Era Of Immunotherapy Research Articles

A randomized controlled study on perioperative treatment of esophageal squamous cell carcinoma with camrelizumab combined with nab-paclitaxel and cisplatin.

e16122 Background: Neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma (ESCC) has received increasing acceptance due to its effectiveness being confirmed by several phase II studies. CheckMate 577 has determined the efficacy of adjuvant immunotherapy in ESCC patients (pts) with R0 resection after neoadjuvant chemoradiotherapy. However, in the era of neoadjuvant immunotherapy, the optimal adjuvant treatment regimen for pts with ESCC warrant further research. This study aims to explore the efficacy and safety of perioperative treatment with camrelizumab combined with nab-paclitaxel and cisplatin for potentially resectable ESCC. Methods: This study planned to enroll 190 pts with potentially resectable stage II/III/IVa (cT1b-4aN0-3M0) ESCC. Eligible pts received 2-cycle of neoadjuvant camrelizumab (200mg, d1, q3w) combined with nab-paclitaxel (125mg/m2, d1,8, q3w) and cisplatin (75mg/m2, d1, q3w). Pts who reached pathologic complete remission (pCR) were randomly assigned to the immunotherapy group (camrelizumab for 16 cycles) and the best supportive care (BSC) group. Pts who did not reach pCR were randomly assigned to the immunochemotherapy group (camrelizumab combined with nab-paclitaxel and cisplatin for 2-4 cycles and camrelizumab for 12-14 cycles) and the immunotherapy group. Primary endpoints were pCR rate and 3-year DFS rate. Secondary endpoints were major pathologic response (MPR) rate, objective response rate (ORR), disease free survival (DFS), overall survival (OS). Results: As of Jan. 9th 2024, 121 pts (83 males and 38 females) with a median age of 65 years were enrolled in the study. One hundred and thirteen pts completed neoadjuvant treatment and 102 pts were available for imaging evaluation, the ORR was 91.9% and the DCR was 98.9%. Ninety six pts underwent surgery, 95 (98.9%) pts had a R0 resection, 32 (33.3%) pts reached pCR, 33 (34.3%) pts reached MPR. TNM down-staging was observed in 74 (77%) pts. Of 81 pts who underwent randomization, 30 pts reached pCR, 14 pts were randomly assigned to immunotherapy group, and 16 were assigned to BSC group. For 51 pts who did not reach pCR, 26 were randomized to the immunochemotherapy group and 25 were assigned to the immunotherapy group. At date cutoff, 5 pts (distant recurrence) relapsed in the immunochemotherapy group and 2 pts (distant recurrence) relapsed in the immunotherapy group who did not reach pCR. One hundred and twtety-one of 123 pts had AEs, and 33 pts had grade ≥3 AEs. The most common grade ≥3 AEs were anemia (9.9%), decreased lymphocyte count (7.4%), leukopenia (4.1%). Conclusions: This ongoing study again confirmed the safety and efficacy of neoadjuvant immunochemotherapy for resectable ESCC. Further data on optimal adjuvant treatment regimen for pts with or without residual disease will be reported in the future. Clinical trial information: NCT05182944 .

JCOG2002: A randomized phase III study of thoracic radiotherapy for extensive stage small cell lung cancer.

