MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.

A Concerted Vision to Advance the Knowledge of Diabetes Mellitus Related to Immune Checkpoint Inhibitors.

The rubric of immune-related (ir) diabetes mellitus (DM) (irDM) encompasses various hyperglycemic disorders related to immune checkpoint inhibitors (ICPis). Beyond sharing similarities with conventional DM, irDM is a distinct, yet important, entity. The present narrative review provides a comprehensive overview of the literature regarding irDM published in major databases from January 2018 until January 2023. Initially considered rare, irDM is increasingly being reported. To advance the knowledge of irDM, the present review suggests a concerted vision comprising two intertwined aspects: a scientific-centered and a patient-centered view. The scientific-centered aspect addresses the pathophysiology of irDM, integrating: (i) ICPi-induced pancreatic islet autoimmunity in genetically predisposed patients; (ii) altered gut microbiome; (iii) involvement of exocrine pancreas; (iv) immune-related acquired generalized lipodystrophy. The patient-centered aspect is both nurtured by and nurturing the four pillars of the scientific-centered aspect: awareness, diagnosis, treatment, and monitoring of irDM. The path forward is a multidisciplinary initiative towards: (i) improved characterization of the epidemiological, clinical, and immunological profile of irDM; (ii) standardization of reporting, management, and surveillance protocols for irDM leveraging global registries; (iii) patient stratification according to personalized risk for irDM; (iv) new treatments for irDM; and (v) uncoupling ICPi efficacy from immunotoxicity.

Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune-related adverse events (irAEs). However, the association between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti-PD-1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+ ), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs- group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression-free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs- group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+ /rash+ group was better than that of those in the irAEs+ /rash- or irAEs- group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio [HR]: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti-PD-1 antibodies.

Increased thyroid uptake on 18F-FDG PET/CT is associated with the development of permanent hypothyroidism in stage IV melanoma patients treated with anti-PD-1 antibodies.

PURPOSE: To determine performances of 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) to detect the development of permanent thyroid dysfunction (PTD), and to evaluate the prognostic value of early increased thyroid uptake in stage IV melanoma patients treated with anti-programmed death 1 (anti-PD-1) antibodies. METHODS: Twenty-nine patients were retrospectively enrolled. PTD was defined as symptomatic thyroid disorder requiring long-term specific treatment. On the first PET performed during follow-up, maximal standardized uptake value of the thyroid (SUVmax-Th) and SUVmax-Th/SUVmax-blood-pool ratio (Th/B) were measured. Areas under ROC curves (AUC) of these parameters for the diagnostic of PTD were compared. Cutoff values were defined to maximize the Youden's index. Survival analyses were performed according to the Kaplan-Meier method and compared using the log-rank method between patients with and without enhanced thyroid uptake according to cutoff values defined with the Hothorn and Lausen method. RESULTS: Four patients presented PTD. Median SUVmax-Th and Th/B were, respectively, 2.11 and 1.00. The median follow-up period was 21.7 months. AUC were 1.0 (CI95% 0.88-1.0) for both parameters. Optimal cutoff values were, respectively, SUVmax-Th > 4.1 and Th/B > 2.0, both conferring sensitivities of 100% (CI95% 40-100%) and specificities of 100% (CI95% 86-100%). The median progression-free survival and overall survival were 11.3 months and 33.5 months, respectively. Using optimized cutoffs, there was no statistically significant difference of survival. CONCLUSION: SUVmax-Th > 4.1 and Th/B > 2.0 provided perfect diagnostic performances to detect patients that developed PTD. No significant survival difference was found between patients with and without increased thyroid uptake.

Comparative effectiveness of second-line ipilimumab vs. nivolumab in combination with ipilimumab in patients with advanced melanoma who received frontline anti-PD-1 antibodies.

INTRODUCTION: Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab. METHODS: A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis. RESULTS: A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab (n = 22) or ipilimumab in combination with nivolumab (n = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p = 0.81. CONCLUSIONS: In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.

Update on the anti-programmed cell death-1 receptor antibodies in advanced cutaneous squamous-cell carcinoma.

