Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

国产PD-1抑制剂在妇科肿瘤中的研究现状

妇科肿瘤是威胁女性生命的恶性疾病,其中最常见的是宫颈癌、卵巢癌和子宫内膜癌,其发病率逐年上升。妇科肿瘤治疗的基础是手术、放疗和化疗的联合治疗,但综合治疗后仍有患者因耐药或复发而死亡。目前PD-1/PD-L1免疫抑制剂应用于妇科恶性肿瘤已初见成效,有望成为未来最有潜力攻克妇科恶性肿瘤的药物。本文主要对当前国产PD-1免疫治疗在妇科肿瘤中的临床研究结果作一综述,以期概括国内妇科肿瘤免疫治疗思路,寻找合适的免疫治疗策略,延长晚期患者的生存期。

Successful re-challenge of PD-1 inhibitors in combination with bevacizumab and pemetrexed for multiple primary NSCLC progressing on prior PD-1 inhibitor therapy:one case report

Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumor therapies,such as chemotherapy,radiotherapy,and targeted therapy,have limited efficacy in the treatment of advanced synchronous multiple primary NSCLC.Immunotherapy is considered the standard of care for advanced or recurrent NSCLC,however,approximately 60%of patients develop primary or secondary resistance to treatment.There are no standard recommendations for overcoming immune resistance.We describe a case of simultaneous multiple primary NSCLC in a patient who received programmed death factor-1(PD-1)inhibitor monotherapy and developed brain metastases.After receiving second-line treatment with a combination of another PD-1 inhibitor,pemetrexed,and bevacizumab,the patient achieved complete remission,although they experienced grade 3 immune-related adverse reactions.Immune re-challenge is safe and feasible,and choosing a synergistic combination regimen is one of the options to overcome immune resistance.A larger sample size is needed to confirm the effectiveness and safety of this strategy in patients with NSCLC resistant to prior PD-1 inhibitors.

Tumor Local Microenvironment Is a Key Factor Affecting the Efficacy of PD-1 Inhibitor in Advanced Cervical Cancer: A Case Report and Literature Review

Introduction: Conventional radiotherapy or chemotherapy is ineffective in the treatment of recurrent and metastatic cervical cancer. In recent years, immunotherapy has shown promise in the treatment of various solid tumours, including cervical cancer. The overall response rate of the PD-1/PD-L1 inhibitor in cervical cancer is 14% - 27%, and when combined with radiotherapy or conventional chemotherapy, the overall response rate can be further improved. Case presentation: We report here a case of a 49-year-old female patient presenting with two metastatic lesions of cervical cancer after postoperative radiotherapy, the first was located in the para-aortic region and the second in the presacral region. The enlarged para-aortic lymph nodes had not previously received radiotherapy, while the enlarged presacral lymph nodes had previously received postoperative radiotherapy. Treatment results showed that the recurrent presacral mass did not respond to the PD-1 inhibitor (camrelizumab) alone, whereas the metastatic para-aortic lymph nodes responded favourably to camrelizumab combined with low-intensity radiotherapy. Conclusion: PD1/PD-L1 inhibitors combined with radiotherapy should make it possible to overcome the bottleneck of conventional radiotherapy, improve patient prognosis or achieve better local control rates with lower radiotherapy doses.

安徽省六安市第二人民医院4种国产PD-1抑制剂的临床应用评价与分析

目的:分析六安市第二人民医院临床常用的国产PD-1免疫检查点抑制剂的临床应用合理性及安全性。方法:回顾性分析2020年1月至2021年12月接受国产PD-1免疫检查点抑制剂治疗的117例恶性肿瘤患者的临床资料,依据药品说明书及现有临床试验证据,统计并分析患者基本信息、用药信息及免疫相关不良事件(Immune-related Adverse Events,irAEs)发生情况等,评价其临床用药合理性和安全性,并探讨irAEs与性别、年龄、基础疾病及肿瘤类型等因素之间的关系。结果:共纳入117例应用国产PD-1抑制剂的住院患者,其中涉及到超适应症用药的有42例(35.90%),包括卡瑞利珠单抗26例、信迪利单抗13例、特瑞普利单抗2例和替雷利珠单抗1例。42例超适应症用药病例中评价为限制使用、特殊使用和不推荐使用的分别占14.29%(6/42)、52.38%(22/42)和33.33%(14/42)。本研究irAEs的总发生率为40.17%(47例患者、66例次),严重irAEs占10.26%(12/117),常见irAEs主要包括皮肤毒性(16.24%)、肺毒性(13.68%)及内分泌毒性(12.82%)等,多为1~2级毒性反应(81.82%);其中有27例未停用PD-1抑制剂,11例永久停用,5例暂停使用,经对症处理后均出现好转。但有2例重启后再激发irAEs,另外有4例因肺毒性导致全身器官衰竭而死亡。经单因素分析提示患者合并慢性疾病和既往胸部放疗史对irAEs的发生有一定影响,且差异有统计学意义(P<0.05)。结论:PD-1抑制剂在我院超说明书用药占比较大,且存在无循证医学证据支持的用药情况,需要加强管理。irAEs发生较多,多为1~2级,但临床用药过程中仍需警惕严重irAEs的发生,对irAEs做到早发现、早对症处理,以保障临床合理安全用药。

