GSK's antigen-specific cancer immunotherapy programme: Pilot results leading to Phase III clinical development

AbstractNatural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.

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AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1124 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1464.1-1465

Author(s):

J. Blaess ◽

J. Walther ◽

J. E. Gottenberg ◽

J. Sibilia ◽

L. Arnaud ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

B Cells ◽

Phase I ◽

Phase Ii ◽

Clinical Development ◽

Phase Iii ◽

Jak Inhibitors ◽

Exclusion Criteria ◽

Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

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The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Therapeutic Advances in Hematology ◽

10.1177/20406207211019622 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110196

Author(s):

Albert Oriol ◽

Laura Abril ◽

Anna Torrent ◽

Gladys Ibarra ◽

Josep-Maria Ribera

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Safety Profile ◽

Proteasome Inhibitors ◽

Clinical Development ◽

Phase Iii ◽

Acceptable Safety Profile ◽

Refractory Multiple Myeloma ◽

High Risk Patients ◽

Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

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New Treatment Approaches in Chronic Kidney Disease-associated Anaemia

European Oncology & Haematology ◽

10.17925/eoh.2011.07.02.132 ◽

2011 ◽

Vol 07 (02) ◽

pp. 132

Author(s):

Lucia Del Vecchio ◽

Francesco Locatelli ◽

◽

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Development ◽

Cold Chain ◽

Phase Iii ◽

Cardiovascular Risks ◽

Administration Schedule ◽

Tumour Control ◽

Human Erythropoietin ◽

Frequent Administration

Recombinant human erythropoietin (rHuEPO) is an effective agent for the treatment of anaemia in patients with chronic kidney disease. However, given its relatively short half-life, it requires a relatively frequent administration schedule. Moreover, it can be administered only subcutaneously or intravenously and is unstable at room temperature, making a strict cold chain control necessary. Pharmacological research has focused on the development of new agents to circumvent these relative disadvantages. Some long-acting erythropoietin-stimulating agents (ESAs) are already available for clinical use that require a less-frequent administration schedule. Peginesatide (Hematide), which is a small dimeric peptide with a chemical structure unrelated to EPO, has recently ended phase III clinical trials. Other new molecules undergoing clinical development are CNTO 530 and CNTO 528, ACE-011 and hypoxia-inducible transcription factor stabilisers. The latter have the advantage that they can be administered orally but their clinical development faces a significant hurdle following a case of fatal hepatitis. Newer molecules in this class are undergoing clinical evaluation. Other strategies, such as EPO fusion proteins, agonistic antibodies targeting the EPO receptor and gene therapy have only been tested in animal models or are undergoing pre-clinical evaluations. Before clinical approval, all these new strategies need to address safety concerns raised recently about the use of ESAs regarding possible increased cardiovascular risks following targeting to high haemoglobin levels and/or exposure to excessive doses without reaching a target in both higher and lower haemoglobin groups, and reduced survival and tumour control in the oncology setting. Many of these molecules will also need careful evaluation for possible immunogenicity.

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Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01207-21 ◽

2021 ◽

Author(s):

Monica M. Kangussu-Marcolino ◽

Upinder Singh

Keyword(s):

Entamoeba Histolytica ◽

Current Treatment ◽

Clinical Development ◽

New Drugs ◽

Phase Iii ◽

Significant Advance ◽

Pi3k Inhibitors ◽

Treatment Regimens ◽

Clinical Resistance ◽

Tk Inhibitors

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened the ReFRAME library (11,948 compounds assembled for Repurposing, Focused Rescue, and Accelerated Medchem) against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation including 6 FDA approved, 5 orphan designation, and 15 which are currently in clinical trials (3 phase III, 7 phase II and 5 phase I). We found that all 26 compounds are active against metronidazole resistant E. histolytica and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 50 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica .

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Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Journal of Clinical Medicine ◽

10.3390/jcm9103323 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3323

Author(s):

Leila Motedayen Aval ◽

James E. Pease ◽

Rohini Sharma ◽

David J. Pinato

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Cancer Therapeutics ◽

Clinical Development ◽

The Body ◽

Small Subset ◽

Type I ◽

Principal Mechanism ◽

Cyclic Dinucleotides ◽

Sting Pathway

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa511 ◽

2020 ◽

Author(s):

Burcu Isler ◽

Patrick Harris ◽

Adam G Stewart ◽

David L Paterson

Keyword(s):

Pseudomonas Aeruginosa ◽

Clinical Studies ◽

Bacterial Infections ◽

Animal Studies ◽

Wide Spectrum ◽

Clinical Development ◽

Phase Iii ◽

Lactam Antibiotic ◽

Tract Infections

Abstract Cefepime, a wide-spectrum β-lactam antibiotic, has been in use for the treatment of serious bacterial infections for almost 25 years. Since its clinical development, there has been a dramatic shift in its dosing, with 2 g every 8 hours being preferred for serious infections to optimize pharmacokinetic/pharmacodynamic considerations. The advent of ESBLs has become a threat to its ongoing use, although future coadministration with β-lactamase inhibitors (BLIs) under development is an area of intense study. There are currently four new cefepime/BLI combinations in clinical development. Cefepime/zidebactam is generally active against MBL-producing Enterobacterales and Pseudomonas aeruginosa, in vitro and in animal studies, and cefepime/taniborbactam has activity against KPC and OXA-48 producers. Cefepime/enmetazobactam and cefepime/tazobactam are potential carbapenem-sparing agents with activity against ESBLs. Cefepime/enmetazobactam has completed Phase III and cefepime/taniborbactam is in Phase III clinical studies, where they are being tested against carbapenems or piperacillin/tazobactam for the treatment of complicated urinary tract infections. While these combinations are promising, their role in the treatment of MDR Gram-negative infections can only be determined with further clinical studies.

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