Regarding the rising incidence and the not negligible mortality, the treatment of cutaneous squamous-cell carcinoma (cSCC) has a high clinical relevance. Immune checkpoint inhibitors (ICI), especially anti-programmed cell death-1 receptor (anti-PD-1) antibodies such as pembrolizumab and cemiplimab have shown promising results in Phase 2 studies for patients with locally advanced and/or metastatic cSCC. We are presenting a review of the latest results in the treatment of cSCC with ICI. Patients with locally advanced or metastatic cSCC have been treated with cemiplimab 3 mg/kg every 2 weeks. For locally advanced cSCC, an objective response was observed in 44% of patients, 13% patients with a complete response, and 31% with a partial response. For metastatic patients, the overall response rate was 49.2%. The approved dose for cemiplimab in the United States and Europe is 350 mg every 3 weeks. These ICI seem to achieve higher response rates compared with epidermal growth factor receptor (EGFR) inhibitors, with a durable response superior to both chemotherapy and EGFR inhibitors. The side effect profile of anti-PD-1 antibodies appears to be favorable compared to chemotherapy. In this way, PD-1 inhibitors are expected to become the new gold-standard treatment for patients with locally advanced and metastatic cSCC.

An Investigation of Nine Patients with Gastrointestinal Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors.

INTRODUCTION/AIMS: Immune checkpoint inhibitors (ICIs) sometimes cause immune-related adverse events (irAEs), of which there is little information in the literatures. The objective of this study was to characterize the clinical features of gastrointestinal irAEs (GI irAEs). MATERIALS AND METHODS: From a total of 250 patients who were administered anti-PD-1 antibodies (nivolumab and pembrolizumab), we retrospectively identified 9 patients with grade 2 or higher GI irAE based on medical records. Patient characteristics, clinical features, imaging and pathological findings, and treatment course were evaluated. RESULTS: Grade 2 or higher GI irAEs were observed in 9 (3.6%) patients. Of the 9 patients who experienced GI irAE, 8 were male, and mean age was 63.2 years. Five patients received nivolumab and 4 received pembrolizumab. The GI irAEs observed were diarrhea in 7 patients and bloody stool in 2 patients. Grade 2 GI irAEs were identified in 3 patients and grade 3 GI irAEs in 6 patients. The average time from ICI administration to the onset of GI irAEs was 22.2 weeks (range 7-56 weeks) for nivolumab and 19.7 weeks (range 11-28 weeks) for pembrolizumab. Endoscopic findings showed ulcerative colitis-like findings in 3 of 7 patients, and pathological examination revealed crypt epithelial cell apoptosis in 6 of 7 patients. Eight of the 9 patients received steroids, and 2 patients received infliximab additionally. All GI irAEs were manageable. CONCLUSIONS: Because of the lack of specific clinical, imaging, and pathological findings, information of ICI use was indispensable for diagnosis. Although GI irAEs are controllable by steroid and infliximab, further studies regarding management strategy will be needed.

[Advances in antibody therapy for B cell lymphoma].

Almost 20 years have passed after rituximab, an anti-CD20 mouse-human chimeric monoclonal antibody therapeutic, was introduced in the clinical setting for the treatment of CD20-positive B cell malignancies. Although the prognosis has significantly improved in most B cell malignancies, resistance to rituximab with/without chemotherapies is also widely recognized. With this background, newer generation antibody therapeutics and other molecular targeting drugs that show more effectiveness especially to refractory patients are critically required. In this review, molecular mechanisms of the second/third generation anti-CD20 antibodies (ofatumumab and obinutuzumab), anti-CD19 chimeric antigen-receptor T-cells (CAR-T-CD19; tisagenlecleucel, axicabtagene ciloleucel), and the anti-PD-1 antibodies (nivolumab and pembrolizumab) are presented. The therapeutic effectiveness of those drugs as monotherapy and/or combined therapy with conventional chemotherapy (immunochemotherapy) and another molecular targeting therapeutics (so-called "chemo-free" regimens) are also reviewed.

