Programmed Death-1 Blockade Research Articles

Brentuximab Vedotin versus checkpoint inhibitors: Which one? When? Why should be preferred?

About 15% of classical Hodgkin lymphoma (cHL) patients remain refractory to first-line therapy and about one third of the responding patients relapse1. The standard of care for relapsed or refractory (R/R) cHL is salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT)2. Three novel agents effective in R/R cHL were introduced; brentuximab-vedotin (BV), anti-CD30 antibody-drug conjugate3 and the programmed-death-1 (PD-1) blocking antibodies, nivolumab and pembrolizumab4, 5 has been approved. The optimal line to incorporate these agents is an actual dilemma. BV and PD1-blockers are effective in R/R cHL after ASCT. KEYNOTE-204 study reported that pembrolizumab treatment was associated with significantly longer PFS compared with BV (median:13.2 vs 8.3 months)6. In case of durable responses with PD1-blockers, cessation of the treatment may be an individualized decision and high response rates to re-treatment with PD1-blockers is an important advantage7. There is not obvious differences in the efficacy and toxicity of nivolumab and pembrolizumab8. We can conclude that PD1-blockers could be preferred over BV in patients who relapse following ASCT and who are naïve to BV and PD-1 blockade. For patients relapsing after ASCT with prior BV or PD1-blocker exposure, selection of the agent that has not been used previously could be recommended8. BV and PD1-blockers are incorporated into the pre-ASCT salvage regimens in clinical trials. In the phase II BRaVE study, BV added to DHAP provided a complete metabolic response rate of 81% before ASCT, with a 2-year PFS and OS rates of 74% and 95%, respectively9. Similarly, pembrolizumab in combination with GVD provided an overall response rate (ORR) of 100%10. BV and nivolumab combination resulted in an ORR of 85%. The 3-year PFS rate for ASCT group was 91%11. Regarding these data, the need for ASCT will be an important point of debate in the next years. In case of primary refractory disease, chemotherapy-based salvage regimens remain the standard. Combination treatment with BV and nivolumab resulted in a 21-month PFS of 65% in this group11, which may be a satisfactory option in the future. Post-ASCT consolidation with BV is now standard of care in patients with risk factors defined by AETHERA trial12, which is supported by real-world data including pre-treated with and responsive to BV patients13. Novel agents are not recommended in the front-line management of early-stage disease. ECHELON-1 study performed on treatment-naïve stage III/IV cHL patients reported 6-year PFS, and OS ratio were 82.3% and 93.9% for BV-AVD cohort versus 74.5% and 89.4% for ABVD cohort14. Beside advanced stage cases, BV-based therapies should be considered for elderly, unfit patients who cannot tolerate combination chemotherapies, as they are associated with longer duration of response compared to BV monotherapy8. Giving decision about novel therapies, major adverse events, such as neuropathy for BV and immune related events for PD1-blockers. Optimal timing of BV and PD1-blockers and treatment strategies in case of resistance to novel agents are critical questions for the future of cHL management, which hopefully will be answered by the results of clinical trials and real-world data.

Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes.

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti–PD-L1 but not anti–CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti–PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti–IFN-γ and anti–TNF-α prevented CPI-DM in anti–PD-L1–treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

