Journal of Immunotherapy and Precision Oncology最新文献

Introduction: Enadenotucirev (EnAd) and successor transgene-armed Tumor-Specific Immuno-Gene (T-SIGn) vectors are replication-competent, blood-stable viral vectors that traffic to tumor sites following intravenous (IV) administration. Following initial proof of mechanism for this immunotherapy modality, there is a need to identify a safe dosing approach, understand whether transgenes affect tolerability, and determine how to measure exposure and pharmacodynamic effects.

Methods: Safety data from multiple phase 1 trials were aggregated to assess various dosing regimens and toxicities, including those that may be associated with transgene arming. Viral delivery to tumors, peripheral viral persistence, transgene expression, and cytokine responses were also assessed and compared between the unarmed EnAd and armed T-SIGn vectors.

Results: IV administration of EnAd and the armed T-SIGn vectors led to virus detection in epithelial tumors and prolonged peripheral virus persistence. Despite the short half-life of the viruses and cell-free nucleic acids, viral DNA or transgene messenger RNA (mRNA) remained detectable in blood at higher dose levels for at least 56 days, indicating sustained release of these molecules likely driven by ongoing viral replication and concomitant transcription of the transgene in tumors. Safety, predominantly defined by the effects of IV administration and associated viremia, was managed by a well-tolerated dosing regimen. To date, no transgene-related or off-target toxicities have been observed. Transient monocyte chemoattractant protein 1 (MCP-1) and interleukin (IL)-6 elevations were associated with viremia. A second phase of elevations of proinflammatory cytokines such as IL-12p70, interferon (IFN) α2, IL-17A, and IFNγ without clinical symptoms started around day 12, suggesting that release of these cytokines was driven by localized pharmacodynamic effects within the tumor microenvironment (TME).

Conclusion: Armed T-SIGn vectors exhibit the same high tumor selectivity and replicative activity as the unarmed parent EnAd and achieve consistent viral delivery to a broad range of epithelial tumor tissues. The aggregated safety analysis revealed that safety and tolerability are defined by systemic viremia but not off-target or transgene-related toxicities. Nucleic acid and cytokine release from tumors and changes in the TME (e.g., CD8+ T cells), indicative of the mechanism of action of replication-competent viral vectors, constitute potentially valuable data to support the definition of a recommended phase 2 dose and the assessment of the benefit of multicycle administration.

Introduction: This study aims to document patient characteristics, treatment modalities, and survival outcomes of patients with lung cancer in Vietnam from 2018 to 2024.

Methods: This was a retrospective study of patients with lung cancer treated at Nghe An Oncology Hospital over a 6-year period (2018-2024). The primary endpoints included lung cancer treatment methods for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and overall survival (OS). Secondary endpoints involved factors related to survival duration.

Results: A total of 3548 patients were included: 3087 with NSCLC (87%) and 419 with SCLC (11.8%) (median age 64 years, range 18-97 years; 3:1 male-to-female ratio). Adenocarcinoma (AC) was the predominant histologic subtype (67%), followed by squamous cell carcinoma (SCC) (13.4%). EGFR mutation was detected in 43.2% of cases. From 2018 to 2024, the proportion of early-stage lung cancer diagnoses (stages I and II) increased from 2.7% to 9%, and the detection rate of advanced or metastatic stages (stages III and IV) decreased. Surgery was the primary treatment for localized NSCLC (62.5%), and stage III cases predominantly received radiation and chemotherapy (40.8%), including 38.6% with concurrent chemoradiotherapy. In stage IV NSCLC, chemotherapy was the most common treatment (53.9%), followed by targeted therapy (25.2%) and immunotherapy (1.9%). SCLC was mostly diagnosed at the extensive stage (68.0%), with chemotherapy being the mainstay of treatment (73.0%), followed by chemoradiotherapy (12.9%) and palliative care (13.1%). Median OS was 15.3 months (95% CI, 14.5-16.1), with a 5-year survival rate of 14.2%. Median OS for NSCLC cases was 16.4 months (95% CI, 15.4-17.4), with 5-year survival rates of 55.2%, 47.6%, 20.2%, and 8.3% for stages I, II, III, and IV, respectively. Median OS for SCLC cases was 11.0 months (95% CI, 9.7-12.4), with a 5-year survival rate of 4.7%. Independent prognostic factors for mortality included male sex, poor performance status (PS ≥ 2), small cell histology, metastatic disease, brain metastases, and initial nonsurgical treatment.