PD-1 inhibitor in combination with fruquintinib therapy for initial unresectable colorectal cancer:A case report

BACKGROUND PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer.In this case report,the combination of a PD-1 inhibitor and fruquintinib demonstrated good efficacy in patients with MSI-H colorectal cancer.CASE SUMMARY The patient was a young man in his 30s who had MSI-H type colon cancer.The patient underwent four cycles of neoadjuvant therapy with a PD-1 inhibitor combined with fruquintinib before surgery,resulting in regression of the mass and a successful surgery.CONCLUSION Some patients with colorectal cancer have the MSI-H type,and the first-line chemotherapy regimen is not effective.However,PD-1 monoclonal antibody immunotherapy has a good therapeutic effect,which can be improved by combination therapy with fruquintinib.We recommend that patients with a history of colon or rectal cancer receive universal MSI testing;then,neoadjuvant therapy should be used.

Progress in the treatment of Bladder Urothelial Carcinoma with PD-1 / PD-L inhibitor

Bladder cancer is one of the most common cancers in the world, and about 80%-90% of bladder cancers are urothelial cancer. Neoadjuvant platinum-based combination chemotherapy is considered to be the standard treatment for bladder cancer. However, the use of this treatment has clinical disadvantages such as small overall benefit, toxic effects on the target population, and inability to select the most beneficial patients. This phenomenon has been improved by the presence of immunological checkpoint inhibitors, of which PD-1/PDL-1 inhibitors are one of them. The use of PD-1/ PD-L1 in urinary cancer is a new treatment and offers new hope for the treatment of platinum-refractory metastatic urothelial bladder cancer. Related drugs have now been approved for use in patients with refractory or unqualified platinum-based chemotherapy drugs. Clinical trials are currently underway to determine how best to use these drugs, and whether they should be used alone or in combination with other treatments. This article will review the research progress of PD-1/PDL-1 inhibitors in bladder tumors.

Traditional Chinese medicine treatment of immune-related pneumonia caused by PD-1/PD-L1 inhibitors

With the wide application of immunotherapy drug PD-1/PD-L1 inhibitor in China and the continuous clinical research,a major problem that we have to face is the immune-related pneumonia caused by PD-1/PD-L1.At present,western medicine mainly treated it by hormone therapy,which may cause side effects,such as obesity,osteoporosis and osteonecrosis for hormone therapy by long-term,and increase the patients'pain.Under the guidance of the theory of syndrome differentiation,traditional Chinese medicine(TCM)advocates the methods of expelling wind and clearing away cold,resolving phlegm and relieving asthma,relieving heat from lung,and invigorating the spleen and tonifying the kidney,etc.Exact differentiation of symptoms and rational usage of drugs can play an important role in the early prevention and treatment of immune-related pneumonia,reflecting the important role of TCM in the prevention and treatment of side effects of new drugs.In order to provide an effective clinical reference for clinicians in the practice of using PD-1/PD-L1,this paper systematically reviewed the use of TCM in the treatment of immune-related pneumonia induced by PD-1/PD-L1 inhibitors.

Benefit-Risk Assessment for PD-1/PD-L1 Inhibitors in the Treatment of Non-Small Cell Lung Cancer

Objective To explore the benefits and risks of PD-1/PD-L1 inhibitors Atezolizumab and Nivolumab in the treatment of non-squamous non-small cell lung cancer and provide some references for clinicians.Methods Based on the data results of relevant studies published by ClinicalTrical.gov in the US clinical trial database and foreign peer-reviewed journals,the internationally recognized multi-criteria decision analysis(MCDA)model was used to assess the benefit and risk of PD-1/PD-L1 inhibitors for non-squamous non-small lung cancer comprehensively.Finally,a sensitivity analysis was performed to test the sensitivity of the weight to the evaluation.Results and Conclusion The benefit-risk evaluation result of Atezolizumab for the treatment of non-squamous non-small cell lung cancer is better than that of Nivolumab.Specifically,Atezolizumab has more benefits than Nivolumab with a lower risk.The results of MCDA model in drug benefit and risk evaluation are easy to understand.However,the selection of indicators in the model and the degree of data acquisition are limited.The evaluation results of the MCDA model should be comprehensively viewed with other evaluations to make decisions objectively.

