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Pulmonary sarcomatoid carcinoma (PSC), characterized by poor differentiation, aggressive progression, and early metastasis, is a rare type of non‐small cell lung carcinoma (NSCLC), which shows a low response rate to conventional antitumor therapies and has a poor prognosis. With the achievements in gene sequencing, targeted therapy, and immunotherapy, several new approaches have recently been explored in PSC treatment. A small case series of PSC patients were found to have programmed death‐ligand 1 (PD‐L1) overexpression, a prerequisite for PD‐1 inhibiting therapy, which made immunotherapy possible. However, anti‐PD‐1 treatment for PSCs was still at a preliminary stage. Here, we report the successful outcome of tislelizumab monotherapy in a patient with advanced PSC with pleural invasion, thus providing a novel promising approach for PSC patients with PD‐L1 overexpression., Pulmonary sarcomatoid carcinoma (PSC) has a low response rate to conventional antitumor therapies and poor prognosis. However, with the achievements in gene sequencing, targeted therapy, and immunotherapy, several new approaches have recently been explored in the treatment of PSC. Here, we report the successful outcome of tislelizumab monotherapy in a patient with advanced PSC and pleural invasion, which provides a novel treatment approach for PSC patients with PD‐L1 overexpression.

Changfang Fu,1 Gang Wang,1 Wulin Yang2 1The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People’s Republic of China; 2Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People’s Republic of ChinaCorrespondence: Wulin YangAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, 230031, Anhui, People’s Republic of ChinaEmail yangw@cmpt.ac.cnGang WangOncology Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, 230001, Anhui, People’s Republic of ChinaEmail wanggang829@126.comAbstract: Immune checkpoint inhibitors may cause unique immune-related adverse events. Vascular thrombosis, especially arterial thrombosis, is rare but life-threatening, and little is known about its relevance to immunotherapy. Here, we reported two cases of vascular thrombosis, including venous and arterial thrombosis in cancer patients receiving anti-PD-1 antibody in combination with chemotherapy. Systemic corticosteroids and anticoagulant treatment were administered immediately in two cases. In case 1, anti-PD-1 antibody was permanently discontinued, and recurrence of vascular thrombosis was not observed during the follow-up. In case 2, the patient continued anti-PD-1 immunotherapy and unfortunately died of cerebral infarction 2 months later. This case report provides a strong evidence for the association between PD-1 blockade and vascular thrombosis and offers some general guidelines on the management of the immune-related vascular thrombosis events induced by anti-PD-1 therapy.Keywords: immune checkpoint inhibitors, immune-related adverse events, pembrolizumab, tislelizumab, pulmonary embolism, deep vein thrombosis

Reports of immune-related adverse events caused by programmed cell death protein-1 inhibitor are becoming increasingly frequent. Herein, we report the first case of pemphigus herpetiformis-type drug reaction presented after the treatment of tislelizumab (6 cycles) in a primary non-small cell lung carcinoma patient. A 56-year-old Chinese man was referred to our department for pruritic annulare erythema and blister for two weeks. Histological finding revealed blister formation in the epidermis and eosinophilic infiltration in the blister fluid. Direct immunofluorescence showed intercellular deposition of IgG and C3 within the lower part of epidermis. Serum anti-intercellular antibodies were positive at 1:100 dilution. Based on history and clinicopathological correlation, herpetiformis-type drug-induced pemphigus was diagnosed, which was possibly be induced by tislelizumab. To the best to our knowledge, there is no report of pemphigus herpetiformis-type drug-induced reaction associated with programmed cell death protein-1 inhibitor treatment.

Yunfang Zhang,1,* Ming Zhang,2,* Jianping Xie,2 Weiwei Wu,2 Jiejie Lu2 1Department of Oncology, Hainan Provincial Hospital of TCM, Haikou, 570203, People’s Republic of China; 2Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Branch of National Clinical Research Center for Skin and Immune Disease, Haikou, 570206, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiejie LuDepartment of Dermatology, The Fifth People’s Hospital of Hainan Province, Branch of National Clinical Research Center for Skin and Immune Disease, No. 33, Southern Road of Longkun, Haikou, 570206, People’s Republic of ChinaTel +86-13519816255Fax +86-898-66729550Email lujiejie677@163.comAbstract: Reports of immune-related adverse events caused by programmed cell death protein-1 inhibitor are becoming increasingly frequent. Herein, we report the first case of pemphigus herpetiformis-type drug reaction presented after the treatment of tislelizumab (6 cycles) in a primary non-small cell lung carcinoma patient. A 56-year-old Chinese man was referred to our department for pruritic annulare erythema and blister for two weeks. Histological finding revealed blister formation in the epidermis and eosinophilic infiltration in the blister fluid. Direct immunofluorescence showed intercellular deposition of IgG and C3 within the lower part of epidermis. Serum anti-intercellular antibodies were positive at 1:100 dilution. Based on history and clinicopathological correlation, herpetiformis-type drug-induced pemphigus was diagnosed, which was possibly be induced by tislelizumab. To the best to our knowledge, there is no report of pemphigus herpetiformis-type drug-induced reaction associated with programmed cell death protein-1 inhibitor treatment.Keywords: programmed cell death protein-1 inhibitor, tislelizumab, pemphigus herpetiformis, drug reaction