Conclusion: This study provides critical data on the epidemiology and prognosis of lung cancer in Vietnam, highlighting the role of personalized treatment approaches in improving clinical outcomes. These findings underscore the urgent need for integrated public health strategies to enhance early detection and access to advanced therapies, thereby reducing the lung cancer burden in Vietnam.

Over the past decade, the discovery of immunotherapy and targeted therapy has set new standards for the management of advanced non-small cell lung cancer (NSCLC). This study aims to investigate the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC within the Middle East and North Africa (MENA) region and to assess the current state of molecular testing and targeted treatments in the Gulf Cooperation Council (GCC) region. The systematic literature review was performed using PubMed, Google Scholar, and Google searches to identify studies on the prevalence of ALK, EGFR, KRAS, ROS1, MET, BRAF, and HER2 mutations in patients with NSCLC in the MENA region. Additionally, 10 experts from the GCC region were interviewed to provide insights into molecular mutation testing, the challenges faced, and the current approaches to targeted therapies. The prevalence of ALK, EGFR, KRAS, ROS1, MET, and BRAF mutations was 7.9% (95% CI, 6.69-9.03%), 24% (95% CI, 22.05-25.41%), 19.7% (95% CI, 15.29-24.07%), 2.2% (95% CI, 0.77-3.57%), 4.7% (95% CI, 2.29-7.07%) and 3.7% (95% CI, 1.54-5.80%), respectively. HER2 mutation data were unavailable. Treatment generally adhered to international guidelines, with therapy selection based on tumor stage, molecular profile, and drug availability. Expert opinions highlighted significant advancements in molecular diagnostics and targeted therapies but also pointed out the challenges in standardizing and implementing these techniques across the GCC region. This review underscores the importance of personalized and region-specific approaches to NSCLC treatment, given the significant differences in mutation patterns in the MENA region. Further research is needed to gain a more comprehensive understanding of the prevalence and effect of driver mutations across broader MENA countries to inform future treatment strategies.

Introduction: Patients with advanced solid tumors may be considered for early phase clinical trials investigating the safety, tolerability, and dosing of experimental therapies. Optimizing participant selection is critical to maximize clinical benefit and meet trial endpoints with fewer participants. One in six participants does not meet routine life expectancy requirements (>3 months), highlighting the need for improved prognostication. Variant allele frequency (VAF) in circulating tumor DNA (ctDNA) correlates with overall survival (OS) in advanced solid tumors. We aimed to derive an optimal VAF threshold as a prognostic biomarker to enhance participant selection.

Methods: ctDNA testing was performed as part of the TARGET (NIHR Clinical Research Network CPMS ID 39172) and TARGET National (NCT04723316) prospective cohort studies, in patients with advanced solid tumors referred for early phase clinical trials. Maximum (maxVAF) and mean VAF (meanVAF) were compared in their association with OS and ability to delineate favorable and poor outcomes at set threshold points using hazard ratios (HRs). Optimal thresholds of VAF were explored using receiver operating characteristic curve analysis to predict 3-month landmark OS. Univariable and multivariable analysis was performed to determine whether VAF was an independent prognostic marker.