TPS8132 Background: Consolidative thoracic radiotherapy (cTRT) has shown a marginal improvement in overall survival (OS) and progression-free survival (PFS) for extensive-stage small-cell cancer (ES-SCLC). Consequently, ASTRO and NCCN guidelines conditionally recommend the use of cTRT. Despite the recent establishment of anti-PD-L1 antibody (aPD-L1) combined with platinum-doublet chemotherapy as the standard first-line treatment for ES-SCLC, the impact of cTRT in the era of immunotherapy remains uncertain. Methods: The JCOG2002 study, a randomized, multicenter phase 3 trial, initiated in October 2021 to assess the superiority of additional cTRT in terms of OS for ES-SCLC following induction aPD-L1 plus platinum doublet chemotherapy. Eligibility patients must meet criteria for the first registration including ES-SCLC, no prior radiation or chemotherapy history, age 20 or older, ECOG performance status 0 or 1, and adequate organ function. Induction treatment involves atezolizumab + carboplatin + etoposide or durvalumab + cisplatin / carboplatin + etoposide. Responding patients proceed to the second registration, randomization (1:1 between 30 Gy in 10 fractions of cTRT plus aPD-L1 maintenance therapy and maintenance therapy only). The cTRT targets metastatic lymph nodes in stations #1-7 and ipsilateral stations #10-12 identified at diagnosis. The adjustment factors include response to induction treatment (CR/PR versus SD), presence of brain metastasis (yes versus no), participating institutions, and aPD-L1 type (atezolizumab versus durvalumab). The primary endpoint is OS, with secondary endpoints being PFS and safety. The study aims to enroll 240 randomized patients, with 330 in the first registration, providing 80 % power at a one-sided 5 % significance level to detect a hazard ratio of 0.69 with 3-year accrual period and 1-year follow-up. As of February 6, 2024, 239 patients initiated induction treatment, and 121 have been randomized. This trial is registered at Japan Registry of Clinical Trials as jRCTs031210393 (https://jrct.niph.go.jp/detail/jRCTs031210393). Clinical trial information: jRCTs031210393 .

Emerging therapeutic options for follicular-derived thyroid cancer in the era of immunotherapy.

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

Multiple Myeloma: The Role of Autologous Stem Cell Transplantation in the Era of Immunotherapy.

Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years. Induction therapy, HDM-ASCT, and subsequent consolidation and maintenance therapy comprise the current fundamental framework for MM treatment. The introduction of anti-CD38 monoclonal antibodies such as daratumumab and isatuximab has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have become the new standard induction therapy. The treatment landscape of MM is undergoing a transformative shift with the introduction of potent new immunotherapies, such as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAbs), which are currently used in the relapsed/refractory setting (RRMM) and are already being tested in the NDMM. This review will focus on the incorporation of immunotherapy in the treatment scenario of NDMM patients eligible for ASCT.

Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

The role of conversion surgery in patients with unresectable biliary tract cancer who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. In this cohort study, patients with advanced biliary tract cancer who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months postinitiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (nonsurgical group). The median interval from the initial antitumor therapy to surgery was 6.7 [interquartile range (IQR) 4.9-9.2] months. Survival with conversion surgery was significantly longer than the nonsurgical cohort, with a median progression-free survival (PFS) [unreached vs. 12.4 months; hazard ratio 0.17 (95% CI: 0.06-0.48); P =0.001] and overall survival (OS) [unreached vs. 22.4 months; hazard ratio 0.28 (95% CI: 0.09-0.84); P =0.02], respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, eight patients survived without recurrence. The estimated 3-year OS, PFS, and recurrence-free survival rate in the surgical cohort were 59.9, 59.2, and 60.6%, respectively. The R0 resection rate reached 92.3%, with two achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS ( P =0.03) and PFS survival ( P =0.003). Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Surgical management of gastric cancer in the era of immunotherapy

With the widespread application of immune checkpoint inhibitors, chemotherapy combined with immunotherapy has shown promising efficacy in the treatment of various cancers. Especially gastric cancer, this strategy is gradually expanding from first-line treatment in advanced stages to perioperative management. Compared to neoadjuvant chemotherapy alone, the combined approach not only improves pathological regression but also leads to better downstaging, which is particularly significant in gastric cancer subsets that are HER2-positive, mismatch repair deficient, PD-L1 combined positive score ≥5, or EB virus-positive. This combined treatment has made it possible to reduce the extent of gastrectomy, perform function-preserving surgeries, or even consider non-surgical strategies. Currently, exploring the optimal protocols for combining immune checkpoint inhibitors with chemotherapy, identifying potential indications for function-preserving surgery, improving surgical methods, and developing non-surgical strategies represent key issues in the surgical management of gastric cancer in the era of immunotherapy.