Programmed cell death protein 1 (PD‐1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well‐known target for cancer immunotherapy. Tislelizumab (BGB‐A317) is an anti‐PD‐1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM‐CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of tislelizumab, and demonstrated that the CC′ loop of PD‐1, a region considered to be essential for binding to PD‐1 ligand 1 (PD‐L1) but not reported as targeted by other therapeutic antibodies, significantly contributes to the binding of tislelizumab. The binding surface of tislelizumab on PD‐1 overlaps largely with that of the PD‐L1. SPR analysis revealed the extremely slow dissociation rate of tislelizumab from PD‐1. Both structural and functional analyses align with the observed ability of tislelizumab to completely block PD‐1/PD‐L1 interaction, broadening our understanding of the mechanism of action of anti‐PD‐1 antibodies., We evaluated the antitumor efficacy of tislelizumab (BGB‐A317), an approved anti‐PD‐1 antibody. Its critical epitopes were investigated by both structural biology and SPR studies, and the CC′ loop of PD‐1 was discovered to be a novel targetable region for anti‐PD‐1 antibodies. The unique epitopes and slow dissociation rate of tislelizumab contribute to its complete blocking activity to PD‐L1.

Tislelizumab, an anti‐programmed death protein‐1 (PD‐1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody‐dependent phagocytosis, a mechanism of T‐cell clearance and potential resistance to anti‐PD‐1 therapy. This single‐arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD‐L1‐positive urothelial carcinoma who progressed during/following platinum‐containing therapy and had no prior PD‐(L)1 inhibitor treatment. Patients were considered PD‐L1 positive if ≥ 25% of tumor/immune cells expressed PD‐L1 when using the VENTANA™ PD‐L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow‐up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy‐evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression‐free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment‐related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3‐4 treatment‐related adverse events and occurred in ≥ 5% of patients. Three investigator‐assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD‐L1‐positive urothelial carcinoma and had a manageable safety profile., Tislelizumab is a unique anti‐PD‐1 antibody that was engineered specifically to minimize FcγR binding in order to limit antibody‐dependent phagocytosis, a potential mechanism of resistance to anti‐PD‐1 therapy. In the current study, tislelizumab demonstrated clinically meaningful antitumor activity in patients with previously treated locally advanced or metastatic PD‐L1‐positive urothelial carcinoma and had a manageable safety profile with no new safety signals compared with other anti‐PD‐L1/PD‐1 therapies. A phase 3 study of tislelizumab as treatment for urothelial carcinoma (NCT03967977) is currently ongoing and is recruiting patients.

BackgroundTumor flare reaction (TFR) is a clinical syndrome, which is mainly associated with painful and swollen lymph nodes or splenomegaly, slight fever, bone pain, and skin rash during treatment with immune-related drugs, causing difficulty in distinguishing TFR from disease progression. Brentuximab vedotin (BV) and programmed death 1 (PD-1) inhibitor are two ideal drugs used for the treatment of classic Hodgkin lymphoma, but few studies have reported their adverse effects in association with TFR. The efficacy and safety of monotherapy or combination therapy with these drugs needs to be further evaluated. It is essential to determine whether treated patients can develop TFR, thus enabling more accurate diagnosis and treatment.Case presentationA 26-year-old female patient, diagnosed with classic Hodgkin lymphoma, had received 2 + 3 cycles of ABVD chemotherapy (a combination of adriamycin, bleomycin, vinblastine, and dacarbazine) and 4 cycles of PD-1 inhibitor (tislelizumab) therapy but exhibited poor efficacy. Subsequently, she was given combination therapy of BV (100 mg) + tislelizumab (200 mg). However, a slight fever, painful and swollen axillary lymph nodes, multiple skin rashes with pruritus, joint pain, and fatigue with poor appetite appeared during the treatment. Ultrasound (US) scans revealed that multiple lymph nodes were significantly enlarged. After treatment with low-dose dexamethasone and cetirizine, the symptoms were alleviated. A biopsy of the left axillary lymph node revealed that lymphoid tissue exhibited proliferative changes, without tumor cell infiltration. These findings were consistent with the clinical and pathological manifestations of TFR.ConclusionCombination therapy with BV and PD-1 inhibitor was effective in the treatment of relapsed or refractory classic Hodgkin lymphoma. The results suggest that the combination therapy may cause TFR, and biopsy and also continuous imaging observation are important to determine the disease stage. This approach allows clinicians to decide whether to continue the current treatment plan, and alerts them to the occurrence of excessive activation of the immune system.

Immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAEs) are becoming important safety issues worthy of attention despite the exciting therapeutic prospects. The growing development of new ICIs also brings new cases of irAEs, raising more challenges to clinicians. Cardiac injury is rare but life-threatening among diverse organ injuries, and effective interventions are critical for patients. Here, we report a novel programmed cell death protein-1 (PD-1) inhibitor tislelizumab-associated severe myocarditis and myositis accompanied by liver and kidney damage in a ureteral urothelial cancer patient, who was firstly treated by cardiologists because of cardiac symptoms. Due to the lack of experience about ICI-associated irAEs, an initial low-dose (0.5 mg/kg/day) and short-term methylprednisolone therapy was used and found to be ineffective and risky to the patient; then, steroid therapy was modulated to a higher dose (1.5 mg/kg/day) with prolonged time course, and improvement of patient symptoms and laboratory markers were observed quickly and persistently. The patient did not show adverse events under this steroid dosage. This case reports a rare tislelizumab-related myocarditis and multiple organ injuries, which provides valuable experience to cardiologists like us. Early recognition of ICI-associated myocarditis and sufficient dosage and time course of glucocorticoid therapy are critical for severe cases. High-quality clinical evidence about the precise diagnosis and therapy in ICI-associated myocarditis and other organ injuries are necessary to guide our clinical works.

Immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors (ICIs) can affect almost any organ systems. Multiple-organs irAEs are a rare occurrence which makes its management and treatment very challenging. This is a case report of a 71-year-old man with advanced non-small cell lung cancer (NSCLC) who developed multiple-organs irAEs (lung, muscle, myocardium, liver, and pituitary) after a single cycle (21 days) of the BGB-A317 (Tislelizumab). After more than two months of immunosuppression treatment with glucocorticoids, the tumor and inflammatory lesions in the lung were reduced. The levels of serum creatase, cardiac troponin T (TNT), and hepatic transaminase were also reduced. Four months after the termination of ICI therapy, the lung tumor reappeared in the previous site. This rare case report supplies several experiences in the management of multiple-organs irAEs, including full-scale monitoring of immunological indicators, early differential diagnosis, and prompt glucocorticoid therapy. This patient was not a candidate for the ICI re-challenge therapy due to the number and seriousness of irAEs. Multiple-organs irAEs add complexity to the management, and additional research is needed to develop optimal therapeutic guidelines.

Epstein-Barr virus (EBV)-associated lymph nodal T/NK cell lymphoma (nodal TNKL) is a rare and aggressive malignancy with an extremely poor prognosis. Although treatments of extranodal NK/T cell lymphoma are frequently reported, the characteristics and pathogenesis of EBV-associated nodal TNKL are different. However, there is no known effective therapy regimen at present. Here, we reported the clinical efficacy and feasibility of the programmed death 1 (PD-1) blockade therapy regimen in an elderly female patient with EBV-associated nodal TNKL. The patient failed to respond to cyclophosphamide, doxorubicin, vindesine, and prednisone regimen but achieved complete response after three cycles of anti-PD-1 antibody (tislelizumab) combined with gemcitabine and oxaliplatin (GemOx) regimen. The finding indicated that tislelizumab combined with the GemOx regimen may be a potent salvage regimen for EBV-associated nodal TNKL.

Over the past decade, diverse PD-1/PD-L1 blockades have demonstrated significant clinical benefit in across a wide range of tumor and cancer types. With the increasing number of PD-1/PD-L1 blockades available in the market, differences between the clinical performance of each of them started to be reported. Here, we provide a comprehensive historical and biological perspective regarding the underlying mechanism and clinical performance of PD-1/PD-L1 blockades, with an emphasis on the comparisons of their clinical efficacy and safety. The real-world evidence indicated that PD-1 blockade may be more effective than the PD-L1, though no significant differences were found as regards to their safety profiles. Future head-to-head studies are warranted for direct comparison between them. Finally, we summarize the yet to be elucidated questions and future promise of anti-PD-1/PD-L1 immunotherapy, including a need to explore novel biomarkers, novel combinatorial strategies, and their clinical use on chronic infection.

