XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

The spatial landscape of T cells in the microenvironment of stage III lung adenocarcinoma.

This study aimed to provide more information for prognostic stratification for patients through an analysis of the T-cell spatial landscape. It involved analyzing stained tissue sections of 80 patients with stage III lung adenocarcinoma (LUAD) using multiplex immunofluorescence and exploring the spatial landscape of T cells and their relationship with prognosis in the center of the tumor (CT) and invasive margin (IM). In this study, multivariate regression suggested that the relative clustering of CT CD4+ conventional T cell (Tconv) to inducible Treg (iTreg), natural regulatory T cell (nTreg) to Tconv, terminal CD8+ T cell (tCD8) to helper T cell (Th), and IM Treg to tCD8 and the relative dispersion of CT nTreg to iTreg, IM nTreg to nTreg were independent risk factors for DFS. Finally, we constructed a spatial immunological score named the GT score, which had stronger prognostic correlation than IMMUNOSCORE® based on CD3/CD8 cell densities. The spatial layout of T cells in the tumor microenvironment and the proposed GT score can reflect the prognosis of patients with stage III LUAD more effectively than T-cell density. The exploration of the T-cell spatial landscape may suggest potential cell-cell interactions and therapeutic targets and better guide clinical decision-making. © 2024 The Pathological Society of Great Britain and Ireland.

Examining the spatial distribution of tumor-infiltrating immune cells in patients with stage I-IIIA LUAD.

This study aimed to examine the spatial distribution of immune cells by application of Gcross function in 170 patients with stage I-IIIA lung adenocarcinoma (LUAD) and explore its prognostic value. A total of 170 stage I-IIIA LUAD patients who underwent radical surgery were enrolled. Paraffinized tumor sections were collected for two panels of multicolor immunofluorescence staining as follows: Panel 1 (CD4, CD8, FOXP3, CD69, CD39, CD73, and DAPI) and Panel 2 (CD68, CD163, CD20, CD11c, PDL1, IDO, and DAPI). The immune cells were categorized as CD8+, CD4+ T-helper cell (CD4Th), Regulatory T cell (Treg), Macrophage type 1 (M1), Macrophage type 2 (M2), Dendritic cell (DC) and B cell. The immune cell numbers were enumerated, and the immune cell proximity score was calculated employing the Gcross function. The correlation between immune cell variables and Disease-Free Survival (DFS) was explored through univariate Cox regression analyses. Factors with P<0.05 were subjected to multivariate analyses. According to univariate Cox regression analyses, total PDL1+ and PDL1+ DC counts were negative factors (P=0.003, 0.031). CD4Th and IDO-DC counts were positive factors (P=0.022, 0.024). The proximity score (M1 to M2) was a positive factor for DFS (P=0.032), and the proximity score (PDL1+DC to M1) was a negative factor (P=0.009) according to univariate Cox analyses. In multivariate analyses, stage (IIIA vs. I+II) [HR: 1.77(1.18, 2.64), P=0.006] and proximity score (PDL1+DC to M1) [HR: 1.60(1.07, 2.37), P=0.021] were independent negative factors and CD4Th counts [HR: 0.60(0.40, 0.90), P=0.013] was an independent positive factor. Our study indicated that a higher level of tumor-infiltrating CD4Th cells predicted longer DFS, and a closer proximity of PDL1+ DCs to M1 cells was associated with dismal DFS in stage I-IIIA LUAD patients.

Pathologic complete response to immune checkpoint inhibitor in a stage IIIB ovarian clear cell carcinoma patient with POLE mutation resistant to platinum-based chemotherapy: a case report.

Background: Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer with unique features at histological and molecular levels. The prevalence of OCCC is higher in east Asia than in Western countries. As cases are usually chemo-resistant, treatment effects of platinum-based chemotherapy are not satisfactory, especially for patients with stage III or IV disease. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with advanced-stage cancers. However, whether advanced OCCC patients benefit from ICIs remains elusive. Case Description: Herein, we report a Chinese patient with stage IIIB inoperable OCCC who was resistant to platinum-based chemotherapy and anlotinib. Next-generation sequencing (NGS) revealed a pathogenic polymerase epsilon (POLE) P286R mutation and a high level of tumor mutation burden (TMB) in tissue and plasma samples. The ICI sintilimab was then used with bevacizumab as third-line treatment. Tumor reduction was observed, and the patient underwent surgical resection which indicated a pathologic complete response (pCR). Maintenance therapy with sintilimab and bevacizumab was applied, and the patient has achieved overall survival (OS) of 35 months since the diagnosis. They have also achieved a progression-free survival (PFS) of 29 months since commencing ICI treatment and have been disease-free for 24 months after surgical resection. Conclusions: The treatment effect of ICI in POLE-mutant OCCC patients has been rarely reported. The treatment benefits observed in the stage IIIB OCCC patient who was resistant to platinum-based chemotherapy may be associated with the presence of POLE mutation and a high level of TMB. Comprehensive genomic profiling could contribute to appropriate treatment decisions for OCCC.

A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: Can the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. PATIENTS AND METHODS: Patients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). RESULTS: Thirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). CONCLUSION: Autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events.

OBJECTIVE: Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs. METHODS: From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests. RESULTS: At the onset of AEs in the irAE group, ferritin (normal range, 35-150 µg/L) rose to a median of 927 µg/L (range, 117-17,825 µg/L) from 86 µg/L at baseline (range, 29-421 µg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 µg/L; range, 32-478 µg/L) (P < 0.001) and the AE group (median, 103 µg/L; range, 23-712 µg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died. CONCLUSIONS: Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.

