Most malignant tumors evidence infiltration of many macrophages. In this study, we investigated an anti‐inflammatory macrophage phenotype (M2) in clear cell renal cell carcinoma (RCC) using CD163 and ...CD204 as markers. Immunostaining showed a correlation between the number of CD163+ cells and age, sex, nuclear grade, and TNM classification. High infiltration of CD163+ cells was significantly associated with poor clinical prognosis in univariate analysis but not in multivariate analysis. We also carried out in vitro studies to examine cell–cell interactions between macrophages and cancer cells. Culture supernatants from RCC cell lines induced polarization of macrophages toward the M2 phenotype. Coculture of macrophages with cancer cells significantly induced activation of signal transducers and activators of transcription‐3 (Stat3) in the cancer cells. Direct coculture of RCC cells with macrophages led to stronger activation of Stat3 in the cancer cells than did indirect coculture using Transwell chamber dishes. Because RCC cells expressed membrane‐type macrophage colony‐stimulating factor (mM‐CSF) on the cell surface, we suggested that this mM‐CSF plays an important role in direct cell–cell interactions. Stat3 activation in cancer cells that was induced by coculture with macrophages was suppressed by downregulation of the M‐CSF receptor (M‐CSFR) in macrophages and by an inhibitor of M‐CSFR. In conclusion, investigation of CD163+ tumor‐associated macrophages would be useful for assessment of the clinical prognosis of patients with ccRCC. Cell–cell interactions mediated by mM‐CSF and M‐CSFR binding could contribute to cancer cell activation. (Cancer Sci 2011; 102: 1424–1431)
Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone‐sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according ...to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer‐related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone‐sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor‐targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration‐resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone‐sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone‐sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor‐targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer, and discusses future perspectives in this field.
Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
In this ...phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
Immune checkpoint blockade is a promising anticancer therapy, but must be used in combination with other anticancer therapies to increase its therapeutic efficacy. Cyclophosphamide (CP) is a ...chemotherapeutic drug that shows immune‐modulating effects. In this study, we examined the effect of CP on anti‐CTL‐associated protein 4 (CTLA‐4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after i.p. injection of CP (100 mg/kg) followed by anti‐CTLA‐4 antibody. However, administration in the reverse order increased apoptosis in tumor‐specific CD8+ T cells. In the RENCA renal carcinoma model, the antitumor effect of combination therapy was marginal and the tumor‐bearing state reduced body weight with an increased serum level of interleukin‐6. Interestingly, although CP monotherapy increased myeloid‐derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti‐CTLA‐4 therapy increased MDSCs only in RENCA‐bearing mice. Additionally, the serum levels of chemokine ligand 2 and C‐X‐C motif chemokine 10 were increased by the combination therapy only in RENCA‐bearing mice and in vivo depletion of Gr‐1+ cells augmented the antitumor effect to some degree. These results reveal a contrasting effect of CP on anti‐CTLA‐4 therapy between the two mouse tumor models. Cyclophosphamide augments the antitumor effect of anti‐CTLA‐4 therapy in CT26‐bearing hosts, whereas CP after anti‐CTLA‐4 therapy attenuates this effect through induction of apoptosis in tumor‐reactive T cells. Alternatively, CP‐induced MDSCs can be increased by anti‐CTLA‐4 therapy only in RENCA‐bearing hosts with an elevated level of interleukin‐6.
The combination of cyclophosphamidea and anti‐CTLA‐4 therapy can regress established colon cancer.
Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB‐1/androgen receptor (AR) signaling. PMD‐026, an oral ...first‐in‐class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD‐026 on YB‐1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration‐resistant prostate cancer 22Rv1 cells that express high‐level AR variants were used in this study. The effect of PMD‐026 on YB‐1/AR signaling was investigated by quantitative real‐time PCR and western blot analysis. The effects of PMD‐026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD‐026 decreased YB‐1 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD‐026 suppressed cell proliferation alone and in combination with the second‐generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD‐026 suppressed tumor growth, and the combination of PMD‐026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD‐026 and the combination effect with the antiandrogen enzalutamide in castration‐resistant prostate cancer. These findings warrant a clinical trial of PMD‐026 in prostate cancer patients.
This study demonstrated an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD‐026 and the combination effect with the antiandrogen enzalutamide in castration‐resistant prostate cancer. These findings warrant a clinical trial of PMD‐026 in prostate cancer patients.
Since the 2000s, there have been dramatic advances in the treatment of metastatic renal cell carcinoma (mRCC), including drugs targeting vascular endothelial growth factor (VEGF) and mammalian target ...of rapamycin (mTOR) pathways. The first VEGF inhibitors approved for mRCC were sorafenib and sunitinib. Subsequently, two mTOR inhibitors (everolimus and temsirolimus) and other VEGF inhibitors (pazopanib and axitinib) were approved. Overall survival (OS) of mRCC patients has significantly increased during this period. Two novel VEGF inhibitors have recently been approved overseas, including cabozantinib and lenvatinib. Additionally, the recent advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment of mRCC. The PD-1 inhibitor nivolumab improved the OS rate of patients with mRCC following VEGF inhibitors. Moreover, the CheckMate 214 trial demonstrated the benefit of nivolumab plus ipilimumab combination therapy in OS and objective response rate in treatment-naive intermediate- and poor-risk mRCC. In this review, current evidence related to the clinical use of targeted therapies and checkpoint inhibitors for the treatment of patients with mRCC is discussed. In addition, we review ongoing trials investigating combinations of checkpoint inhibitors with targeted agents and the identification of biomarkers to guide patient selection and enable individualization of therapy.
Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating ...irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.
Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the ...biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C–C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors.
Abstract
Much attention has been paid to immune checkpoint inhibitors to various cancer treatments. In urothelial cancer, pembrolizumab was initially approved for patients who either recurred or ...progressed following platinum-based chemotherapy. For the platinum-fit population, although the standard first-line treatment is still platinum-based systemic chemotherapy, avelumab has been recently approved as a maintenance therapy for patients who have not had disease progression with four to six cycles of first-line chemotherapy. In addition, adjuvant nivolumab has just prolonged disease-free survival (DFS) by ~10 months, compared with placebo in patients with muscle-invasive bladder urothelial cancer or upper tract urothelial cancer at high-risk of recurrence after radical surgical resection.
On the other hand, in kidney cancer, nivolumab was initially approved for advanced renal cell carcinoma patients after one or two prior anti-angiogenic therapies. Next, combinations of two immune checkpoint inhibitors (nivolumab + ipilimumab) and immune checkpoint inhibitor + tyrosine kinase inhibitors (pembrolizumab + axitinib and avelumab + axitinib) were approved for the first-line treatment for patients with advanced renal cell carcinoma. Recently, new generation tyrosine kinase inhibitors, such as cabozantinib and lenvatinib have been combined with immune checkpoint inhibitors. Both nivolumab + cabozantinib and pembrolizumab + lenvatinib have demonstrated superior progression-free survival and objective response rate, compared with sunitinib. So far, no prospective trials have demonstrated the duration of immune checkpoint inhibitor treatments. We are now doing the Japan Clinical Oncology Group 1905 trial, where patients with advanced renal cell carcinoma who have received an immune checkpoint inhibitor for 24 weeks are divided into two groups: those who continue immune checkpoint inhibitor treatment and those who discontinue immune checkpoint inhibitor treatment.
We summarize current status and future perspectives of immunotherapy against urothelial and kidney cancer. In both cancers, immune checkpoint inhibitors are spreading in the first line, subsequent lines and adjuvant settings.
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