Expert Opinion on Biological Therapy最新文献

Introduction: Locally advanced esophageal cancer (EC) has poor prognosis. Preliminary clinical studies have demonstrated the synergistic efficacy of radiotherapy combined with immunotherapy in EC. Adjusting the radiotherapy target volume to protect immune function favors immunotherapy. However, there is no clear consensus on the exact definition of the EC target volume.

Areas covered: Preclinical studies have provided a wealth of information on immunotherapy combined with different radiotherapy modalities, and several clinical studies have evaluated the impact of immunotherapy combined with radiotherapy on locally advanced EC. Here, we illustrate the rational target volume delineation for radiotherapy in terms of patient prognosis, pattern of radiotherapy failure, treatment-related toxicities, tumor-draining lymph nodes, and systemic immunity and summarize the clinical trials of radiotherapy combined with immunotherapy in EC.

Expert opinion: We recommend applying involved-field irradiation (IFI) instead of elective nodal irradiation (ENI) for irradiated fields when immunotherapy is combined with chemoradiotherapy (CRT) for locally advanced EC. We expect that this target design will be evaluated in clinical trials to further explore more precise diagnostic modalities, long-term toxic responses, and quality of survival, and stratification factors for personalized treatment, and to provide more treatment benefits for patients.

Introduction: Less than half of the subjects with hypertension have been diagnosed and treated, with only 21% having their blood pressure under control. Many of the subjects find it difficult to adhere to daily antihypertensives. Zilebesiran reduces hepatic angiotensinogen messenger RNA levels to inhibit the renin-angiotensin-aldosterone system and is being developed as a long-acting anti-hypertensive agent.

Areas covered: KARDIA-1; a phase 2 clinical trial of zilebesiran with mild-to-moderate hypertension. Most doses of zilebesiran (150-600 mg) modestly reduced blood pressure from baseline to month 3. Adverse events included hyperkalemia and kidney failure.

Expert opinion: The main problem with zilebesiran is that it only has a modest effect on blood pressure, and it is likely to have to be used as add-on therapy, which will probably reduce any benefits on adherence it has. It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long term or (ii) will it be effective in a high sodium diet.

Introduction: Systemic treatment options for renal cell carcinoma (RCC) have expanded considerably in recent years, and both tyrosine kinase inhibitors and immune checkpoint inhibitors, alone or in combination, have entered the clinical arena. Adoptive cell immunotherapies have recently revolutionized the treatment of cancer and hold the promise to further advance the treatment of RCC.

Areas covered: In this review, we summarize the latest preclinical and clinical development in the field of adoptive cell immunotherapy for the treatment of RCC, focusing on lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, tumor-infiltrating T cells (TILs), TCR-engineered T cells, chimeric antigen receptor (CAR) T cells, and dendritic cell vaccination strategies. Perspectives on emerging cellular products including CAR NK cells, CAR macrophages, as well as γδ T cells are also included.

Expert opinion: So far, areas of greater therapeutic success of adoptive cell therapies include the adjuvant administration of CIK cells and the transfer of anti-CD70 CAR T cells in patients with metastatic RCC. Bench to bedside and back research will be needed to overcome current limitations of adoptive cell therapies in RCC, primarily aiming at improving the safety of immune cell products, optimizing their antitumor activity and generating off-the-shelf products ready for clinical use.

Background: Currently, adeno-associated viruses (AAVs) are the most commonly used in vivo gene therapy (GT) vector platform. Risks posed to the environment, including the public, have not been well studied in the past. There is uncertainty concerning the necessary level of biocontainment and appropriate hygiene behavior for the handling of secreta/excreta of GT patients during the shedding phase.

Research design and methods: Here, feces and urine samples from non-human primates, treated with an AAV9-based vector at 2 × 10¹³ vector genomes per kilogram body weight (vg/kg), were analyzed for vector presence and subsequently analyzed for their capacity to bind to cells.

Results: Both sample types contained particles which bound to cells at concentrations in the range of ~10⁴ (and higher) vg/mL of culture medium. Novel control rAAV vector displayed a ~2-3 orders of magnitude higher affinity to cells than shed particles.

Conclusions: The lower binding capacity of the shed vector particles speaks in favor of a more relaxed containment and hygiene approach in the context of GT. It is recommended that current hygiene and contact-avoidance-based containment measures after GT administration are reduced. The results also support the efforts to achieve a simplification of the regulatory review process of medicinal genetically modified organisms.

Introduction: Treatment of ulcerative colitis (UC) aims to reduce symptoms and complications by decreasing intestinal inflammation. A proportion of patients do not respond to, do not tolerate, or are inappropriate candidates for current therapies. Interleukin (IL)-23 is a therapeutic target and mirikizumabis the first p19-targeted IL-23 antibody approved for the treatment of moderately to severely active UC.

Areas covered: This review summarizes the pro-inflammatory effects of IL-23 and outlines the pharmacokinetics of mirikizumab. It provides a synopsis of the available phase II and phase III evidence for the efficacy and safety of mirikizumab in UC.

Expert opinion: The mirikizumab clinical development program demonstrated its superiority over placebo and its favorable safety profile in the treatment of UC. Its positioning in therapeutic algorithms remains to be fully understood but mirikizumab has proven efficacy in both advanced therapy (AT)-naïve and AT-experienced patients. The inclusion in the license of extended induction for non-responders as well as rescue intravenous dosing allows for flexibility in patient with limited primary response and secondary loss of response.

Introduction: Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adult patients. The landscape of CLL therapy has changed in the last decades with the introduction of antibody-based therapies and novel targeted agents resulting in improved outcomes.

Areas covered: This article describes the use of monoclonal antibodies, bispecific antibodies and antibody-drug conjugates in the treatment of relapsed and refractory CLL. The mechanism of action and clinical applications and safety of antibody-based therapies, both as monotherapy and in combination with other drugs, are discussed. A literature search was performed using PubMed, Web of Science, and Google Scholar for articles published in English. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Expert opinion: Antibody-based therapeutic strategies have drastically changed the treatment of CLL, as they have introduced the concept of boosting immune responses against tumor cells. While immunotherapy is generally effective, some treatment failure can occur due to antigen loss, mutation, or down-regulation, and this remains the main obstacle to cure. The development of novel antibody therapies, including their combinations with targeted drugs and bispecific antibodies, might help to reduce toxicity and improve efficacy.

Background: The dynamics of biological markets with multiple biosimilar competitors in the United States are poorly understood. Moreover, due to confidentiality issues, the relationship between originator biologic net prices, rebates, and biosimilar entry is largely unexplored.

Research design and methods: We conducted a review of the Food Drug Administration (FDA) purple book and manufacturer websites to identify all originator biologics with multiple competitors and their characteristics. We leveraged a novel data source to examine originator biologic net prices and rebates over time and used descriptive statistics and interrupted time-series analyses to assess their relationship with biosimilar entry.

Results: By December 2022, only five originator biologics had three or more available biosimilar competitors. Mean time between biosimilar approval and biosimilar launch was 9 months (SD = 7.04 months). By third biosimilar competitor, entry net prices for originator biologics had decreased by 9.34% to 50.93%, while rebates had increased by 25.35% to 89.71%.

Conclusions: Very few originator biologics have multiple available biosimilar competitors. Barrier to biosimilar availability seems to be at the approval level as the time between approval and launch is relatively short. However, originator biologics respond quickly to biosimilar competition, mainly through an increase in rebates.