Long-term complete response to anti-programmed-death-1 monotherapy in a patient with relapsed and refractory ovarian adenocarcinoma: A case report

BACKGROUND Ovarian cancer is the most common malignant tumor of the female reproductive system,and the survival rate of patients with relapsed and refractory ovarian cancer is very low.CASE SUMMARY Here,we report a case of high-grade serous papillary adenocarcinoma of the ovary that was successfully treated with immunotherapy.Radical surgery and adjuvant chemotherapy for the 56-year-old patient were successful;however,her tumor relapsed.Subsequent second-line chemotherapy,targeted agents,and other treatments were ineffective,as the tumor continued to recur and metastasize.Anti-programmed cell death-1(PD-1)monotherapy(tislelizumab)completely alleviated the tumor,and the multiple metastatic tumors disappeared.To date,the patient has used anti-PD-1 for 32 months,experiencing no disease progression and maintaining good health without additional treatment.CONCLUSION This case suggests that anti-PD-1 immunotherapy may have long-term positive effects on outcomes in some refractory recurrent solid tumors.Further research is needed to identify patients most likely to respond to anti-PD-1 therapy.

Immunotherapy in biliary tract cancers:Current evidence and future perspectives

Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.

Viro-immune therapy:A new strategy for treatment ofpancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.

Immunotherapy in pancreatic cancer:Unleash its potential through novel combinations

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell responses.However,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive microenvironment.In this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted therapy.These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

Verteporfin synergizes the efflcacy of anti-PD-1 in cholangiocarcinoma

Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.

Camrelizumab-induced anaphylactic shock in an esophageal squamous cell carcinoma patient:A case report and review of literature

BACKGROUND Camrelizumab(SHR-1210),an immune checkpoint inhibitor,is clinically used as a therapeutic option for various types of tumors.However,reports of adverse reactions associated with camrelizumab are gradually increasing.Anaphylactic shock due to camrelizumab has not been reported previously,until now.We report here,for the first time,a case of anaphylactic shock associated with camrelizumab in a patient with esophageal squamous cell carcinoma.CASE SUMMARY An 84-year-old male esophageal cancer patient received radiotherapy and chemotherapy 11 years ago.He was diagnosed with advanced esophageal squamous cell carcinoma with liver metastasis(Tx N1 M1)and received the first immunotherapy(camrelizumab 200 mg/each time,once every 3 wk)dose in December 2020,with no adverse reactions.Three weeks later,a generalized rash was noted on the chest and upper limbs;palpitations and breathing difficulties with a sense of dying occurred 10 min after the patient had been administered with the second camrelizumab therapy.Electrocardiograph monitoring revealed a 70 beats/min pulse rate,69/24 mm Hg(1 mm Hg=0.133 k Pa)blood pressure,28 breaths/min respiratory rate,and 86%pulse oximetry in room air.The patient was diagnosed with anaphylactic shock and was managed with intravenous fluid,adrenaline,dexamethasone sodium phosphate,calcium glucosate,and noradrenaline.Approximately 2 h after treatment,the patient’s anaphylactic shock symptoms had been completely relieved.CONCLUSION Due to the widespread use of camrelizumab,attention should be paid to anti-programmed cell death 1 antibody therapy-associated hypersensitivity or anaphylactic shock.

Deep diving in the PACIFIC:Practical issues in stage III non-small cell lung cancer to avoid shipwreck

After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.

Immunotherapy combinations and chemotherapy sparing schemes in first line non-small cell lung cancer

In recent years,studies have explored different combinations of immunotherapy and chemotherapy.The rationale behind these is the improved survival outcomes of new immunologic therapies used in first-line-treatment of advanced non-small cell lung cancer.Moreover,for the most-studied combinations of anti-programed death-1(PD-1)/programed death ligand-1(PD-L1)with the addition of platinumbased chemotherapy,recent research is investigating whether combining different immunologic antitumoral mechanisms of action,such as anti-PD-1/PD-L1 and anti-CTLA-4,or anti-PD-L1 and anti-TIGIT,with or without chemotherapy,can improve efficacy outcomes compared with more classical combinations,or compared with standard chemotherapy alone.Here,we present the data of the main randomized studies that have evaluated these combinations,focusing on the basic rationale behind the different combinations,and the efficacy and tolerability data available to date.

Precision medicine becomes reality- tumor type--agnostic therapy

Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

Camrelizumab(SHR-1210)treatment for recurrent hepatocellular carcinoma after liver transplant:A report of two cases

Immune checkpoint inhibitors are generally contraindicated for post-transplant patients.However,we report two patients with metastatic hepatocellular carcinoma(HCC)treated with camrelizumab(SHR-1210),an anti-programmed cell death 1(PD-1)agent,after liver transplant.Before undergoing immunotherapy,both patients underwent liver allograft biopsy and obtained negative PD-L1 expression in tumor and liver graft specimens by immunohistochemistry.Then,camrelizumab(200 mg)was administered once every 3 weeks.During immunotherapy,the targeted therapy was continued,and the immunosuppression regimen was adjusted to a low-dose level.No graft rejection or other severe adverse reactions were observed.The disease remained stable(SD,mRECIST)for 3 months in one patient and 10 months in the other.Therefore,camrelizumab may have safety and potential benefits in advanced HCC after liver transplant.