Results: Of 631 patients, 587 had evaluable ctDNA results. MeanVAF and maxVAF exhibited similar correlation with OS (r_s = -0.32 vs -0.35, respectively) and similar prognostic utility at matched threshold points. A maxVAF value of 4% was selected as optimal for prognostic subgrouping (area under curve 0.77). OS was 5.9 versus 12.1 months (p < 0.0001) for patients with more than 4% and 4% or less maxVAF, respectively. Multivariable analysis confirmed more than 4% maxVAF as independently associated with reduced 3-month landmark OS (HR 2.17 [1.76-2.70], p < 0.001).

Conclusion: VAF is an independent prognostic marker in patients with advanced solid tumors, with 4% maxVAF deemed optimal for delineating favorable and poorer prognostic subgroups in this patient cohort. Further validation and integration into existing prognostic scores are warranted.

The combination of targeted therapies and immunotherapies for advanced and metastatic sarcomas has been proposed owing to the enhanced effect of antiangiogenic therapies on the tumor microenvironment. We found eight studies published to date assessing the effectiveness of combined multitargeted vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors with immune checkpoint inhibitors (ICIs) in sarcoma. It is difficult to draw conclusions owing to limited data and primarily single-arm studies, although initial literature appears promising and requires further study. It remains unknown which sarcoma subtypes may derive the most benefit owing to the limited literature. Benefit was seen primarily in angiosarcoma (AS) and alveolar soft part sarcoma (ASPS), as well as in other tumor subtypes, with few patients achieving complete response (CR). The patients who achieved CRs had desmoplastic small round cell tumor (DSRCT), AS, and chondrosarcoma (CS). Mixed results were found in patients with leiomyosarcoma (LMS), gastrointestinal stromal tumor (GIST), and bone sarcomas, although combination therapy appears to be less effective in these subtypes. Further studies are required to explore optimal treatment agents and dosing strategies to improve both efficacy and tolerability. Although initial results are promising in select patients, phase 3 randomized controlled trials are necessary to determine true treatment effect with combination therapy versus VEGF-inhibitor or ICI alone.

Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC) with limited treatment options and poor prognosis. EGFR mutations generally respond to tyrosine kinase inhibitors (TKIs)-based targeted therapy but are typically associated with resistance to immunotherapy. We report a case of oligometastatic PSC harboring compound EGFR mutations (p.G719C and S768I). The patient exhibited disease progression despite sequential treatment with EGFR TKIs, including osimertinib, afatinib, and mobocertinib, in combination with chemotherapy. The treatment strategy was then shifted to immunotherapy with pembrolizumab alongside carboplatin and paclitaxel, leading to a remarkable response. Given the oligometastatic nature of the disease and the sustained response, bilateral adrenalectomy was performed, revealing a complete pathological response. The patient remains disease-free posttreatment, with no evidence of recurrence on follow-up imaging. This case challenges the conventional paradigm that EGFR-mutated NSCLC does not benefit from immunotherapy, highlighting the potential for an alternative treatment approach in rare subtypes such as PSC. Our findings emphasize the importance of comprehensive molecular profiling and a personalized treatment strategy to optimize outcomes in aggressive and refractory lung cancers.

Comprehensive genomic profiling (CGP) and the subsequent discussions in molecular tumor boards (MTBs) are becoming an integral part of personalized cancer care. The patient with metastatic renal cell carcinoma (mRCC) presented here demonstrated an absence of a favorable response accompanied by adverse events after receiving dual immunotherapy with nivolumab plus ipilimumab in combination with a poly (adenosine diphosphate-ribose) polymerase inhibitor, niraparib. This determination was made based on the initial CGP report and the initial MTB. Following the progression of the disease and the emergence of immune-related adverse events, a second CGP was conducted, and several subsequent MTBs were held. The decision was made to transition the patient's treatment to temsirolimus plus bevacizumab, with the rechallenge of immunotherapy with pembrolizumab. The response evaluation revealed a complete radiographic and molecular response. This case study underscores the mounting significance of precision oncology in the management of mRCC, thereby suggesting that mammalian target of rapamycin inhibitor may augment the efficacy of immunotherapy in select patients based on their genomic findings. A digital poster of this case is included in the supplemental materials.