CD25-targeted antibody-drug conjugate camidanlumab tesirine for relapsed or refractory classical Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) accounts for more than 90% of HL in developed countries. Although the current combined modality therapy make it have a high cure rate, the prognosis for heavily pretreated patients with relapsed or refractory (R/R) cHL remains poor. A novel antibody-drug conjugate (ADC), named camidanlumab tesirine (ADCT-301, Cami), is currently being evaluated for its efficacy and safety in R/R cHL. The primary objective of this review is to examine the current pharmacological properties of camidanlumab tesirine as well as its clinical antitumor activity and safety. Camidanlumab tesirine comprises a human IgG1 anti-CD25 monoclonal antibody HuMax®-TAC, conjugated to a pyrrolobenzodiazepine dimer toxin. Once it bound to CD25-expressing cells, camidanlumab tesirine is internalized by cells and delivers SG3199, then SG3199 irreversibly binds to DNA and forms DNA interstrand crosslinks, ultimately leading to cell death. In the phase 1 study, patients with R/R cHL who received camidanlumab tesirine had an overall response rate (ORR) of 71% and a complete response rate (CRR) of 42%. Additionally, the recommended doses provided in R/R cHL were determined to be 30 and 45μg/kg. The pivotal phase 2 trial showed significant antitumor activity of camidanlumab tesirine in heavily pretreated R/R cHL patients who failed brentuximab vedotin and programmed death-1 blockade: ORR was 70.1% and CRR was 33.3%, and the median duration of response was 13.7months. Adverse events such as fatigue, maculopapular rash, and anemia were frequently observed following administration of camidanlumab tesirine. Moreover, camidanlumab tesirine may cause Guillain-Barré syndrome or polyradiculopathy.

How representative are data from global trials on programmed death-1 blockade in melanoma?

Abstract Linked Article: Bai et al. Br J Dermatol 2022; 187:401–410.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Hydrazide-manganese coordinated multifunctional nanoplatform for potentiating immunotherapy in hepatocellular carcinoma

Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H2O2 to O2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment.

Efficacy and safety of anlotinib plus programmed death-1 blockade versus anlotinib monotherapy as second or further-line treatment in advanced esophageal squamous cell carcinoma: A retrospective study.

BackgroundBoth anlotinib and programmed death-1 (PD-1) blockade have been approved for the second-line treatment of metastatic esophageal squamous cell carcinoma (ESCC). However, the combination of these two therapies has not been evaluated. This study investigated the efficacy and safety of anlotinib, a novel multitarget tyrosine kinase inhibitor targeting tumor angiogenesis, combined with PD-1 blockade as second or further-line treatment for advanced ESCC.MethodsBetween January 2019 and February 2021, 98 advanced ESCC patients receiving anlotinib plus PD-1 blockade or anlotinib monotherapy as second or further-line treatment at Henan Cancer Hospital were retrospectively analyzed. Patients receiving anlotinib plus PD-1 blockade were grouped as cohort A (n=48), while those receiving anlotinib monotherapy were grouped as cohort B (n=50). The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR) and toxicity. Furthermore, independent prognostic factors were identified by Cox regression analysis. A two-sided p-value of <0.05 was considered statistically significant.ResultsData was collected until May 1, 2021, with a median follow-up time of 9.30 months (8.23–10.37 months) in cohort A and11.10months (7.82–14.38 months) in cohort B. For patients with advanced ESCC, cohort A resulted in significantly longer PFS (5.40 vs. 3.00 months, P<0.001) and higher DCR (71.7% vs. 47.9%, P=0.019) than cohort B. The ORR indicated no significant difference between cohort A (23.9%) and cohort B (10.4%) (P=0.082). Adverse reactions were mainly grade1/2 in the two groups. Compared with cohort B, a significantly higher rate of grade 1–2 hypothyroidism was observed in patients in cohort A (P= 0.034). Three patients (6.3%) developed grade 1/2 immune-related pneumonia. There was no significant difference in the incidence of grade 3-4 toxicities. Multivariable Cox regression analysis showed that the drug regimen (P<0.001), Eastern Cooperative Oncology Group Performance Status (P=0.002), distant organ metastasis (P=0.008), and metastatic sites (P=0.032) were independent prognostic factors for PFS.ConclusionsAnlotinib plus PD-1 blockade showed promising anti-tumor activity and manageable toxicity as second or further-line treatment of advanced ESCC.

Preclinical Characterization of Relatlimab, a Human LAG-3-Blocking Antibody, Alone or in Combination with Nivolumab.

Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune-checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen-like protein-1, and to reverse LAG-3-mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced antitumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase II/III trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrates superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.

PD-1 blockade following ART interruption enhances control of pathogenic SIV in rhesus macaques

Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after anti-retrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIV-specific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100- to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research.

The interaction between the soluble programmed death ligand-1 (sPD-L1) and PD-1+ regulator B cells mediates immunosuppression in triple-negative breast cancer.

