eosinophil counts were significantly reduced, with 50% of patients treated with 180 mg and 360 mg having <15 peak eos/hpf compared with 0% placebo (p < 0.0001 for both comparisons), and 25% of patients in the 180 mg RPC4046 group and 20% in the 360 mg RPC4046 group having <6 peak eos/hpf after treatment. Regarding symptom improvement, a non-significant trend in favor of RPC4046 was reported, particularly in dysphagia. Results from the open-label extension study showed a sustained symptomatic and histologic improvement at week 52 following successful induction therapy among patients treated with the 360 mg dose [109]. Long-term assessment of the effectiveness of RP4046 in the sustained control of EoE is required.
A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice
Published in OncoImmunology, 2019
Sarah Lévesque, Julie Le Naour, Federico Pietrocola, Juliette Paillet, Margerie Kremer, Francesca Castoldi, Elisa E. Baracco, Yan Wang, Erika Vacchelli, Gautier Stoll, Ariane Jolly, Pierre De La Grange, Laurence Zitvogel, Guido Kroemer, Jonathan G. Pol
Based on the aforementioned results, we decided to investigate the impact of fasting and of two different CRMs, namely HC and spermidine (Spd), on the composition of the immune infiltrate of cancers in the context of MTX-based chemotherapy. At day 3 post-chemotherapy (that was optionally preceded by a 2-day fasting regimen or by a 24-h treatment with either HC or Spd; the latter being maintained/repeated – Supplemental Figure 1(a)), no significant increments in the innate immune cell infiltrates (i.e. DC and natural killer cells) were detected in response to fasting, HC or Spd, perhaps because of the signs of immunodepletion mediated by MTX; a well-documented acute phenomenon46 (Supplemental Figure 1(b–e), Supplemental Table 8). However, RNA-Seq analyses of whole tumors yielded convincing evidence in favor of local immunomodulation by fasting or CRMs upon chemotherapy. Indeed, 480 genes involved in immunological activities were significantly affected between MTX chemotherapy alone versus MTX + fasting (n = 82) or MTX + Spd (n = 429) (Supplemental Figure 2(a)). Among them, 31 modulated genes were common to both combinatorial regimens and a REACTOME pathway analysis revealed a significant enrichment in 20 cellular pathways including the signaling of interleukins (i.e. Il1rap, Il6st, Il4ra, Il1rl1, Il13ra2) (Supplemental Figure 2(b)).
CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?
Published in Expert Review of Anticancer Therapy, 2018
Brooke L. Prinzing, Stephen M. Gottschalk, Giedre Krenciute
The majority of preclinical studies have used xenograft models. Initial studies focused on targeting IL13Ra2-positive glioma with T cells expressing a first-generation CAR that used a mutated IL13 (IL13 mutein) as an antigen-binding domain [26]. IL13Ra2-CAR T cells had potent antiglioma activity in vitro and in vivo. Subsequently, second-generation IL13 mutein-based CARs were developed, which showed improved antiglioma activity [27], and a CAR with a 41BB.ζ endodomain is currently undergoing clinical evaluation. IL13Rα2-specific CARs have also been developed that take advantage of an IL13Rα2-specific scFv as an antigen-binding domain [30]. Use of a scFv-based IL13Rα2-CAR might be advantageous since these CARs do not recognize IL13Rα1, a broadly expressed molecule that has been reported to be recognized by some of the designed IL13 mutein-based CARs [31].