From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis

After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.

Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer

Objective:The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics,as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer(NSCLC).Methods:We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1(PD-1)/programmed death-ligand 1(PD-L1)immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients.Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+tumor-infiltrating lymphocytes(TILs).Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm.Results:Based on East Asian NSCLC patients,TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy,epidermal growth factor receptor(EGFR)-mutant and anaplastic lymphoma kinase(ALK)-rearranged tumors yielded inferior responses;however,although Kirsten rat sarcoma viral oncogene homolog(KRAS)-mutant tumors responded better,the difference was not statistically significant(EGFR:P=0.037;ALK:P<0.001;KRAS:P=0.701).Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns.The results showed remarkably higher PD-L1-and TIL-positive KRAS-mutant tumors,suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance.However,the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors,suggesting an uninflamed phenotype with immunological ignorance.Notably,similar to triple wild-type NSCLC tumors,EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype,suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy(P<0.05).Furthermore,the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+T cell population(P<0.001),as well as a lack of CD8+T cells(P<0.01),and activated memory CD4+T cells(P=0.001).Conclusions:Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.

PD-1/PD-L1 antagonists in gastric cancer:Current studies and perspectives

Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.

Current situation of programmed cell death protein 1/programmed cell death ligand 1 inhibitors in advanced triple-negative breast cancer

Triple-negative breast cancer(TNBC)has the worst prognosis among all molecular types of breast cancer.Because of the strong immunogenicity of TNBC cells,programmed death 1/programmed death ligand 1(PD-1/PD-L1)inhibitors,two kinds of immune checkpoint blockade agents,might help improve the prognosis of TNBC.However,how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial.This article summarizes published clinical studies in which PD-1/PD-L1 inhibitors were used in patients with advanced TNBC to explore how to maximize effectiveness of these medications.

PD-L1表达指导的信迪利单抗与帕博利珠单抗联合或不联合含铂双药化疗治疗未经治晚期非小细胞肺癌患者:一项2期随机对照试验(CTONG1901)

No direct comparison has been performed between different programmed cell death-1(PD-1)inhibitors for first-line treatment in patients with advanced non-small cell lung cancer(NSCLC).The feasibility of using PD-L1-expression-guided immunotherapy remains unknown.In this open-label,phase 2 study(NCT04252365),patients with advanced NSCLC without EGFR or ALK alterations were randomized(1:1)to receive sintilimab or pembrolizumab monotherapy(PD-L1 expression≥50%),or sintilimab or pembrolizumab plus platinum-based chemotherapy(PD-L1 expression<50%).The sample size was calculated by optimal two-stage design.The primary endpoint was the objective response rate(ORR).The study included 71 patients(sintilimab arms,n=35;pembrolizumab arms,n=36)and met its primary endpoint,with a confirmed ORR of 51.4%(18/35)in the sintilimab arms.The confirmed ORR(95%confidence interval)was 46.2%(19.2%,74.9%)and 42.9%(17.7%,71.1%)for patients treated with sintilimab and pembrolizumab monotherapy;and 54.5%(32.2%,75.6%)and 45.4%(24.4%,67.8%)for those treated with sintilimab-and pembrolizumab-based combination therapies.The median progression-free survival was6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies.The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies.Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies.However,the incidence of rash was higher with sintilimab than pembrolizumab monotherapy.This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC.Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer

The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment(TIME).This study aimed to mechanistically assess whether Chang Wei Qing(CWQ)Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy.PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repairdeficient/microsatellite instability-high(dMMR/MSI-H)colorectal cancer(CRC),rather than those with mismatch repairproficient/microsatellite stable(pMMR/MSS)CRC.Hence,immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients.Flow cytometry was used to analyze T-lymphocytes in tumors from mice.Western blot was used to measure the expression of PD-L1 protein in mouse tumors.The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry.16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice.Subsequently,Spearman’s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes.The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins.In vivo,CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+and PD-1+CD8+T cells in tumors.Additionally,the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone.CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes,and Actinobacteria.Additionally,the proportion of infiltrated CD8+PD-1+,CD8+,and CD3+T cells were found to be positively correlated with the abundance of Akkermansia.Accordingly,CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.

Anlotinib in combination with Envolizumab plus Etoposide for the treatment of EX-SCLC:a case report

Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.