Accumulating evidence suggests that regulatory B cells (Bregs) play important roles in inhibiting the immune response in tumors. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important molecules that maintain the balance of the immune response and immune tolerance. This study aims to evaluate the soluble form of PD-L1 and its function in inducing the differentiation of B lymphocytes, investigate the relationship between soluble PD-L1 (sPD-L1) and B-cell subsets, and explore the antitumor activity of T lymphocytes after PD-L1 blockade in coculture systems. In an effort to explore the role of sPD-L1 in human breast cancer etiology, we examined the levels of sPD-L1 and interleukin-10 (IL-10) in the serum of breast tumor patients and the proportions of B cells, PD-1+ B cells, Bregs, and PD-1+ Bregs in the peripheral blood of patients with breast tumors and assessed their relationship among sPD-L1, IL-10, and B-cell subsets. The levels of sPD-L1 and IL-10 in serum were found to be significantly higher in invasive breast cancer (IBCa) patients than in breast fibroadenoma (FIBma) patients. Meanwhile, the proportions and absolute numbers of Bregs and PD-1+ Bregs in the peripheral blood of IBCa patients were significantly higher than those of FIBma patients. Notably, they were the highest in triple-negative breast cancer (TNBC) among other subtypes of IBCa. Positive correlations of sPD-L1 and IL-10, IL-10 and PD-1+ Bregs, and also sPD-L1 and PD-1+ Bregs were observed in IBCa. We further demonstrated that sPD-L1 could induce Breg differentiation, IL-10 secretion, and IL-10 mRNA expression in a dose-dependent manner in vitro. Finally, the induction of regulatory T cells (Tregs) by Bregs was further shown to suppress the antitumor response and that PD-L1 blockade therapies could promote the apoptosis of tumor cells. Together, these results indicated that sPD-L1 could mediate the differentiation of Bregs, expand CD4+ Tregs and weaken the antitumor activity of CD4+ T cells. PD-L1/PD-1 blockade therapies might be a powerful therapeutic strategy for IBCa patients, particularly for TNBC patients with high level of PD-1+ Bregs.

Blockade of PD-1/PD-L1 increases effector T cells and aggravates murine chronic graft-versus-host disease

T-cells mediated immunopathology is crucial for pathogenesis of chronic graft-versus-host disease (cGVHD), a common complication following allogeneic hematopoietic cell transplantation. Programmed death-1 (PD-1) regulates long-term survival and functional exhaustion of T-cell which might play a role in regulating cGVHD. We examined PD-1 expression on T cells of cGVHD mice and tested the impact of a PD-1 antibody on severity of cGVHD in murine allotransplant models. We also used a murine graft-versus-tumor (GVT) model to explore how tumor cell-derived PD-L1 affect the GVT effect and occurrence of cGVHD. PD-1 fluorescence intensity on CD4+ T-cells increased in mice developing cGVHD. PD-1High T cells expressed higher levels of IFNγ and IL-17, comparing with PD-1Low T cells. Giving the PD-1 antibody increased proportions of Th1, Th17 and Tc1 cells, but decreased proportion of Treg cells in allotransplant mice. The PD-1 antibody decreased survival of recipients and induced severe lung cGVHD. In the GVT model, knockdown of PD-L1 in A20 tumor cells enhanced GVT effect but increased cGVHD. In vitro study showed knockdown of PD-L1 in tumor cells increased cytotoxicity of T cells and reduced apoptosis of T cells. Knockdown of PD-L1 in tumor cells increased protein levels of phosphorylated AKT, Bcl-2 and Mcl-1, but decreased protein levels of Bak and Bax in co-cultured allogeneic T cells. In conclusion, expression of PD-1 on T cells increased in mice undergoing cGVHD. Intervention of the PD-1/PD-L1 pathway showed a significant impact on occurrence of cGVHD and GVT effect.

PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

BackgroundNeoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.MethodsWe initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.ResultsA total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.ConclusionsMismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.)

