Expert Review of Anticancer Therapy最新文献

Introduction: The outcome of immune checkpoint inhibition (ICI) therapy of cancer appears to be influenced by the gut microbiota composition of the patient. Microbiome-based therapy by fecal microbiota transplantation (FMT) appears to improve the outcome of ICI therapy. The ideal composition of the microbiota as well as treatment schedule are not yet established.

Areas covered: The most recently published studies are reviewed, as well as the study designs of registered clinical trials which are ongoing. The effect of pretreatment of patients with antibiotics, aimed to improve engraftment of the transplant, is evaluated.

Expert opinion: The optimal treatment schedule would be to start with FMT, followed by ICI, implying FMT should be given to ICI naive patients. Rather than donor derived FMT, defined consortia of microbiota could be preferred.

Introduction: Razoxane, discovered in the 1960s, was evaluated as a topoisomerase II inhibitor to treat cancer. Cancer therapeutic models of the mid-1900's were based on the following three assumptions: treatment agents should demonstrate activity as a single agent, should reduce tumor size, or could exacerbate tumor hypoxia. Razoxane fulfilled none of these requirements.

Areas covered: Although well-tolerated, safe, and approved for cancer treatment, Razoxane lacks the cell-killing activity exhibited by other agents and was a commercial failure. It blocks the cell cycle at G2/M boundary, leading to cell cycle synchrony where radiation and chemotherapeutics are most effective. Daughter chromatid separation is inhibited; metaphase clefts do not form; and cells continue to synthesize DNA and become polyploidal, polynucleate, and hypertrophic, demonstrating a senescent phenotype where weakened cells are removed. Cell proliferation halts, allowing neovasculature to mature with structured endothelial lining and reduced sinusoids, thus eliminating a major route by which tumor cells enter the bloodstream and metastasize.

Expert opinion: Blockade of the cell cycle at G2/M maximizes DNA alteration in response to therapy; improved oxygenation enhances the generation of reactive oxygen species during polytherapy; and increased vascularity facilitates synergy with radiation and chemotherapy by improving drug delivery.

Background: Cancer survivors experience disproportionate burdens of health-related social needs (HRSNs), yet the mortality implications of cumulative HRSN burden remain poorly characterized.

Research design and methods: We analyzed 3643 adult cancer survivors from the 1999-2018 National Health and Nutrition Examination Survey. HRSNs burden was assessed based on eight indicators. Cox proportional hazard models were applied to estimate the associations between cumulative number of unmet HRSNs and all-cause, cardiovascular disease (CVD), and cancer mortality, reporting hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Over a median 85-month follow-up, 1304 (24.99%) participants died, including 433 from cancer and 334 from CVD. Compared to those with 0-1 unmet HRSN, HRs (95% CIs) for participants with 6-8 unmet HRSNs were 4.01 (2.89-5.58) for all-cause mortality, 2.34 (1.08-5.06) for CVD mortality, and 4.00 (2.41-6.64) for cancer mortality. Restricted cubic spline curves found no evidence of non-linear relationships between unmet HRSNs count and all-cause, CVD, and cancer mortality. Associations between HRSN burden and all-cause and cancer mortality were more pronounced in participants under 60 years of age.

Conclusion: Cumulative HRSN burden is associated with mortality risk among cancer survivors, particularly younger adults. Routine HRSNs assessment should be integrated into survivorship care to identify high-risk patients.

Introduction: Tenosynovial giant cell tumor (TGCT) is a rare, benign neoplasm driven by overexpression of colony-stimulating factor 1 (CSF-1), which recruits CSF-1 receptor (CSF-1 R)-bearing macrophages and other inflammatory cells to promote tumor formation. While surgery remains the first-line treatment for TGCT, many patients experience unresectable or recurrent disease with high morbidity, highlighting the need for effective systemic treatments.

Areas covered: This review summarizes the molecular pathogenesis, diagnostic approach, and evolving systemic treatment landscape for TGCT, with a focus on treatments directed at CSF-1/CSF-1 R inhibition. Relevant literature published between 2005 and 2025 was identified through PubMed searches and manual review of reference lists. Clinical efficacy and safety data for approved and investigational CSF-1/CSF-1 R inhibitors, including pexidartinib, vimseltinib, and emerging agents, are discussed.

Expert opinion: Pexidartinib and vimseltinib demonstrate comparable efficacy in TGCT with objective response rates (ORR) of 39% and 40%, respectively, at week 25 of treatment; however, vimseltinib offers improved hepatic safety and tolerability, supporting its use as the preferred first-line systemic therapy. Emerging agents, including pimicotinib and emactuzumab, show potential for higher response rates and favorable safety profiles and may further reshape the TGCT treatment paradigm pending phase 3 trial results.

Introduction: Chimeric antigen receptor T (CAR-T) therapy represents a significant advance in the treatment of hematologic malignancies, yet its global implementation remains limited by regulatory, logistical, and manufacturing challenges. Understanding differences among international regulatory frameworks is essential for expanding safe and equitable access, particularly in emerging academic programs.

Areas covered: This review examines the regulatory pathways, manufacturing requirements, and quality standards governing CAR-T therapies in Brazil, comparing them with those in the United States and the European Union. A focused literature search encompassed peer-reviewed articles, institutional guidelines, and regulatory documents from 2016 to 2025. Key elements assessed include GMP expectations, analytical method validation, biosafety considerations, and infrastructure requirements. The analysis also explores expanded-access mechanisms and summarizes clinical experiences that have used these pathways in the real world.