Assessment of the safety and efficacy of combination chemotherapy and PD-1/PD-L1 inhibitor treatment of breast cancer:A meta-analysis

Background:As the efficacy of programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1)inhibitors combined with chemotherapy in curing breast cancer is still controversial,this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer,which provides guidance for the clinical treatment.Methods:Relevant studies published as of April 2022 in the various databases including EMBASE,PubMed,and Cochrane Library were selected.Randomized controlled trials(RCTs)in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation.Investigations without complete information,researches from which information could not be extracted,duplicate articles,animal studies,review articles,and systematic reviews were excluded.STATA 15.1 was employed for all statistical analyses.Results:In total,eight eligible studies were identified,revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival(PFS)relative to chemotherapy alone(hazard ratio[HR]=0.83,95%confidence interval[CI]:0.70–0.99,P=0.032)but not overall survival(HR=0.92,95%CI:0.80–1.06,P=0.273).Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group(risk ratio[RR]=1.08,95%CI:1.03–1.14,P=0.002).Specifically,nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy(RR=0.48,95%CI:0.25–0.92,P=0.026).Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone(HR=0.79,95%CI:0.69–0.89,P≤0.001;HR=0.79,95%CI:0.67–0.92,P=0.002).Conclusions:The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients,but have no statistically significant effect on overall survival(OS).Additionally,combination therapy can significantly improve complete response rate(CRR)compared with chemotherapy alone.However,combination therapy was associated with greater rates of adverse events.

Immune checkpoint inhibitors in cancer therapy

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic Tlymphocyte antigen-4（CTLA-4） and programmed cell death protein 1（PD-1） which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1（CD80） and B7-2（CD86）, plays a pivotal role in attenuating the activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.

Immune checkpoint inhibitors in malignant lymphoma: Advances and perspectives

Classical Hodgkin lymphoma(cHL) has been identified with universal genetic alterations of chromosome 9p24.1,which contains PD-L1/PD-L2 genes.The amplification of 9p24.1 is associated with the increased expression of PDL1 and PD-L2 on RS cells, which promotes their immune evasion, and subsequently makes cHL sensitive to PD-1 blockade.Several PD-1 inhibitors have shown significant efficacies with overall response rate(ORR) of 70%-90% in relapse/refractory(r/r) cHL and have acquired the approvals for this indication.Recently, more and more studies are conducted to investigate PD-1 blockade in earlier disease course and in combination with neo-agents or chemotherapy.Unlike cHL, non-Hodgkin lymphoma(NHL) consists of numerous subtypes harboring highly biological heterogeneity.Only a few subtypes have been shown to have genetic alteration of 9p24.1 including primary mediastinal B cell lymphoma(PMBL), gray zone lymphoma(GZL) with features intermediate between diffuse large B cell lymphoma(DLBCL) and cHL, primary central nervous system lymphoma(PCNSL) and primary testicular lymphoma(PTL).Epstein-Barr virus(EBV)-associated lymphomas have a virally mediated overexpression of PD-L1, also making them sensitive to PD-1 blockade.Therefore, PD-1 inhibitors are less effective in most r/r NHL than in r/r cHL.Further understanding of the biological features of NHL and immune checkpoint inhibitors(ICPi) combined therapy is the research focus in the future.In this review, we outlined the recent progress of ICPi in lymphoma originating from clinical studies.

Prognostic and Predictive Value of Pretreatment Derived Neutrophil-to-Lymphocyte Ratio in Non-Small-Cell Lung Cancer Patients Treated with an Immune Checkpoint Inhibitor

Background: Immune checkpoint inhibitors produce prolonged responses in select non-small cell lung cancer (NSCLC) patients, however the identification of patients most likely to benefit is difficult. Pretreatment derived neutrophil-to-lymphocyte ratio (dNLR) is an easily calculated marker available in routine clinical care that has shown prognostic value in many cancer treatment settings, but its association with survival in NSCLC patients treated with immune-checkpoint inhibitors is less understood. Patients and Methods: We retrospectively reviewed 72 NSCLC patients receiving either nivolumab or pembrolizumab between 3/1/15 and 3/1/17 with a median follow-up time of 5.1 months. Patients were compared using Cox proportional hazards models to detect an association between pretreatment dNLR 3 vs ≥3 on overall survival (OS), progression-free survival (PFS) and overall response rate. Results: Median age was 65 (range: 41 - 86), 65% were male, 40% received ≥ 2 prior systemic therapies and 14% had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2. Pretreatment dNLR ≥ 3 was independently associated with shortened OS (median 3.6 vs 8.5 months;HR: 5.4;95% CI: 2.0 - 14.6;p = 0.001) and PFS (median 2.1 vs 3.4;HR: 2.3;95% CI: 1.1 - 4.8;p = 0.027). Conclusion: Pretreatment dNLR ≥ 3 was independently associated with inferior survival in NSCLC treated with immune checkpoint inhibitors in routine practice. Prospective verification of this marker is warranted as it could serve as an inexpensive and widely-available marker for identifying NSCLC patients most likely to benefit from PD-1 inhibitors.