Management of High-Risk Neuroblastoma with Soft-Tissue-Only Disease in the Era of Anti-GD2 Immunotherapy.

Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, MYCN or MDM2-CDK4 amplification, 11q, histology, diploidy with ALK or TERT mutations, and ATRX aberrations. Anti-GD2 immunotherapy has significantly improved the outcome of high-risk (HR) NB and is mostly effective against osteomedullary minimal residual disease (MRD), but less so against soft tissue disease. The question is whether adding anti-GD2 monoclonal antibodies (mAbs) benefits patients with HR-NB compounded by only soft tissue. We reviewed 31 patients treated at SJD for HR-NB with no osteomedullary involvement at diagnosis. All tumors had molecular genetic features of HR-NB. The outcome after first-line treatment showed 25 (80.6%) patients achieving CR. Thirteen patients remain in continued CR, median follow-up 3.9 years. We analyzed whether adding anti-GD2 immunotherapy to first-line treatment had any prognostic significance. The EFS analysis using Cox models showed a HR of 0.20, p = 0.0054, and an 80% decrease in the risk of relapse in patients treated with anti-GD2 immunotherapy in the first line. Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival.

Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion.

Cancer immune evasion represents a leading hallmark of cancer, posing a significant obstacle to the development of successful anticancer therapies. However, the landscape of cancer treatment has significantly evolved, transitioning into the era of immunotherapy from conventional methods such as surgical resection, radiotherapy, chemotherapy, and targeted drug therapy. Immunotherapy has emerged as a pivotal component in cancer treatment, harnessing the body's immune system to combat cancer and offering improved prognostic outcomes for numerous patients. The remarkable success of immunotherapy has spurred significant efforts to enhance the clinical efficacy of existing agents and strategies. Several immunotherapeutic approaches have received approval for targeted cancer treatments, while others are currently in preclinical and clinical trials. This review explores recent progress in unraveling the mechanisms of cancer immune evasion and evaluates the clinical effectiveness of diverse immunotherapy strategies, including cancer vaccines, adoptive cell therapy, and antibody-based treatments. It encompasses both established treatments and those currently under investigation, providing a comprehensive overview of efforts to combat cancer through immunological approaches. Additionally, the article emphasizes the current developments, limitations, and challenges in cancer immunotherapy. Furthermore, by integrating analyses of cancer immunotherapy resistance mechanisms and exploring combination strategies and personalized approaches, it offers valuable insights crucial for the development of novel anticancer immunotherapeutic strategies.

Clinical Controversies and Research Progress in Lymph Node Dissection for Cervical Cancer

Regional lymph node metastasis (LNM) is the main metastatic route of cervical cancer, whose rate of LNM increases in the cancer progression. LNM of cervical cancer is closely related to the cervical cancer staging, treatment method and prognosis. Lymph node dissection (LND) is an important part of standard cervical cancer staging surgeries. In recent years, Sentinel Lymph Node Biopsy (SLNB) has been used in treatments of some tumors, being considered as an alternative to Pelvic Lymph Node Dissection (PLND) in early-stage cervical cancer. However, validation regarding the feasibility of using SLNB alone as an alternative to PLND is still needed. Some scholars support PLND for patients with suspicious lymph nodes detected preoperatively due to reasons such as lower diagnostic sensitivity and specificity of preoperative imaging and potentially better prognosis for surgical staging of advanced stage of cervical cancer. However, recent basic research suggests that lymph nodes are important organs for providing tumor-specific immunity, the preservation of which facilitates immunotherapy. In this way, controversies about whether to use PLND still exist. This paper presents a brief review of the relevant research progress and discusses the new clinical definition and value of lymph nodes in the era of immunotherapy, with a view to providing new directions and ideas for the rational application of LND.