Expert opinion: Despite structural differences, all jurisdictions converge on core principles emphasizing product quality, long-term safety, and traceability. However, Brazil faces unique multi-agency coordination requirements and infrastructural constraints that may delay national deployment. Global evidence indicates that strengthening GMP facilities, analytical validation strategies, and harmonized regulatory processes, particularly for academic and point-of-care manufacturing, will be crucial to broaden access and sustain innovation in CAR-T therapies.

Introduction: The rapid progress of immuno-oncology has transformed cancer pharmacotherapy through immune checkpoint inhibitors (ICIs); however, only a minority of patients experience durable benefits. Recent evidence suggests that concomitant administration of H1 antihistamines may synergistically enhance ICI efficacy by modulating the tumor immune microenvironment. This meta-analysis evaluated the association between H1 antihistamine use and outcomes in cancer patients undergoing ICI therapy.

Methods: Comprehensive searches were conducted in PubMed, Embase, and Web of Science to identify studies comparing overall survival (OS) and progression-free survival (PFS) between ICI users with and without H1 antihistamines. Pooled hazard ratios (HRs) were calculated using a random-effects model (REML) in R software (v4.4.2).

Results: Six retrospective cohort studies encompassing 2166 patients (417 antihistamine users and 1749 non-users) were included, primarily involving lung cancer (34.5%) and melanoma (13%). H1 antihistamine use was significantly associated with improved OS (HR = 0.64; 95% CI 0.42-0.97; p = 0.035) and PFS (HR = 0.54; 95% CI 0.44-0.66; p < 0.001).

Conclusions: These findings indicate that H1 receptor blockade may potentiate the therapeutic efficacy of ICIs, resulting in better survival and delayed disease progression. The integration of antihistamines with ICIs may represent a promising and cost-effective adjunct strategy in cancer immunotherapy.

Registration: PROSPERO (CRD420251207396).

Introduction: ROS1 fusion - positive non-small cell lung cancer (NSCLC) represents a rare but clinically important subset, occurring in 1-2% of patients and often associated with younger, never-smoker populations. Current first-generation tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib provide meaningful benefit but are limited by poor central nervous system (CNS) penetration and the development of resistance mutations, particularly G2032R.

Areas covered: This review evaluates the development, pharmacologic properties, and clinical outcomes of taletrectinib, a next-generation ROS1 inhibitor recently approved by the FDA. Taletrectinib demonstrated high objective response rates in both TKI-naïve (88.8%) and TKI-pretreated (55.8%) patients, including robust intracranial activity and efficacy against the G2032R mutation. The safety profile is favorable, with predominantly low-grade gastrointestinal and hepatic adverse events and minimal neurologic toxicity.

Expert opinion: Taletrectinib addresses major limitations of earlier ROS1 inhibitors by combining systemic potency, CNS activity, and tolerability. While its approval represents a significant advance for ROS1+ NSCLC, challenges remain, including resistance mechanisms such as L2086F, limited global access, and the absence of phase III confirmatory trials. Ongoing research into sequencing strategies, resistance profiling, and novel combination regimens will be essential to optimize patient outcomes.

Introduction: Zolbetuximab is a first-in-class monoclonal antibody targeting claudin 18.2 (CLDN18.2) demonstrating clinical benefit in gastroesophageal adenocarcinomas. CLDN18.2 is a gastric lineage-restricted tight-junction protein normally concealed in healthy gastric mucosa but aberrantly exposed on tumor cells due to polarity loss following malignant transformation. Unlike canonical oncogenic drivers, CLDN18.2 has no known oncogenic signaling role and serves as a therapeutic anchor rather than a target for tumor growth inhibition.

Areas covered: This review synthesizes preclinical, translational, and clinical evidence to clarify zolbetuximab's mechanism of action. Preclinical studies demonstrated that antitumor efficacy is mediated through immune effector pathways - antibody-dependent cellular cytotoxicity (ADCC) via NK cells and complement-dependent cytotoxicity (CDC). The effect requires high antigen density and is enhanced by chemotherapy-induced CLDN18.2 upregulation. Phase I pharmacodynamic studies confirmed that (i) patients retain intact NK and complement function, (ii) ADCC and CDC are rapidly engaged following infusion, and (iii) activity persists across the dosing interval.

Expert opinion: Zolbetuximab exemplifies a novel therapeutic class which can be classified as targeted cytolytic antibodies. Future work should test combinations with checkpoint blockade, refine biomarkers, and define resistance mechanisms.

Introduction: Angiogenesis, the formation of new blood vessels from existing ones, plays a critical role in cancer development and progression. Given its significance, inhibiting angiogenesis has emerged as a key strategy in anticancer therapy.

Areas covered: This review outlines the biological process of angiogenesis and explores the clinical development of anti-angiogenic therapies across various cancer types. A comprehensive literature search was conducted focusing on approved therapies, emerging agents, combination strategies, and clinical outcomes. The review highlights current limitations, including variable efficacy, drug resistance, and associated toxicities. It also examines recent advances such as biomarker discovery, synergistic combinations with immunotherapy, and novel therapeutic targets.

Expert opinion: Although anti-angiogenic agents have transformed certain aspects of cancer therapy, their full potential remains unrealized. Future strategies should focus on personalized approaches aided by predictive biomarkers, and rational combinations to enhance efficacy and reduce resistance.