The role of transplantation in Hodgkin lymphoma.

Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in nearly 50% of cases. The quality of response at transplantation is the most relevant prognostic aspect, as patients in complete response can obtain better outcomes. Therefore, first-line salvage treatments applied before transplantation need to produce high quality responses without excessive myelotoxicity and without affecting peripheral blood stem cell mobilisation. In this sense, the incorporation of new agents active in Hodgkin lymphoma, such as brentuximab vedotin and anti-programmed death 1 antibodies, in conventional regimens, may help to enhance complete remission rates. Working on conditioning regimen and applying a post-autologous consolidation treatment (for example with brentuximab vedotin) are two ways for improving transplant outcomes, particularly in patients displaying high-risk features for early relapse or progression. Allogeneic transplantation maintains its curative potential also in the era of new drugs, although its most correct timing and the most suitable sequence of post-autologous salvage treatments still remain to be determined.

[Lichenoid drug reactions]. / Lichenoide Arzneimittelreaktionen.

Lichenoid drug reactions are rare compared to typical morbilliform drug exanthema or urticaria. They are associated with specific drugs or drug families like gold, antimalarial drugs, ß­blockers and angiotensin-converting-enzyme inhibitors. Recent observations included associations with novel drugs such as biologics (e. g. tumour necrosis factor antagonists) and immune checkpoint inhibitors (anti-programme cell death protein 1 antibodies). Lichenoid drug reactions most often resemble lichen planus mainly in areas of ultraviolet-light exposed skin, but also mucosal lichen planus and even bullous lesions may occur.

Newer developments in the immunotherapy of malignant melanoma.

Individuals with malignant melanoma present a variety of immune abnormalities including but not limited to cellular immune dysfunction, antigen presentation deficits, and cytokine production defects. Therefore, enhancing the immune system potential represents an appealing avenue for melanoma therapy. The authors review the immune therapies currently in clinical use as well as the most promising immunotherapy candidates. Ipilimumab, a monoclonal antibody against the CTLA-4, was approved for the therapy of advanced melanoma in 2011. In addition, sizeable anti-melanoma activity has recently been shown with the use of other agents including anti-PD-1/anti-PD-1 ligand antibodies. Consequently, these experimental immunotherapy agents may soon become important items in the anti-melanoma armamentarium.

Chemo-Free Treatment Using Anti-PD-1 Antibodies with Lenvatinib in Unresectable Gallbladder Cancer: PD-L1 May Be a Potential Biomarker for a Better Outcome.

BACKGROUND: Recently, anti-PD-1 antibodies plus lenvatinib has been administered in a series of solid tumors. Yet, the efficacy of chemo-free treatment of this combined therapy has seldom been reported in gallbladder cancer (GBC). The aim of our study was to initially evaluate the efficacy of the chemo-free treatment in unresectable GBCs. METHODS: We retrospectively collected the clinical data of unresectable GBCs treated using chemo-free anti-PD-1 antibodies plus lenvatinib in our hospital from March 2019 to August 2022. The clinical responses were assessed, and PD-1 expression was evaluated. RESULTS: Our study enrolled 52 patients, with the median progression-free survival being 7.0 months and the median overall survival being 12.0 months. The objective response rate was 46.2% and the disease control rate was 65.4%. The expression of PD-L1 in patients with objective response was significantly higher than those with progression of disease. CONCLUSIONS: For patients with unresectable GBC, when not eligible for systemic chemotherapy, chemo-free treatment using anti-PD-1 antibodies with lenvatinib may become a safe and rational choice. The expression of PD-L1 in tumor tissues may be correlated to the objective response, and thus is expected to be a predictor of efficacy, and further clinical studies are certainly needed.

Efficacy and safety of anti-PD-1 antibody plus chemoradiotherapy in locally advanced esophageal squamous cancer.