Response to gefitinib/crizotinib combination in a pulmonary sarcomatoid carcinoma patient harboring concurrent EGFR mutation and MET amplification.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an extremely poor prognosis making it a therapeutic challenge. However, the development of genetic variation molecular diagnosis and targeted agents has brought the treatment of such malignancies to the precision era. Co-existing mutations of EGFR and MET have been reported in NSCLC, but rarely found in PSC. We herein present a rare case of a 74-year-old female patient diagnosed with PSC, carrying an activating mutation in exon 21 L858R of EGFR and a concurrent MET amplification prior to treatment. Combined application of gefitinib and crizotinib, inhibitors targeting EGFR and MET, respectively, was prescribed. The patient experienced a partial response and was stable for 9.7 months off therapy. The observation stresses the importance of genetic testing and paves the way for combined targeted strategies in PSC.

Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: A preliminary study.

BACKGROUND: Programmed death-1 (PD-1) blocking antibodies have been shown to improve progression-free survival (PFS) and overall survival in a subset of patients with non-small cell lung cancer (NSCLC). However, the objective response rate with these agents remains low, and the vast majority of NSCLC patients require alternative combination treatment regimens to prolong their survival. The purpose of this study was to evaluate the clinical efficacy of autologous cytokine-induced killer (CIK) cell infusions combined with PD-1 blocking antibodies in patients with NSCLC. METHODS: In this preliminary study, we investigated the safety and immune function effectiveness of PD-1 blockade antibodies pembrolizumab or nivolumab administered in combination with or without autologous CIK cell infusions in 18 patients with advanced NSCLC. The peripheral blood mononuclear cells were isolated from these patients and the expression level of some cell surface molecules like PD-1 were detected using flow cytometry to reflect the effectiveness of this combination regimen. RESULTS: No treatment-related deaths occurred in either cohort. In comparison with the pretreatment level, CD3+ CD56+ CD16+ T cells were significantly increased with the combination therapy, while myeloid-derived suppressor cells were significantly increased with PD-1 blocking antibody therapy alone but not with combination therapy. Although the serum interleukin-4 level was downregulated following treatment with the combination regimen, interferon-γ levels were unchanged. CONCLUSIONS: The purpose of this clinical study was to report the clinical efficacy and lack of exacerbated autoimmune adverse events with a combination of PD-1 blockade and CIK cell infusions in patients with advanced NSCLC, further supporting assessments of this combination in future clinical trials.

[Efficacy and Survival Analysis of Apatinib in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer after Failure of First-line Treatment].

BACKGROUND: The efficacy of second or third-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is low. The use of targeted drugs brings survival benefit for some patients. Apatinib, as a novel small molecule antiangiogenic drug, has demonstrated satisfactory anticancer activity across a broad range of malignancies. The aim of this study is to evaluate the efficacy and safety of apatinib in patients with advanced NSCLC after first-line treatment failure. METHODS: A retrospective study of 128 patients was conducted to evaluate the safety, short-term efficacy and survival status with different regimens. Kaplan-Meier method and Cox regression model were used for analysis. RESULTS: Compared with chemotherapy alone, the median progression free survival (PFS) in apatinib monotherapy, chemotherapy alone and apatinib combined with chemotherapy were 3.0 (P=0.381), 3.7 and 6.0 months (P<0.001), respectively. The median overall survival (OS) were 6.0 (P=0.494), 6.5 and 9.0 months (P=0.001), respectively. The incidence of adverse events in grades 3-4 were 18.5%, 15.8% and 16.0%, respectively (P=0.947). Different treatment regimens (P=0.018) and performance status (PS)(P<0.001) were the independent factors of PFS. The smoking history (P=0.014), treatment regimens (P=0.002) and PS (P<0.001) were independent influencing factors of OS. CONCLUSIONS: Apatinib has a good security. After first-line treatment failure of lung cancer, chemotherapy combined with apatinib in second or third-line is beneficial in PFS and OS when compared with chemotherapy alone. But when making comparison between apatinib monotherapy and chemotherapy alone, there is no significant difference in PFS and OS. Patients who never smoke or has a better PS or use combination therapy have longer survival time.
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Primary hepatic angiosarcoma and potential treatment options.

Angiosarcomas account for a mere 2-3% of adult soft tissue sarcomas, with an overall poor outcome. Depending on the primary site, angiosarcomas have distinct prognosis. Primary hepatic angiosarcomas (PHAs) are much rare tumors, with worse prognosis compared with other angiosarcomas. PHA is reported to be associated with vinyl chloride, but the majority of patients were still with unknown etiology. As PHA lacks specific symptoms, signs, or images, pathological diagnosis is necessary. The review summarizes 25 articles published from January 2000 to December 2012, including 64 cases of PHA with detailed information. Survival curves are estimated using the Kaplan-Meier method by SPSS 21.0. We find that the median survival time is 5 months; local excision alone or combination with adjuvant therapy is the optimal choice, with median survival time of 17 months. In addition, liver transplant is abandoned for high recurrence rate; emergent transcatheter arterial embolization is thought to be an efficient method for controlling intra-abdominal bleeding; and transcatheter arterial chemoembolization and chemotherapy may be helpful in improving survival.

Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer.

Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33(+) progenitors isolated from healthy donors' umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs' immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.