Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence.

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.

Principles of risk assessment in colon cancer: immunity is key.

In clinical practice, the administration of adjuvant chemotherapy (ACT) following tumor surgical resection raises a critical dilemma for stage II colon cancer (CC) patients. The prognostic features used to identify high-risk CC patients rely on the pathological assessment of tumor cells. Currently, these factors are considered for stratifying patients who may benefit from ACT at early CC stages. However, the extent to which these factors predict clinical outcomes (i.e. recurrence, survival) remains highly controversial, also uncertainty persists regarding patients' response to treatment, necessitating further investigation. Therefore, an imperious need is to explore novel biomarkers that can reliably stratify patients at risk, to optimize adjuvant treatment decisions. Recently, we evaluated the prognostic and predictive value of Immunoscore (IS), an immune digital-pathology assay, in stage II CC patients. IS emerged as the sole significant parameter for predicting disease-free survival (DFS) in high-risk patients. Moreover, IS effectively stratified patients who would benefit most from ACT based on their risk of recurrence, thus predicting their outcomes. Notably, our findings revealed that digital IS outperformed the visual quantitative assessment of the immune response conducted by expert pathologists. The latest edition of the WHO classification for digestive tumor has introduced the evaluation of the immune response, as assessed by IS, as desirable and essential diagnostic criterion. This supports the revision of current cancer guidelines and strongly recommends the implementation of IS into clinical practice as a patient stratification tool, to guide CC treatment decisions. This approach may provide appropriate personalized therapeutic decisions that could critically impact early-stage CC patient care.

The Prognostic Immune and Nutritional Indices Are Independent Prognostic Factors for Esophageal Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: Recently, the prognostic immune and nutritional index (PINI) was developed and reported to be a promising nutritional and inflammatory prognostic marker. The aim of the present study was to clarify the clinical impact of the PINI for esophageal cancer patients who received curative treatment. PATIENTS AND METHODS: We conducted a retrospective review of medical records and collected data on consecutive esophageal cancer patients who underwent curative resection at Yokohama City University between 2005 and 2020. The PINI was calculated by dividing the serum ALB concentration (g/dl) by the serum monocyte concentration, both of which were measured before surgery. RESULTS: A total of 180 patients were included in this study. The cutoff value of the PINI was 3.0 in the present study. The 3- and 5-year overall survival rates were 45.2% and 33.5%, respectively, in the PINI-low subgroup, and 69.1% and 61.8%, respectively, in the PINI-high subgroup. A multivariate analysis demonstrated that the PINI was an independent prognostic factor for overall survival (hazard ratio=2.091, 95% confidence interval=1.287-3.399, p=0.003). Similar results were observed for recurrence-free survival. When comparing the sites of recurrence between the two groups, the incidence of hematological recurrence was significantly greater in the PINI-low subgroup compared to the PINI-high subgroup (46.8% vs. 21.1%, p<0.001). CONCLUSION: The PINI is a promising nutritional and inflammatory marker for esophageal cancer patients. The PINI might be a useful marker for the treatment and management of esophageal cancer patients.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Identification of a Gene Expression Signature to Predict the Risk of Early Recurrence and the Degree of Immune Cell Infiltration in Triple-negative Breast Cancer.

BACKGROUND/AIM: Patients with triple-negative breast cancer (TNBC) have a high rate of recurrence within 3 years of diagnosis and a high rate of death within 5 years compared to other subtypes. The number of clinical trials investigating various new agents and combination therapies has recently increased; however, current strategies benefit only a minority of patients. This study aimed to identify specific genes that predict patients at high risk of recurrence and the immune status of the tumor microenvironment at an early stage, thereby providing insight into potential therapeutic targets to improve clinical outcomes in TNBC patients. MATERIALS AND METHODS: We evaluated the prognostic significance of microarray mRNA expression of 20,603 genes in 233 TNBC patients from the METABRIC dataset and further validated the results using RNA-seq mRNA expression data in 143 TNBC patients from the GSE96058 dataset. RESULTS: Eighteen differentially expressed genes (AKNA, ARHGAP30, CA9, CD3D, CD3G, CD6, CXCR6, CYSLTR1, DOCK10, ENO1, FLT3LG, IFNG, IL2RB, LPXN, PRKCB, PVRIG, RASSF5, and STAT4) identified in both datasets were found to be reliable biomarkers for predicting TNBC recurrence and progression. Notably, the genes whose low expression was associated with increased risk of recurrence and death were immune-related genes, with significant differences in levels of immune cell infiltration in the tumor microenvironment between high- and low- expression groups. CONCLUSION: Genes reported herein may be effective biomarkers to identify TNBC patients who will and will not benefit from immunotherapy and may be particularly important genes for developing future treatment strategies, including immunotherapy.

Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ.

BACKGROUND AND AIM: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. METHODS: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls). RNA was extracted from DCIS samples and subjected to next-generation sequencing gene expression analysis of 395 immune-related genes. Correlations between DCIS immune-related gene expression and IBE were analyzed using weighted Cox regression for nested case-control data. RESULTS: Eight immune-related genes were differentially expressed between cases and controls. MAGEA10 expression (present vs. absent) and high expression levels of IFNA17 and CBLB (Q4 vs. Q1) were observed more frequently in DCIS of women with subsequent IBE, mainly invasive (p-valueFDR < 0.05). Conversely, expression of IL3RA1, TAGAP, TNFAIP8, and high expression levels of CCL2 and LRP1 were associated with a lower risk of IBE (p-valueFDR < 0.05). CONCLUSION: This exploratory analysis of pure DCIS showed significant differences in immune-related gene expression profiles between women with and with no subsequent IBE, particularly as invasive IBE. These results, after additional validation, could improve risk stratification and management of DCIS patients.

Hybrid Ginseng-derived Extracellular Vesicles-Like Particles with Autologous Tumor Cell Membrane for Personalized Vaccination to Inhibit Tumor Recurrence and Metastasis.

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice.

BACKGROUND: Liver-resident natural killer (lr-NK) cells are distinct from conventional NK cells and exhibit higher cytotoxicity against hepatoma via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). However, the mechanism by which partial hepatectomy (PH) significantly suppresses TRAIL expression in lr-NK cells remains unclear. METHODS: This study aimed to investigate the PH influence on the function and characteristics of liver-resident NK (lr-NK) cells using a PH mouse model. RESULTS: Here, we report that PH alters the differentiation pattern of NK cells in the liver, and an aryl hydrocarbon receptor (AhR) molecule is involved in these changes. Treatment with the AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) inhibited the maturation of NK cells. FICZ increased the immature subtype proportion of NK cells with high TRAIL activity and decreased the mature subtype of NK cells with low TRAIL activity. Consequently, FICZ increased the expression of TRAIL and cytotoxic activity of NK cells in the liver, and this effect was confirmed even after hepatectomy. The participation of AhR promoted FoxO1 expression in the mTOR signaling pathway involved in the maturation of NK cells, resulting in TRAIL expression. CONCLUSION: Our findings provide direct in-vivo evidence that partial hepatectomy affects lrNK cell activity through NK cell differentiation in the liver. Perioperative therapies using an AhR agonist to improve NK cell function may reduce the recurrence of hepatocellular carcinoma after hepatectomy.

Peripheral low-density granulocytes after colorectal cancer surgery in predicting recurrence.

BACKGROUND: Low-density granulocytes (LDGs) have been shown to be increased in the peripheral blood of patients with inflammatory and malignant diseases. This study evaluated LDGs in patients who underwent radical surgery for colorectal cancer (CRC) and their impact on survival. METHODS: Patients who underwent radical colectomy between 2017 to 2021 were screened for enrolment in the study. Peripheral blood was obtained in the operating room before and after surgery and cells were recovered from the mononuclear layer after density gradient preparations. The ratio of CD66b(+) LDG to CD45(+) leukocytes was determined with flow cytometry, and the association of the ratios with patient outcomes was examined. The main outcome of interest was recurrence-free survival (RFS). RESULTS: Out of 228 patients treated, 176 were enrolled, including 108 colonic and 68 rectal cancers. Overall, 38 patients were stage I, 30 were stage II, 72 were stage 3, and 36 were stage IV. The number of LDGs was markedly increased immediately after surgery and the proportion of LDGs correlated positively with operating time (r = 0.2806, P < 0.001) and intraoperative blood loss (r = 0.1838, P = 0.014). Purified LDGs produced high amounts of neutrophil extracellular traps after short-term culture and efficiently trapped tumour cells in vitro. The proportion of postoperative LDGs was significantly higher in 13 patients who developed recurrence (median 9 (range 1.63-47.0)) per cent versus median 2.93 ((range 0.035-59.45) per cent, P = 0.013). When cut-off values were set at 4.9 per cent, a higher proportion of LDGs was strongly and independently associated with decreased RFS (P = 0.005). In patients with stage III disease, adjuvant chemotherapy significantly improved RFS of patients with high ratios of LDGs, but not low LDGs. CONCLUSION: LDGs are recruited to circulating blood by surgical stress early in the postoperative interval after colectomy for colonic cancer and their postoperative proportion is correlated with recurrence.