Objective: To compare effects and adverse events of anti-programmed cell death protein 1 (anti-PD-1) antibody combined with chemoradiotherapy (CRT) and CRT alone as the initial treatment in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: We retrospectively reviewed locally advanced ESCC patients who received Anti-PD-1+CRT as initial treatment at 3 institutions. Primary outcomes of interest were progression-free survival (PFS) and overall survival (OS); secondary outcomes were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and treatment-related adverse events (AEs) including immune-related adverse events (irAEs). Results: At data cutoff, 81 patients were included (30 Anti-PD-1+CRT, 51 CRT). Median follow-up was 31.4 months. Anti-PD-1+CRT resulted in significant improvements in PFS (median, 18.6 vs. 11.8 months, HR 0.48 [95% CI, 0.29-0.80], P = 0.008), and OS (median, 27.7 vs. 17.4 months, HR 0.37 [95% CI, 0.22-0.63], P = 0.002), compared with CRT in ESCC. The ORR and DCR of patients treated with Anti-PD-1+CRT were also significantly higher than those treated with CRT (80.0% vs. 56.9%, P = 0.034), (100% vs. 82.4%, P = 0.023), respectively. Anti-PD-1+CRT had better durable response compared with CRT, with DoR (median,17.3 vs. 11.1 months, P = 0.022). Treatment-related adverse event incidence was similar between the two groups (any Grade, 93.3% vs. 92.2%; ≥Grade 3, 50.0% vs. 33.3%). Conclusion: Anti-PD-1 plus chemoradiotherapy demonstrated promising antitumor activity and was well tolerated in locally advanced ESCC.

Postoperative adjuvant immunotherapy for high-risk hepatocellular carcinoma patients.

Background and aim: Standardized approach to postoperative adjuvant therapy for hepatocellular carcinoma (HCC) remains elusive. This study endeavors to examine the effects of postoperative PD-1 adjuvant therapy on the short-term and long-term prognosis of patients at a heightened risk of post-surgical recurrence. Methods: The data of HCC patients who underwent hepatectomy at our center from June 2018 to March 2023 were collected from the hospital database. Propensity score matching (PSM) was employed to perform a 1:1 match between the postoperative anti-PD-1 antibody group and the postoperative non-anti-PD-1 antibody group. Kaplan-Meier method was utilized to compare the overall survival (OS) and recurrence-free survival (RFS) between the two groups. Cox regression analysis was conducted to identify the prognostic factors affecting patient outcomes. Subgroup analyses were performed for different high-risk factors. Results: Among the 446 patients included in the study, 122 patients received adjuvant therapy with postoperative anti-PD-1 antibodies. After PSM, the PD-1 group had postoperative 1-year, 2-year, 3-year, and 4-year OS rates of 93.1%, 86.8%, 78.2%, and 51.1%, respectively, while the non-PD-1 group had rates of 85.3%, 70.2%, 47.7%, and 30.0%. The PD-1 group had postoperative 1-year, 2-year, 3-year, and 4-year RFS rates of 81.7%, 77.0%, 52.3%, and 23.1%, respectively, whereas the non-PD-1 group had rates of 68.4%, 47.7%, and 25.8% in 1-year, 2-year, 3-year. A multifactorial Cox regression analysis revealed that postoperative PD-1 use was a prognostic protective factor associated with OS and RFS. Subgroup analysis results indicated that HCC patients with high recurrence risks significantly benefited from postoperative anti-PD-1 antibody treatment in terms of OS and RFS. Conclusion: For HCC patients with high-risk recurrence factors and undergoing hepatectomy, postoperative adjuvant therapy with anti-PD-1 antibodies can effectively improve their survival prognosis.

Postoperative adjuvant tyrosine kinase inhibitors combined with anti-PD-1 antibodies improves surgical outcomes for hepatocellular carcinoma with high-risk recurrent factors.