High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy.

Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.

Immunotherapy combined with cranial radiotherapy for driver-negative non-small-cell lung cancer brain metastases: a retrospective study.

Background: This study assesses immune checkpoint inhibitors' efficacy for non-small-cell lung cancer (NSCLC) with brain metastases (BM) and explores the role of cranial radiation therapy (CRT) in the immunotherapy era. Methods: The retrospective analysis screened NSCLC patients with BMs from July 2018 to December 2021. Treatment involved chemotherapy combined with immune checkpoint inhibitors as the first-line, with patients divided into CRT and non-CRT groups. Overall survival (OS), progression-free survival and intracranial progression-free survival were calculated and compared. Results: Among 113 patients, 74 who received CRT had significantly better median OS (not reached vs 15.31months), particularly among those with one to three BMs. Factors correlating with better OS included CRT, PD-L1 expression and diagnosis-specific graded prognostic assessment scores. Conclusion: Integrating CRT with anti-PD-1 therapy notably enhanced long-term survival in NSCLC patients with BMs.

Fasting and fasting-mimicking conditions in the cancer immunotherapy era.

Fasting and fasting-mimicking conditions modulate tumor metabolism and remodel the tumor microenvironment (TME), which could be exploited for the treatment of tumors. A body of evidence demonstrates that fasting and fasting-mimicking conditions can kill cancer cells, or sensitize them to the antitumor activity of standard-of-care drugs while protecting normal cells against their toxic side effects. Pre- and clinical data also suggest that immune responses are involved in these therapeutic effects. Therefore, there is increasing interest in evaluating the impact of fasting-like conditions in the efficacy of antitumor therapies based on the restoration or activation of antitumor immune responses. Here, we review the recent progress in the intersection of fasting-like conditions and current cancer treatments, with an emphasis on cancer immunotherapy.

CLO24-077: Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma in the Era of Immunotherapy: An Analysis of the National Cancer Database (NCDB).

CLO24-077: Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma in the Era of Immunotherapy: An Analysis of the National Cancer Database (NCDB).

Tumor neoantigens and tumor immunotherapies.

As a high-risk group of patients with cancer, the elderly exhibit limited efficacy with traditional treatments. Immunotherapy emerges as a promising adjunctive therapeutic approach that holds potential in addressing the needs of geriatric patients with cancer. Neoantigens, a unique class of tumor-specific antigens generated by non-synonymous mutations, are garnering increasing attention as targets for immunotherapy in clinical applications. Newly developed technologies, such as second-generation gene sequencing and mass spectrometry, have provided powerful technical support for the identification and prediction of neoantigens. At present, neoantigen-based immunotherapy has been extensively applied in clinical trials and has demonstrated both safety and efficacy, marking the beginning of a new era for cancer immunotherapy. This article reviews the conception, classification, inducers, and screening process of tumor neoantigens, as well as the application prospects and combination therapy strategies of neoantigen-based cancer immunotherapy.

A single-cell characterised signature integrating heterogeneity and microenvironment of lung adenocarcinoma for prognostic stratification