Developing an immune-related gene prognostic index associated with progression and providing new insights into the tumor immune microenvironment of prostate cancer.

We developed an immune-related gene prognostic index (IGPI) associated with progression and provided new insights into the tumour immune microenvironment (TIME) for prostate cancer (PCA) patients undergoing radical prostatectomy. All analyses were conducted with R software (version 3.6.3) and its suitable packages. Meta-analysis was performed with STATA 16.0. TUBB3, WDR62 and PPARGC1A were finally identified to establish the IGPI score. The IGPI score increased with the augment of the Gleason score and T stage, as well as biochemical recurrence (BCR) and prostate specific antigen (PSA). Patients with a higher IGPI score were at a higher risk of progress (HR: 2·88; 95%CI: 95%CI: 1·80-4·61). Gene set enrichment analysis indicated that patients in high-risk group were positively associated with mismatch repair, cell cycle, DNA replication, base excision repair, nucleotide excision repair, homologous recombination and pyrimidine metabolism. We observed that patients in the high-risk group had significantly higher tumour mutation burden score and microsatellite instability score than those in the low-risk group. For analysis of immune checkpoint, ADORA2A, CD80, TNFRSF4, TNFRSF18 and TNFRSF25 were differentially expressed between no progress and progress groups and were significantly associated with progress free survival. We observed positive correlations between the IGPI score and lymphoid immune cells, macrophages M2 and immune score, while negative association between the IGPI score and dendritic cells, fibroblasts, stromal score and microenvironment score. In conclusion, the IGPI score constructed in this study might serve as an independent risk factor associated with PCA progression. ADORA2A, CD80, TNFRSF4, TNFRSF18 and TNFRSF25 might be the potential targets in the treatment of PCA.

Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.

PURPOSE: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. PATIENTS AND METHODS: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. RESULTS: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation. CONCLUSIONS: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.

Mapping Proteome Changes in Microsatellite Stable, Recurrent Colon Cancer Reveals a Significant Immune System Signature.

BACKGROUND/AIM: Better stratification of the risk of relapse will help select the right patients for adjuvant treatment and improve targeted therapies for patients with colon cancer. MATERIALS AND METHODS: To understand why a subset of tumors relapse, we compared the proteome of two groups of patients with colon cancer with similar stage, stratified based on the presence or absence of recurrence. RESULTS: Using tumor biopsies from the primary operation, we identified dissimilarity between recurrent and nonrecurrent mismatch satellite stable colon cancer and found that signaling related to immune activation and inflammation was associated with relapse. CONCLUSION: Immune modulation may have an effect on mismatch satellite stable colon cancer. At present, immune therapy is offered primarily to microsatellite instable colon cancer. Hopefully, immune therapy in mismatch satellite stable colon cancer beyond PD-1 and PD-L1 inhibitors can be implemented.

Identification of genomic signatures in bone marrow associated with clinical response of CD19 CAR T-cell therapy.