Background: The clinical value of postoperative adjuvant therapy (PAT) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore the effect of PAT with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies on the surgical outcomes of HCC patients with high-risk recurrent factors (HRRFs). Methods: HCC patients who underwent radical hepatectomy at Tongji Hospital between January 2019 and December 2021 were retrospectively enrolled, and those with HRRFs were divided into PAT group and non-PAT group. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups after propensity score matching (PSM). Prognostic factors associated with RFS and OS were determined by Cox regression analysis, and subgroup analysis was also conducted. Results: A total of 250 HCC patients were enrolled, and 47 pairs of patients with HRRFs in the PAT and non-PAT groups were matched through PSM. After PSM, the 1- and 2-year RFS rates in the two groups were 82.1% vs. 40.0% (P < 0.001) and 54.2% vs. 25.1% (P = 0.012), respectively. The corresponding 1- and 2-year OS rates were 95.4% vs. 69.8% (P = 0.001) and 84.3% vs. 55.5% (P = 0.014), respectively. Multivariable analyses indicated that PAT was an independent factor related to improving RFS and OS. Subgroup analysis demonstrated that HCC patients with tumor diameter > 5 cm, satellite nodules, or vascular invasion could significantly benefit from PAT in RFS and OS. Common grade 1-3 toxicities, such as pruritus (44.7%), hypertension (42.6%), dermatitis (34.0%), and proteinuria (31.9%) were observed, and no grade 4/5 toxicities or serious adverse events occurred in patients receiving PAT. Conclusions: PAT with TKIs and anti-PD-1 antibodies could improve surgical outcomes for HCC patients with HRRFs.

Patient-derived melanoma organoid models facilitate the assessment of immunotherapies.

BACKGROUND: Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy. METHODS: Here, we report two different methods for generating melanoma patient-derived organoids (MPDOs), one is embedded in collagen gel, and the other is inlaid in Matrigel. MPDOs in Matrigel are used for assessing the therapeutic effects of anti-PD-1 antibodies (αPD-1), autochthonous tumor infiltrating lymphocytes (TILs), and small molecule compounds. MPDOs in collagen gel are used for evaluating the chemotaxis and migratory capacity of TILs. FINDING: The MPDOs in collagen gel and Matrigel have similar morphology and immune cell composition to their parental melanoma tissues. MPDOs show inter- and intra-tumoral heterogeneity and contain diverse immune cells such as CD4+, CD8+ T, Treg, CD14+ monocytic, CD15+, and CD11b+ myeloid cells. The tumor microenvironment (TME) in MPDOs is highly immunosuppressive, and the lymphoid and myeloid lineages express similar levels of PD-1, PD-L1, and CTLA-4 as their parental melanoma tissues. Anti-PD-1 antibodies (αPD-1) reinvigorate CD8+ T cells and induce melanoma cell death in the MPDOs. TILs expanded by IL-2 and αPD-1 show significantly lower expression of TIM-3, better migratory capacity and infiltration of autochthonous MPDOs, and more effective killing of melanoma cells than TILs expanded by IL-2 alone or IL-2 with αCD3. A small molecule screen discovers that Navitoclax increases the cytotoxicity of TIL therapy. INTERPRETATION: MPDOs may be used to test immune checkpoint inhibitors and cellular and targeted therapies. FUNDING: This work was supported by the NIH grants CA114046, CA261608, CA258113, and the Tara Miller Melanoma Foundation.

Downstaging and laparoscopic hepatectomy plus intraoperative radiofrequency ablation for the treatment of initially unresectable multifocal hepatocellular carcinomas.