Abstract 4121: Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma

Abstract Background: Recurrent respiratory papillomatosis (RRP) is a human papilloma virus (HPV) associated benign disease, which, in rare cases, can develop into lung squamous cell carcinoma. Treatment options are limited with no approved systemic adjuvant therapy and the disease requires frequent surgical resection to prevent airway obstruction. Therefore, expanding available treatment options remains a highly important, but unmet need in RRP. Herein, we present a case of RRP with squamous cell carcinoma of lung that demonstrated durable stable disease with nivolumab and subsequent bevacizumab. Case presentation: A 48-year-old woman with long standing RRP since teenager, who underwent multiple microsuspension laryngoscopies, debridements including laryngeal lesions, and ultimately, 5 years ago, video assisted thoracic surgery (VATS) resection of right upper lobe mass, confirming squamous cell carcinoma, has been managed with debulking surgery on tracheal lesions by ENT on regular basis. Nivolumab, a programmed death-1 blockade, 3 mg/kg every 2 weeks was started given squamous cell carcinoma of lung. Stable disease (SD) in lung lesions was achieved on nivolumab for one year but she required more frequent debulking of tracheal lesions. After multidisciplinary discussion with Otorhinolaryngology, she was started on bevacizumab, vascular endothelial growth factor inhibitor, 10 mg/kg every 6 weeks. Follow-up CT scans in 10 weeks showed a decrease in size of a left lower lobe mass to 27 mm from 32 mm in the previous image. After one year, administration of bevacizumab was spaced out to every 12 weeks. She requires less debulking surgery and the last debulking surgery was approximately 3 years ago. She maintains SD for over 4 years since starting bevacizumab. Discussion: Our patient with RRP and squamous cell carcinoma of lung demonstrated SD on nivolumab before she was switched to bevacizumab. In addition, her SD on bevacizumab of more than 4 years with 12 weeks of maintenance interval is encouraging as there is no current standard of care treatment for RRP. Despite difficulty in running clinical trials in RRP due to its rareness, additional studies evaluating the efficacy of PD-1 inhibitor or anti-VEGF monoclonal antibody on RRP are warranted. Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Young Kwang Chae. Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4121.

Blockade of TIM-3 and PD-1 enhances the antitumor effects of MAGE-A11 antigen-specific cytotoxic T lymphocytes

Cancer immunotherapy is an attractive approach for antigen-specific T cell-mediated antitumor therapy, especially for the induction of cytotoxic T lymphocytes (CTLs). An human leukocyte antigen (HLA)-A2-restricted melanoma-associated antigen-A11 (MAGE-A11) peptide was developed that exhibited a potent capacity to induce cytotoxicity towards MAGE-A11-positive breast cancer cells by activating CTLs. However, this antitumor immune response can be suppressed by inhibitory pathways. Programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain 3 (TIM-3) pathways are two important pathways involved in the tumor-mediated immune suppression. The present study aimed to augment the efficacy of MAGE-A11 antigen-specific CTLs via blocking PD-1 and TIM-3. The results showed that the expression levels of PD-1 and TIM-3 were unregulated during T cell induction, expansion and target cell killing. Blockade of PD-1 and TIM-3 modulated T cell proliferation, transformation and survival. In addition, treatment of cells with antibodies against PD-1 and TIM-3 enhanced the cytotoxicity of MAGE-A11 antigen-specific CTLs against breast cancer cells. The aforementioned findings suggested that MAGE-A11 antigen-specific CTLs accompanied by PD-1 and TIM-3 blockade could be considered as a potential therapy approach for breast cancer.

OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.

Prediction of immune checkpoint blockade-related hepatitis in metastatic melanoma patients.

The introduction of clinical antibodies against programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has revolutionized cancer treatment. Immune checkpoint blockade has enormous therapeutic potential and is widely prescribed for treating various cancers. However, immune-related adverse events in checkpoint blockade-treated patients are common and limit its clinical application. Despite efforts to understand the etiology of immune-related adverse events, the underlying cellular reactions remain elusive. Recently, our group identified a subset of patients with metastatic melanoma that are predisposed to hepatitis after combined PD-1 and CTLA-4 blockade. These patients are characterized by pre-treatment expansion of effector memory CD4+ T cells (TEM cells) in blood. We attributed this expansion to chronic or recurrent subclinical immune responses against cytomegalovirus (CMV) infection. Accordingly, baseline expansion of TEM cells is a reliable biomarker of hepatitis risk that identifies a subgroup of patients who might benefit from prophylactic CMV treatment with valganciclovir.