CD19 CAR T-cell immunotherapy is a breakthrough treatment for B cell malignancies, but relapse and lack of response remain a challenge. The bone marrow microenvironment is a key factor in therapy resistance, however, little research has been reported concerning the relationship between transcriptomic profile of bone marrow prior to lymphodepleting preconditioning and clinical response following CD19 CAR T-cell therapy. Here, we applied comprehensive bioinformatic methods (PCA, GO, GSEA, GSVA, PAM-tools) to identify clinical CD19 CAR T-cell remission-related genomic signatures. In patients achieving a complete response (CR) transcriptomic profiles of bone marrow prior to lymphodepletion showed genes mainly involved in T cell activation. The bone marrow of CR patients also showed a higher activity in early T cell function, chemokine, and interleukin signaling pathways. However, non-responding patients showed higher activity in cell cycle checkpoint pathways. In addition, a 14-gene signature was identified as a remission-marker. Our study indicated the indexes of the bone marrow microenvironment have a close relationship with clinical remission. Enhancing T cell activation pathways (chemokine, interleukin, etc.) in the bone marrow before CAR T-cell infusion may create a pro-inflammatory environment which improves the efficacy of CAR T-cell therapy.

Balstilimab and other immunotherapy for recurrent and metastatic cervical cancer.

Recurrent and metastatic cervical cancer is generally treated by cisplatin, paclitaxel, and bevacizumab with limited benefit this constituting an unmet need. Immune checkpoint inhibitors, namely the inhibitors of programmed death 1 and programmed death ligand 1 have been proved to be efficacious in the treatment of patients with advanced cervical cancer. Recently, a PD-1 inhibitor, pembrolizumab was approved for such cancer. However, there is much scope of improvement of current outcome. Dual blockade of cytotoxic T lymphocyte-associated protein 4 and PD-1 is an attractive therapeutic approach. It is used in other cancers and is currently proposed for cancer cervix also. Search is on for single or combined regimen showing efficacy in multiple pathological conditions of cancer cervix irrespective presence of PD-L1 in malignant tissue. An effort to meet such unmet need has culminated in inventing new immune checkpoint inhibitors namely PD-1 inhibitor, AGEN2034 (Balstilimab) and CTLA-4 inhibitor, AGEN1884 (Zalifrelimab).They have shown meaningful and durable activity as single-agent therapy in previously treated patients with persistent R/M CC in a large phase II trial (NCT03104699) in PD-L1 + and PD-L1- tumour. Responses were found both in squamous cell carcinoma & adenocarcinoma cell types. Balstilimab plus zalifrelimab combination (NCT03495882) produced improved clinical benefit over monotherapy as evidenced by higher relative response rates and longer response duration, as well as a manageable safety profile. Interesting development of this combination and other immunotherapies in R/M CC are discussed in this ensuing review.

A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer.

BACKGROUND: PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer. METHODS: Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101. DISCUSSION: PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04678102 .

Long-term activity of tandem CD19/CD20 CAR therapy in refractory/relapsed B-cell lymphoma: a single-arm, phase 1-2 trial.

Increasing the remission rate and reducing the recurrence rate can improve the clinical efficacy of chimeric antigen receptor (CAR) T cell therapy in recurrent/refractory non-Hodgkin lymphoma (r/rNHL). In this open-label, single-arm phase I/II trial, 87 patients with r/rNHL, including 58 patients with aggressive diffuse large B-cell lymphoma and 24 with high tumour burden, received an infusion at doses of 0.5 × 106-8 × 106 TanCAR7 T cells per kilogram of body weight after conditioning chemotherapy. The best overall response rate was 78% (95% confidence interval [CI], 68-86); response rates were consistent across prognostic subgroups. The median follow-up was 27.7 months. The median progression-free survival was 27.6 months (95% CI, 11 to not reached). Cytokine release syndrome (CRS) occurred in 61 patients (70%) with 60% of cases being grade 1 or 2 and 10% being grade 3 or greater. Grade 3 CAR T cell-related encephalopathy syndrome (CRES) occurred in 2 patients (2%). Two patients died from treatment-associated severe pulmonary infection, and one died from CRS-related pulmonary injury between 1 and 3 months post infusion. Long-term remissions were observed following the use of TanCAR7 T cells in r/rNHL with a safety profile that included CRS but few cases of CRES.

Alteration of the immune environment in bone marrow from children with recurrent B cell precursor acute lymphoblastic leukemia.

Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High-dimensional single-cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1-polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune-related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1-polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse.