Senescent cells re‐engineered to express soluble programmed death receptor‐1 for inhibiting programmed death receptor‐1/programmed death ligand‐1 as a vaccination approach against breast cancer

Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent‐cell‐based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple‐negative breast cancer. However, the programmed death receptor‐1/programmed death ligand‐1 (PD‐1/PD‐L1) pathway was found to play an important role in vaccine failure. Hence, we further developed soluble programmed death receptor‐1 (sPD1)‐expressing senescent cells to overcome PD‐L1/PD‐1‐mediated immune suppression while vaccinating to promote dendritic cell (DC) maturity, thereby amplifying T‐cell activation. In the present study, sPD1‐expressing senescent cells showed a particularly active status characterized by growth arrest and modified immunostimulatory cytokine secretion in vitro. As expected, sPD1‐expressing senescent tumor cell vaccine (STCV/sPD‐1) treatment attracted more mature DC and fewer exhausted‐PD1⁺ T cells in vivo. During the course of the vaccine studies, we observed greater safety and efficacy for STCV/sPD‐1 than for control treatments. STCV/sPD‐1 pre‐injections provided complete protection from 4T1 tumor challenge in mice. Additionally, the in vivo therapeutic study of mice with s.c. 4T1 tumor showed that STCV/sPD‐1 vaccination delayed tumorigenesis and suppressed tumor progression at early stages. These results showed that STCV/sPD‐1 effectively induced a strong antitumor immune response against cancer and suggested that it might be a potential strategy for TNBC prevention.     

Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma

Advanced renal cell carcinoma has historically carried a poor prognosis with very limited treatment options. However, in recent years, the treatment landscape has changed drastically, with many new therapeutic options and improved survival for patients. Novel treatments consist of molecularly targeted agents against the vascular endothelial growth factor (VEGF) pathway as well as the immune checkpoint inhibitors, which stimulate an antitumor immune response. Recent strategy has focused on the development of combination therapy with the use of VEGF inhibitors and immune checkpoint inhibitors in the first-line setting. As more treatments are approved and the options for therapy expand further, there is a growing need for predictive biomarkers to personalize treatment choices for individual patients. Prospective clinical trials comparing the sequencing of treatments are needed to help determine the best therapeutic approach.     

PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin–granulocyte‐macrophage‐colony stimulating factor (SA–GM‐CSF) surface‐modified bladder CSCs vaccine previously developed using our protein–anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor‐1 (PD‐1)/program death ligand 1 (PD‐L1) signaling in tumor microenvironment results in tumor‐adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8⁺T cells, a part of these CD8⁺T cells expressed PD‐1. Moreover, the CSCs vaccine upregulated the PD‐L1 expression of tumor cells, resulting in immune resistance. Adding PD‐1 blockade to the CSCs vaccine therapy increased the population of CD4⁺, CD8⁺ and CD8⁺IFN‐γ⁺ but not CD4⁺ Foxp3⁺T cells and induced the highest production of IFN‐γ. PD‐1 blockade could effectively enhance the functions of tumor‐specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM‐1 cell challenge. These results indicate that PD‐1 blockade combined with the GM‐CSF‐modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.     

Clinical significance of programmed death‐1 and programmed death‐ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma

Recently, immunotherapy based on blocking immune checkpoints with programmed death‐1 (PD‐1) or PD‐ligand 1 (PD‐L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor‐infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF‐TKI‐treated primary ccRCC tissues. Upregulated expression of PD‐1 and PD‐L1 by TIIC, and PD‐L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD‐1 and PD‐L1 expression by TIIC was associated with a poorer response to VEGF‐TKI, whereas PD‐L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD‐1‐positive TIIC and PD‐L1‐positive TIIC were observed in tumors treated with VEGF‐TKIs compared with those in untreated tumors. Our data suggest that PD‐1 and PD‐L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF‐TKI treatment.     

Programmed death ligand‐1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder

Drugs blocking programmed death ligand‐1 (PD‐L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD‐L1 with tumor‐infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD‐L1 expression and stromal CD8⁺ TIL, Th1 orientation T cell (T‐bet⁺) and PD‐1⁺ TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD‐L1 expression in tumor cells and 55% in tumor‐infiltrating immune cells. CD8⁺ TIL, T‐bet⁺ TIL and PD‐1⁺ TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD‐L1⁺ tumor cells and PD‐L1⁺ immune cells were positively associated with aggressive clinical features (all P < .05). Both PD‐L1⁺ tumor cells and PD‐L1⁺ immune cells were associated with poorer recurrence‐free and overall survival (all P < .05). Multivariate analysis showed that PD‐L1⁺ immune cells were an independent prognostic factor for overall (P = .001) and recurrence‐free survival (P = .024). Notably, high stromal CD8⁺ TIL and PD‐1⁺ TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8⁺ TIL density has strong positive association with PD‐L1⁺ immune cells and PD‐1⁺ TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune‐checkpoint inhibitors may be effective for resectable patients with UCB.     

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8⁺ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8⁺ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8⁺ expression might be the subset that would poorly benefit from such treatment.     

High IDO‐1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma

Nivolumab belongs to the standard therapy in the second‐line setting of metastatic renal cell carcinoma (mRCC). Although deep and long‐lasting responses are seen in some patients, the majority of patients will further progress. PD‐L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO‐1, a negative immune‐regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO‐1 and other immune inhibitory molecules (PD‐L1, PD‐L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin‐fixed, paraffin‐embedded sections of RCC specimens by immunohistochemistry. IDO‐1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO‐1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non‐responders (33.3%, n = 3/9; P = .028), resulting in a better progression‐free survival during immunotherapy (IDO‐1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log‐rank test). In addition, IDO‐1 was positively correlated with CD8⁺ T cell expression (r_s = .691, P = .006). PD‐L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non‐responders: 83.3% vs 88.9%). No differences were noticed in the PD‐L1 expression on tumor‐infiltrating immune cells (PD‐L1 < 1% in 66.7% of both responders and non‐responders). In contrast to PD‐L1, these results suggest that IDO‐1 may be a more promising predictive biomarker for response to immune‐based cancer therapy in mRCC.     

程序性死亡受体1和程序性死亡受体配体1在非小细胞肺癌组织中的表达情况及临床意义

目的探讨程序性死亡受体1(PD-1)和程序性死亡受体配体1(PD-L1)在非小细胞肺癌(NSCLC)组织中的表达情况及临床意义。方法选择150例NSCLC患者的NSCLC组织及其癌旁组织,采用实时荧光定量聚合酶链反应(PCR)检测两种组织中PD-1 mRNA和PD-L1 mRNA的相对表达量。采用免疫组织化学染色法检测NSCLC组织中PD-1和PD-L1的表达情况,分析PD-1和PD-L1表达情况与患者临床特征的关系。采用流式细胞术检测NSCLC组织和癌旁组织中CD4^+-PD-1、CD8^+-PD-1、CD14^+-PD-L1、CD68^+-PD-L1的表达水平。结果NSCLC组织中PD-1 mRNA和PD-L1 mRNA的相对表达量分别为(5.03±1.92)和(4.95±1.09),分别高于癌旁组织的(1.72±0.81)和(1.25±0.24),差异均有统计学意义(P﹤0.05)。TNM分期为Ⅲ~Ⅳ期、低分化、有淋巴结转移、有远处转移的NSCLC患者NSCLC组织中PD-1和PD-L1的高表达率均明显高于TNM分期为Ⅰ~Ⅱ期、高+中分化、无淋巴结转移、无远处转移的患者,差异均有统计学意义(P﹤0.01)。NSCLC组织中CD4^+-PD-1、CD8^+-PD-1、CD14^+-PD-L1、CD68^+-PD-L1的表达水平均明显高于癌旁组织,差异均有统计学意义(P﹤0.01)。结论PD-1和PD-L1在NSCLC组织中高表达,可能成为一种新的生物标志物,PD-1/PD-L1信号通路可能参与了NSCLC的免疫逃逸过程,对其逃逸机制进行研究可以为NSCLC患者的临床治疗提供新靶点。     

High expression of interleukin‐11 is an independent indicator of poor prognosis in clear‐cell renal cell carcinoma

Interleukin‐11 (IL‐11), a member of the IL‐6 family of cytokines, exerts pleiotropic oncogenic activities by stimulating angiogenesis and metastasis in many cancer types. The present study aims to evaluate the impact of IL‐11 expression on recurrence and mortality of patients with clear‐cell renal cell carcinoma (ccRCC). We retrospectively enrolled 193 ccRCC patients undergoing nephrectomy at a single center. Clinicopathologic features, recurrence‐free survival (RFS) and overall survival (OS) were recorded. IL‐11 intensity was assessed by immunohistochemistry in tumor specimens. The Kaplan–Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. The concordance index (C‐index) was calculated to assess predictive accuracy. High IL‐11 expression is associated with increased risk of recurrence and poor survival for ccRCC patients (P < 0.001 and P < 0.001, respectively), especially those with early‐stage disease (TNM stage I + II). Multivariate analyses confirmed that IL‐11 expression was an independent prognostic factor for RFS and OS (P = 0.006 and P = 0.008, respectively). The predictive accuracy of well‐established prognostic models was improved when IL‐11 expression was integrated. In conclusion, high IL‐11 expression is an independent predictor of poor prognosis in ccRCC patients. It may help identify patients who could benefit from additional treatments and closer follow up.     

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8⁺ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies.     

Phase 1 trial of CV301 in combination with anti-PD-1 therapy in nonsquamous non-small cell lung cancer

CV301, a poxviral-based vaccine, has been evaluated in a phase 1 clinical trial (NCT02840994) and shown to be safe and immunologically active (phase 1a). Preclinical data support a combination of CV301 with programmed death-1 inhibitors, which has been evaluated in the phase 1b part of this trial and is reported here. Patients with advanced nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations received two priming doses of modified vaccinia Ankara-BN-CV301 (MVA) 4 weeks apart, followed by boosting doses of fowlpox-CV301 (FPV) at increasing time intervals for a maximum of 17 doses in combination with nivolumab for cohort 1 (C1) and 15 doses in combination with pembrolizumab for cohort 2 (C2). The primary objective was evaluation of safety and tolerability. Between October 2017 and September 14, 2018, patients were enrolled (C1: 4; median age: 64 years). Mean treatment duration was 332 days in C1 and 289 days in C2. CTCAE ≥grade 3 adverse events (AEs) were observed in four (100%) patients in C1 and three (37.5%) patients in C2. There was one death on trial. Immune-related AEs (irAEs) fulfilling criteria for a dose-limiting toxicity included 1 case of pneumonitis. Among 11 evaluable patients, 1 (9%) had a complete response, 1 (9%) had a partial response and 9 (82%) had stable disease. We conclude that CV301 administered with PD-1 inhibitors is safe and clinically active in patients with advanced NSCLC. The frequency or severity of AEs is not increased, including irAEs for each component of the combination.     

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.     

High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006

BACKGROUND: The treatment of metastatic renal cell carcinoma (RCC) with high-dose interleukin-2 (HD IL-2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors' 20-year experience administering this immunotherapeutic agent. METHODS: Patients with metastatic RCC (n = 259) were treated with HD IL-2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment-related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study. RESULTS: A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow-up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment-related mortalities over this same time period. A higher baseline weight (P = .05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatment-related factors maintained significance, but none more so than response (P < .0001). CONCLUSIONS: HD IL-2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease-free intervals. Given its relative safety, HD IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status.     

Dynamic contrast-enhanced MRI as a predictor of programmed death ligand-1 expression in patients with oral squamous cell carcinoma

Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) are highly promising therapies for oral squamous cell carcinoma (OSCC). The assessment of PD-L1 expression may help predicting the therapeutic effect of ICIs and, thus, benefit patient selection. Contrast index (CI) parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been proven as efficient to assess microvessel density (MVD) in OSCC. The present study aimed to determine the correlation between DCE-MRI parameters and MVD and between DCE-MRI parameters and PD-L1 expression to determine whether DCE-MRI could be used non-invasively to evaluate PD-L1 expression in patients with OSCC. A total of 21 patients with primary OSCC who had undergone a 3T MRI scan, including DCE-MRI, were included in the present study, and CI curve-derived parameters were examined. The MVD and PD-L1 expression in the surgically resected specimens were analyzed using immunohistochemistry (IHC) staining for CD31 and IHC staining for PD-L1, respectively. The results demonstrated that the expression levels of these markers were correlated with DCE-MRI parameters. PD-L1 expression levels were found to be significantly correlated with the maximum CI (CI-max; P=0.007), peak CI (CI-peak; P=0.007), maximum CI gain (CI-gain; P=0.006) and MVD (P=0.001) values. The mean CI-max, CI-peak, CI-gain and MVD values were significantly higher in tumors with high PD-L1 expression (P<0.05). MVD levels were also significantly correlated with the time of CI-max (T-max; P=0.003) and CI-gain (P=0.037). The mean CI-gain was significantly increased, and the mean T-max was significantly shorter in high MVD tumors (P<0.05 and P<0.01, respectively). In summary, the findings from the present study confirmed the correlation between CI parameters, derived from DCE-MRI, and MVD, and suggested that these parameters may be correlated with PD-L1 expression in OSCC tumor cells.     

肾癌术后免疫治疗T细胞亚群检测及疗效观察

目的:检测肾癌术后患者IL-2免疫治疗前后对外周血T淋巴细胞亚群的水平影响,进一步观察其对肾癌术后患者的疗效。方法:肾癌术后患者98例随机分为两组:实验组58例采用IL-2治疗,皮下注射小剂量（60-100万IU/次）,隔日1次,共3月,以后每年方案同前1年。对照组40例只给予肾癌根治术,不予免疫治疗。应用流式细胞技术检测两组患者不同时间段（治疗前,治疗后2月、6月）外周血CD3+、CD4+、CD8+、CD4+/CD8+,并进行对比研究。观察两组治疗后1年、3年生存率、生活质量(KPS)评分以及不良反应。结果:实验组与对照组CD3+、CD4+、CD4+/CD8+在治疗前无明显差异(P＞0.05),治疗后2月、6月较对照组明显升高(P＜0.05)。术后1年实验组生存率100％(58/58),对照组97.5%（39/40）,两者无明显差异(P＞0.05);术后3年实验组生存率84.5％（49/58）,明显高于对照组（67.5%,27/40)(P＜0.05)。实验组术后1年生活质量评分平均升高19.6分,3年生活质量评分平均升高11.5分,均明显高于对照组3.7分、1.4分(P＜0.05)。实验组不良反应共12例,均为一过性,未影响免疫治疗。对照组无相关不良反应。结论:肾癌根治术后应用IL-2进行免疫治疗,可以提高患者免疫水平,发挥抗肿瘤作用,提高生存率,改善生活质量,不良反应较轻。     

Adenoviral production of interleukin‐2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy

Systemic high dose interleukin‐2 (IL‐2) postconditioning has long been utilized in boosting the efficacy of T cells in adoptive cell therapy (ACT) of solid tumors. The resulting severe off‐target toxicity of these regimens renders local production at the tumor an attractive concept with possible safety gains. We evaluated the efficacy and safety of intratumorally administered IL‐2‐coding adenoviruses in combination with tumor‐infiltrating lymphocyte therapy in syngeneic Syrian hamsters bearing HapT1 pancreatic tumors and with T cell receptor transgenic ACT in B16.OVA melanoma bearing C57BL/6 mice. The models are complementary: hamsters are semi‐permissive for human oncolytic adenovirus, whereas detailed immunological analyses are possible in mice. In both models, local production of IL‐2 successfully replaced the need for systemic recombinant IL‐2 (rIL‐2) administration and increased the efficacy of the cell therapy. Furthermore, vectored delivery of IL‐2 significantly enhanced the infiltration of CD8+ T cells, M1‐like macrophages, and B‐cells while systemic rIL‐2 increased CD25 + FoxP3+ T cells at the tumor. In contrast with vectored delivery, histopathological analysis of systemic rIL‐2‐treated animals revealed significant changes in lungs, livers, hearts, spleens, and kidneys. In summary, local IL‐2 production results in efficacy and safety gains in the context of ACT. These preclinical assessments provide the rationale for ongoing clinical translation.     

Treatment of renal cell carcinoma: Current status and future directions

Answer questions and earn CME/CNE Over the past 12 years, medical treatment for renal cell carcinoma (RCC) has transitioned from a nonspecific immune approach (in the cytokine era), to targeted therapy against vascular endothelial growth factor (VEGF), and now to novel immunotherapy agents. Multiple agents—including molecules against vascular endothelial growth factor, platelet‐derived growth factor, and related receptors; inhibitors of other targets, such as the mammalian target of rapamycin and the MET and AXL tyrosine‐protein kinase receptors; and an immune‐checkpoint inhibitor—have been approved based on significant activity in patients with advanced RCC. Despite these advances, important questions remain regarding biomarkers of efficacy, patient selection, and the optimal combination and sequencing of agents. The purpose of this review is to summarize present management and future directions in the treatment of metastatic RCC. CA Cancer J Clin 2017;67:507‐524. © 2017 American Cancer Society.