The high heterogeneity of tumour and the complexity of tumour microenvironment (TME) greatly impacted the tumour development and the prognosis of cancer in the era of immunotherapy. In this study, we aimed to portray the single cell-characterised landscape of lung adenocarcinoma (LUAD), and develop an integrated signature incorporating both tumour heterogeneity and TME for prognosis stratification. Single-cell tagged reverse transcription sequencing (STRT-seq) was performed on tumour tissues and matched normal tissues from 14 patients with LUAD for immune landscape depiction and candidate key genes selection for signature construction. Kaplan-Meier survival analyses and in-vitro cell experiments were conducted to confirm the gene functions. The transcriptomic profile of 1949 patients from 11 independent cohorts including nine public datasets and two in-house cohorts were obtained for validation. We selected 11 key genes closely related to cell-to-cell interaction, tumour development, T cell phenotype transformation, and Ma/Mo cell distribution, including HLA-DPB1, FAM83A, ITGB4, OAS1, FHL2, S100P, FSCN1, SFTPD, SPP1, DBH-AS1, CST3, and established an integrated 11-gene signature, stratifying patients to High-Score or Low-Score group for better or worse prognosis. Moreover, the prognostically-predictive potency of the signature was validated by 11 independent cohorts, and the immunotherapeutic predictive potency was also validated by our in-house cohort treated by immunotherapy. Additionally, the in-vitro cell experiments and drug sensitivity prediction further confirmed the gene function and generalizability of this signature across the entire RNA profile spectrum. This single cell-characterised 11-gene signature might offer insights for prognosis stratification and potential guidance for treatment selection. Support for the study was provided by National key research and development project (2022YFC2505004, 2022YFC2505000 to Z.W. and J.W.), Beijing Natural Science Foundation (7242114 to J.X.), National Natural Science Foundation of China of China (82102886 to J.X., 81871889 and 82072586 to Z.W.), Beijing Nova Program (20220484119 to J.X.), NSFC general program (82272796 to J.W.), NSFC special program (82241229 to J.W.), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012, 2022-I2M-1-009 to Z.W. and J.W.), Beijing Natural Science Foundation (7212084 to Z.W.), CAMS Key lab of translational research on lung cancer (2018PT31035 to J.W.), Aiyou Foundation (KY201701 to J.W.). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022003 to J.X.).

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

Abstract 873: Elucidating immune-related gene transcriptional programs via factorization of large-scale RNA profiles

Abstract Background: Despite the recent success in Immune checkpoint blockade (ICB) therapy, limited patients benefit due to immune-related adverse events or treatment resistance, especially in solid tumors. To overcome these hurdles, understanding the molecular mechanisms behind treatment response is essential. However, the current lack of immune gene transcriptional programs (GTPs) hampers data-driven immunological discovery. Constructing immunity-specific knowledgebases with rigorously curated gene sets (irGSs) and rich immunological language can unlock new insights, enabling interpretation of high-throughput immune microenvironment profiling studies and fostering personalized, effective cancer treatments. Methods: We collected 83 BulkRNAseq datasets from the ImmuneSigDB. These datasets contain 1826 samples challenged with infections, cytokines or immunological perturbations of different kinds and magnitude, possessing yet-to-be discovered immune functions that lie beneath the transcriptomic profiles. Using non-negative matrix factorization (NMF), we identified gene sets with coordinated expression. We used CITE-seq and selected scRNAseq to annotate the immunological functions of each gene set and validated the clinical utilities of these gene sets from different aspects using data from Cancer Genome Atlas Program (TCGA) pan-cancer, ICB cohorts and a 10X Genomics Visium FFPE Human Breast Cancer spatial slide. Results: We presented 19 lymphoid-data derived and 9 myeloid-data derived gene sets (irGSs), encompassing a diverse array of immune functions. Through extensive validation using BulkRNAseq, scRNAseq and spatial transcriptomics data, we revealed six irGSs-defined pan-cancer microenvironment subtypes in TCGA with significantly distinct survival patterns regardless of cancer types. Moreover, irGSs are associated with T cell exhaustion phenotypes, which in turn well predicted (classification accuracy of 72%) Nivolumab response using 104 treatment-naïve melanoma patients. Lastly, irGSs simultaneously isolated out tumor regions and highlighted immune infiltration with high specificity in breast cancer spatial transcriptomics H&amp;E image. Conclusions: These pioneering gene sets, originally derived from non-cancerous experiments, hold tremendous promise for cancer research across diverse contexts. Similarities between cancerous and sepsis immune microenvironments underscore their wide applicability. By studying gene set activities, immunologists can gain profound insights into cancer survival drivers, unravel the intricacies of ICB treatment mechanisms, and potentially conquer therapeutic resistance. These translational utilities herald a transformative era in cancer immunotherapy and open new frontiers in the fight against cancer. Citation Format: Shan He, Vakul Mohanty, Matthew Gubin, Hind Rafei, Rafet Basar, Merve Dede, Xianli Jiang, Yukun Tan, Maura Gillison, Katayoun Rezvani, Weiyi Peng, Ken Chen. Elucidating immune-related gene transcriptional programs via factorization of large-scale RNA profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 873.