Background: Using TKIs plus anti-PD-1 antibodies combined with TACE in the treatment of patients with initially unresectable multiple HCCs has a high tumour response rate, and using laparoscopic hepatectomy (LH) combined with intraoperative RFA for radical treatment of multiple HCCs after successful downstaging treatment has not been reported. Methods: Consecutive patients with multiple HCCs (≤4 lesions) who were downstaged with TKIs plus anti-PD-1 antibodies combined with TACE were analysed. Imaging examinations were performed monthly, and RECIST v1.1 criteria were used to evaluate treatment effect and resectability. Results: Forty-five consecutive patients with multiple HCCs who met the inclusion criteria received downstaging treatment with TKIs plus anti-PD-1 antibodies combined with TACE. Nine patients were successfully downstaged and met the R0 resection criteria, and 8 patients underwent surgery. Among the patients, 5 patients had BCLC stage C, and 3 patients had BCLC stage B. There were 2 lesions in 5 patients, 3 lesions in 2 patients, and 4 lesions in 1 patient. The average size of the main HCC was 8.5 cm (range: 5.4-9.1 cm), and the diameter of the remaining HCCs was 1.6 cm (range: 0.8-2.9 cm). The average time from the start of downstaging therapy to surgery was 81 days (range: 60-210 days). All 8 patients underwent LH of the main HCC, and the remaining HCCs were targeted with RFA. The mean operation time was 220 min (range 150-370 min), the average intraoperative blood loss was 260 ml (range 100-750 ml), there was no case conversion to laparotomy, and the average postoperative hospital stay was 9 days (range 7-25 days). The incidence of postoperative complications was 37.5% and there were no deaths. The average follow-up time was 18.2 months (range 6.1-22.4 months), 5 patients survived tumour-free, 2 patients had tumour recurrence, and 1 patient died. Conclusions: After successful downstaging of multiple HCCs by treatment with TKIs plus anti-PD-1 antibodies and TACE, LH combined with RFA for radical surgery is safe and feasible, and the treatment effect is satisfactory. It is worthy of clinical reference, and its long-term effects require further research for confirmation.

Mesenchymal stem cells elicits Anti-PD1 immunotherapy by targeted delivery of CX3CL1.

Anti-PD1/PDL1 monotherapy has failed to acquire sufficiently ideal results in most solid tumors. Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on some tumors, but the functions of MSCs in colorectal cancer (CRC) need further research. In this study, we aimed to investigate the therapeutic effect and the improvement of sensitivity of MSCs to anti-PD1 antibodies (αPD1) in CRC and to evaluate the possible mechanism. The relative distribution of immune cells in tumor microenvironment was examined after the mice were treated with MSC and/or αPD1. Our study revealed that MSC recruits CX3CR1high macrophages and promotes M1 polarization to inhibit tumor growth via highly secretion of CX3CL1.The combination of MSC and αPD1 was superior to monotherapy against CRC. MSC inhibits PD1 expression on CD8+ T cells by facilitating M1 macrophage polarization, which promotes the proliferation of CD8+ T cells, thus improving the sensitivity to αPD1 therapy in CRC. Additionally, the above therapeutic effect disappeared after inhibiting the secretion of CX3CL1 in MSC. Our MSC-based immunotherapeutic strategy simultaneously recruited and activated immune effector cells at the tumor site, suggesting that the combination of MSC and αPD1 could be a potential therapy for CRC.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.

INTRODUCTION: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. METHODS: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. RESULTS: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed. CONCLUSION: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.

Peripheral Blood Mononuclear Cells Predict Therapeutic Efficacy of Immunotherapy in NSCLC.

In lung cancer immunotherapy, biomarkers to guide clinical decisions are limited. We now explore whether the detailed immunophenotyping of circulating peripheral blood mononuclear cells (PBMCs) can predict the efficacy of anti-PD-1 immunotherapy in patients with advanced non-small-cell lung cancer (NSCLC). We determined 107 PBMCs subpopulations in a prospective cohort of NSCLC patients before starting single-agent anti-PD-1 immunotherapy (study group), analyzed by flow cytometry. As a control group, we studied patients with advanced malignancies before initiating non-immunotherapy treatment. The frequency of PBMCs was correlated with treatment outcome. Patients were categorized as having either high or low expression for each biomarker, defined as those above the 55th or below the 45th percentile of the overall marker expression within the cohort. In the study group, three subpopulations were associated with significant differences in outcome: high pretreatment levels of circulating CD4+CCR9+, CD4+CCR10+, or CD8+CXCR4+ T cells correlated with poorer overall survival (15.7 vs. 35.9 months, HR 0.16, p = 0.003; 22.0 vs. NR months, HR 0.10, p = 0.003, and 22.0 vs. NR months, HR 0.29, p = 0.02). These differences were specific to immunotherapy-treated patients. High baseline levels of circulating T cell subpopulations related to tissue lymphocyte recruitment are associated with poorer outcomes of immunotherapy-treated advanced NSCLC patients.