Effectiveness and Safety of Anlotinib with or without PD-1 Blockades in the Treatment of Patients with Advanced Primary Hepatocellular Carcinoma: A Retrospective, Real-World Study in China.

PurposeAnlotinib, a novel multi-target tyrosine kinase inhibitor, has shown encouraging antitumor effects in advanced hepatocellular carcinoma (HCC). This study evaluated the effectiveness and safety of anlotinib with or without programmed death-1 (PD-1) blockades for patients with advanced primary HCC in a real-world setting in China.Patients and MethodsBetween July 2019 and May 2021, 27 patients with advanced primary HCC who received at least 2 cycles of anlotinib were included in this retrospective study. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsOf the 27 patients, ORR and DCR were 25.93% and 74.07%, respectively. The median follow-up time was 6.27 months (range: 1.30–17.40) with a median PFS and OS of 3.29 months (95% CI: 1.31–15.47) and 6.21 months (95% CI: 2.23–15.87), respectively. A total of 14 patients received anlotinib and PD-1 blockade combination therapy, and 13 received anlotinib monotherapy. No significant differences were observed in ORR (28.57 vs 23.08%), DCR (71.43 vs 76.92%), PFS (3.38 [95% CI: 2.66–13.14] vs 11.86 months [95% CI: 4.27–15.93]) and OS (4.90 [95% CI: 2.56–13.60] vs 11.04 months [95% CI: 1.31–17.18]) between the two groups (all p>0.05). Treatment-related AEs were reported in 88.89% of patients. Grade 3 AE was bleeding, which occurred in 3 patients (11.11%).ConclusionAnlotinib yielded a promising efficacy and manageable safety in patients with advanced primary HCC irrespective of whether patients received PD-1 blockades, indicating that anlotinib might be a promising treatment option for this patient population.

Neuropilin-1 is a valuable biomarker for predicting response of advanced non-small cell lung cancer patients to hypofractionated radiotherapy and PD-1 blockade

Programmed death-1 (PD-1) blockade promoted the combination therapy of advanced non-small cell lung cancer (NSCLC), induces changes in peripheral memory T cell subsets. Neuropilin-1 (NRP1) is a new T cell memory checkpoint, its association with the clinical prognosis of NSCLC is less reported. Here, we detected the expression of NRP1 and the depletion-associated factor thymocyte selection-associated HMG box protein (TOX) in peripheral T cell subsets with responders treated with hypofractionated radiotherapy (HFRT) combined with PD-1 blockade and chemoimmunotherapy, aimed to explore their association with the prognosis of advanced NSCLC. NRP1 and TOX expression was localized on tissue-infiltrating T cells by immunofluorescence assay in nine patients who had undergone surgery. Flow cytometry was used to detect the expression of NRP1 and TOX in peripheral circulating T cells in patients with advanced NSCLC before and after HFRT combined with PD-1 blockade (HFRT+PD-1) and chemoimmunotherapy in thirty-nine patients. NSCLC patients showed an increase in NRP1 and TOX in peripheral T cells as compared to that in healthy controls. The expression of NRP1 and TOX in CD8+ T cells was higher in tumor tissues than in uninvolved tissues. Patients who responded to HFRT+PD-1 blockade showed a reduction in NRP1+CD8+, TOX+CD4+, and TOX+CD8+ levels, chemoimmunotherapy responders showed decreased expression of NRP1 in the CD4+ T cell subpopulation.In conclusion, lower expression levels of NRP1 and TOX in peripheral circulating CD8+ T cells were associated with a better prognosis for advanced NSCLC patients treated with HFRT+PD-1 blockade.

PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration

Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.

Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway

ABSTRACT Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.