Primary results of the AGO-Zervix-1 Study: A prospective, randomized phase III study to compare the effects of paclitaxel and topotecan with those of cisplatin and topotecan in the treatment of patients with recurrent and persistent cervical cancer

BackgroundBefore the era of immunotherapies and antibody–drug conjugates, there were limited chemotherapeutic options for patients with recurrent and metastatic cervical cancer. Combination therapies with cisplatin have shown some superiority over monotherapy. This study examined platinum-free treatment regimens, comparing a combination of topotecan and paclitaxel (TP) with topotecan and cisplatin (TC) in patients with recurrent or metastatic cervical cancer, with or without prior platinum-based treatment. MethodsThe AGO-Zervix-1 Study (NCT01405235) is a prospective, randomized phase III study in which patients were randomly assigned at a 1:1 ratio to treatment within the control arm with topotecan (0.75 mg/m2) on days 1–3 and cisplatin (50 mg/m2) on day 1 every 3 weeks and in the study arm topotecan (1.75 mg/m2) and paclitaxel (70 mg/m2) on days 1, 8, and 15 every 4 weeks or treatment. The primary study aim was overall survival; progression-free survival, toxicity, and quality of life were secondary aims. The interim and final analysis is here reported after recruitment of 173 of 312 planned patients. ResultsMedian overall survival in the TP arm was 9.6 months, compared with 12.0 months in the TC arm (log-rank test, P = 0.33). Median progression-free survival rates were 4.4 months with TP and 4.2 months with TC (log-rank test, P = 0.47). Leukopenia and nausea/vomiting were more frequent in the cisplatin-containing arm. Otherwise, toxicity profiles were comparable. There were no differences in FACT-G–assessed quality of life. ConclusionPlatinum-based combination chemotherapy remains the standard of care chemotherapy regimen for patients with recurrent or metastatic cervical cancer.

Impact of Center Volume on Cardiopulmonary and Mortality Outcomes after Immune-Checkpoint Inhibitors for Cancer: A Systematic Review and Meta-Analysis.

Immune-checkpoint inhibitors (ICIs) were proven effective in inducing tumor regression. However, its toxicity tends to be fatal. We sought to investigate the hospital volume/outcomes relationship. Databases were searched for studies reporting immune-checkpoint inhibitors adverse events (AEs) in patients with solid-organ malignancies. The outcomes were A) the pooled events rate (PER) of grade 5, grade 3-4, cardiac-related, and pulmonary-related AEs, and B) the assessment of the volume/outcomes relationship. One hundred and forty-seven studies met our inclusion criteria. The PER of grade 5, grade 3-4, and any-grade AEs was 2.75% (95%CI: 2.18-3.47), 26.69% (95%CI: 21.60-32.48), and 77.80% (95%CI: 70.91-83.44), respectively. The PER of pulmonary-related AEs was 4.56% (95%CI: 3.76-5.53). A higher number of annual cases per center was significantly associated with reduced grade 5 (p = 0.019), grade 3-4 (p = 0.004), and cardiac-related AEs (p = 0.035) in the meta-regression. In the current era of cancer immunotherapy, knowledge regarding the early diagnosis and management of immunotherapy-related AEs is essential. Our meta-analysis demonstrates the importance of center volume in improving outcomes and reducing the incidence of severe AEs.

Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells

The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.