Plasmablastic lymphoma (PBL) is a rare and aggressive hematological malignancy. PBL commonly occurs in immune incompetent patients, such as those with human immunodeficiency virus (HIV), post-transplant status, or immunosenescence. Given its rarity, there is no specific standard treatment for PBL. However, small case series have shown that intensive chemotherapies combined with anti-myeloma agents such as bortezomib and lenalidomide were effective in treating PBL. Unfortunately, some fragile patients could not tolerate intensive chemotherapeutic regimens, especially the elderly patients. Here we presented a 76-year-old female PBL patient refractory to miniCHOP regimen combined with bortezomib but achieved complete remission when treated with tislelizumab combined with lenalidomide, indicating that immune therapy may be a potential treatment for PBL. To our knowledge, this is the first chemoresistant PBL patient that has been successfully treated with checkpoint inhibitor plus lenalidomide, thus providing new insight towards PBL management.

IntroductionTransarterial chemoembolization (TACE) is inefficient at converting unresectable hepatocellular carcinoma (uHCC) to resectable. Treatment with immune checkpoint inhibitors (ICIs) is an emerging strategy for uHCC. Combined therapy of TACE with ICIs is considered to improve the therapeutic effect.Case presentationA 45-year-old man was diagnosed with a bulky HCC under cirrhotic background without distant metastasis. Curative resection was infeasible, and TACE plus tislelizumab (an ICI targeting PD-1) was applied. The treatment course, starting from TACE and followed by tislelizumab one week later, was repeated every four weeks. After three courses, the tumor showed striking shrink in volume with complete radiological response, which permitted salvage resection. Notably, pathological examination found complete necrosis of the tumor with massive infiltration of lymphocytes in the tumor-nontumor interface and extensive granulomatous inflammation in the surrounding nontumor liver, indicating activated immune response synergistically caused by TACE with tislelizumab. The patient is now living well without tumor recurrence for 6 months after surgery.ConclusionTACE in combination with tislelizumab may represent a potent strategy for uHCC. Data from randomized clinical trials are needed to assess its safety and effect in the setting of preoperative downstaging therapy.

Hepatocellular carcinoma (HCC) has an increasing incidence worldwide, and the global 5-year survival rate ranges from 5–30%. In China, HCC seriously threatens the nation's health; the incidence of HCC ranks fourth among all theriomas, and the mortality rate is the third highest worldwide. The main therapies for HCC are surgical treatment or liver transplantation; however, most patients with HCC will experience postoperative recurrence or metastasis, eventually resulting in mortality. As for advanced or unresectable HCC, the current appropriate treatment strategy is transarterial chemoembolization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Previous studies have demonstrated that PD-L1 expression on host cells and myeloid cells plays an important role in PD-L1 blocked-mediated tumor regression. Thus, further research on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is required. Countries including the United States, France, Britain and China have developed PD-1/PD-L1 blockers, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, toripalimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in HCC. Factors that influence the clinical outcome of PD-1 have also been discovered, such as inflammatory genes, specific receptors and signaling pathways. The discovery of these factors will help to identify novel methods, such as combination treatment, to decrease the influence of other factors on the efficacy of PD-1/PD-L1. Sorafenib and lenvatinib have been approved for first-line treatment for patients with advanced HCC. When first-line treatment frequently fails, pembrolizumab and ipilimumab plus nivolumab are used following sorafenib (but not lenvatinib) treatment in advanced HCC. Thus, tumor immunotherapy using PD-1/PD-L1 blockers exhibits promising outcomes for the treatment of HCC, and more novel PD-1/PD-L1 inhibitors are being developed to fight against this disease. The present review discusses the clinical results and influencing factors of PD-1/PD-L1 inhibitors in HCC to provide insight into the development and optimization of PD-1/PD-L1 inhibitors in the treatment of HCC.

BackgroundAs an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin’s lymphoma (NHL) is rare, especially in the treatment of ICIs.Case presentationA 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment.ConclusionTislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.

Mixed serous-endometrioid endometrial carcinoma is a type of endometrial cancer with relatively low incidence. The genetic factors contributing to the tumorigenesis of mixed carcinoma remains to be explored. Here, we report the first identification of two germline mutations in BRCA1 and MSH2 in a woman with mixed serous papillary adenocarcinoma and endometrioid carcinoma. Immunohistochemistry analysis showed loss of MSH2 and MSH6 protein expression in the endometrioid component. The patient showed partial response to tislelizumab treatment following progression on chemotherapy. Two germline mutations in BRCA1 and MSH2 may collectively promote the tumorigenesis of uterine endometrium with two distinct histological components.