Journal of Immunotherapy最新文献

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, patients with pre-existing autoimmune diseases (PADs) have largely been excluded from clinical trials evaluating this drug class. This study evaluates the effectiveness and safety of ICI therapy in individuals with PAD in a real-world setting. A retrospective study of patients exposed to ICI therapy between 2012 and 2019 was conducted. Patients with PAD were identified and matched to an ICI-exposed group without PAD based on age, sex, and cancer type. Primary outcomes included toxicity, time to treatment failure, overall survival, and objective response rate. The association between PAD status and outcomes was determined using Cox and logistic regression modeling. A total of 813 patients exposed to ICI therapy were identified, of which 8.2% (N=67) had a PAD. When compared with a matched cohort without PAD (N=132), there was no significant difference in the rates of new immune-related adverse events (irAEs, 42.4% in the non-PAD group vs. 47.8% in the PAD group, P=0.474). After controlling for the type of ICI, there was no significant association between PAD status and irAE (odds ratio 1.67, 95% CI: 0.9-3.21 P=0.1). There was no significant association between overall survival and PAD status (hazard ratio 1.12, 95% CI: 0.76-1.66. P=0.56) or between time to treatment failure and PAD status (hazard ratio 0.82, 95% CI: 0.6-1.12, P=0.22). There was an association between PAD status and objective response rate (odds ratio 3.28, 95% CI: 1.28-8.38, P=0.013). In summary, PAD status was not associated with enhanced toxicity when compared with patients without PAD, with similar oncologic effectiveness between these 2 groups.

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.

Immune checkpoint inhibitors have improved the treatment of many cancers. However, immune-related (IR) adverse events can limit their use. A rare but potentially severe IR adverse event is IR-cholangitis, which is mostly induced by anti-programmed cell death 1 (PD1) antibodies and is often corticosteroid-resistant. Consequently, immunosuppressive therapy is increased, which interferes with the antitumor response and bears the risk of infection. We report on 2 patients with BRAF V600E mutant melanoma, who presented with IR-sclerosing cholangitis under triplet therapy with atezolizumab [anti-programmed cell death ligand 1 (PD-L1) antibody], vemurafenib (BRAF inhibitor), and cobimetinib (MEK inhibitor). In both cases, the administration of corticosteroids initially resulted in a marginal improvement but was followed by a rebound of biliary enzymes and the subsequent emergence of pyogenic liver abscesses with bacteremia. Liver abscesses developed without preceding invasive procedures, which implies that a more restrictive approach to immunosuppressive therapy for IR-cholangitis should be considered. To our knowledge, we report the first 2 cases of IR-cholangitis and subsequent liver abscesses without prior invasive intervention, the first cases of IR-cholangitis induced by triplet therapy, and 2 of the few anti-PD-L1 induced cases contributing to the evidence that both anti-PD1 and anti-PD-L1 antibodies induce IR-cholangitis. Treatment strategies for IR-cholangitis need to be improved to prevent life-threatening infectious complications.

Laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical technique used to ablate intra-axial brain tumors. The impact of LITT on the tumor microenvironment is scarcely reported. Nonablative LITT-induced hyperthermia (33-43˚C) increases intra-tumoral mutational burden and neoantigen production, promoting immunogenic cell death. To understand the local immune response post-LITT, we performed longitudinal molecular profiling in a newly diagnosed glioblastoma and conducted a systematic review of anti-tumoral immune responses after LITT. A 51-year-old male presented after a fall with progressive dizziness, ataxia, and worsening headaches with a small, frontal ring-enhancing lesion. After clinical and radiographic progression, the patient underwent stereotactic needle biopsy, confirming an IDH-WT World Health Organization Grade IV Glioblastoma, followed by LITT. The patient was subsequently started on adjuvant temozolomide, and 60 Gy fractionated radiotherapy to the post-LITT tumor volume. After 3 months, surgical debulking was conducted due to perilesional vasogenic edema and cognitive decline, with H&E staining demonstrating perivascular lymphocytic infiltration. Postoperative serial imaging over 3 years showed no evidence of tumor recurrence. The patient is currently alive 9 years after diagnosis. Multiplex immunofluorescence imaging of pre-LITT and post-LITT biopsies showed increased CD8 and activated macrophage infiltration and programmed death ligand 1 expression. This is the first depiction of the in-situ immune response to LITT and the first human clinical presentation of increased CD8 infiltration and programmed death ligand 1 expression in post-LITT tissue. Our findings point to LITT as a treatment approach with the potential for long-term delay of recurrence and improving response to immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancer, however, often with immune-related adverse events (irAEs). Adverse events involving the bladder were extremely rare with only few cases. Herein, we described a rare, recurrent cystitis associated with 2 programmed death 1 inhibitors (pembrolizumab and toripalimab) in 1 patient with advanced liver cancer. Cystitis associated with toripalimab, a novel humanized programmed death 1 monoclonal antibody, was first presented in our case. Cystitis is an extremely rare irAE associated with ICIs, especially anti-programmed death 1 antibodies. With widening indications of ICIs in clinical practice, physicians should be also aware of this rare irAE.

Immune checkpoint inhibitors (ICI) have gained approval as a treatment for a wide array of cancers. Their mechanism of action prevents the inactivation of cytotoxic T-cells, allowing for its cytotoxic response. However, the upregulation of the immune system by ICI also leads to many undesired adverse events known as immune-related adverse events (irAEs), ranging from dermatologic manifestations, such as rashes, to inflammation of mucous membranes, to hematologic toxicities. Here, we report a case of ICI-induced pure white cell aplasia, secondary to the agent durvalumab, which responded to treatment with filgrastim, prednisone, and cyclosporine. ICI-neutropenia accounts for 0.6% of all irAEs or 17% of hematologic irAEs. Given the rarity of hematologic irAEs, the available treatment guidelines are based on expert consensus. As ICI becomes more widely used, we can expect an increase in the prevalence of rare irAEs as well. This case report aims to present a rare side effect of ICI and demonstrate its response to immunosuppressive therapy while providing guidance for future clinicians and further elucidating the mechanism behind these irAEs.

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non-small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non-small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab-chemotherapy combination). Information was collected from patients' medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59-72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1-positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1-45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9-9.2) and 22 (8.5-25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide "real-world" cohort reproduced those obtained in clinical trials.

The emergence of immunotherapy has introduced a promising, novel approach to cancer treatment. While multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy against leukemia, their effect on solid tumors has been limited. One potential option for treating solid tumors is the engineering of natural killer (NK) cells with CARs. Mesothelin (MSLN), a tumor differentiation antigen, is expressed on triple-negative breast cancer (TNBC) cells, making it a potential target for CAR-NK therapy in the treatment of TNBC. We first constructed induced pluripotent stem cells with stable anti-MSLN-CAR expression and subsequently differentiated these cells into mesothelin-targeted CAR-NK (MSLN-NK) cells. We then assessed the effects of MSLN-NK cells on TNBC cells both in vitro (using the MDA-MB-231 cell line), in vivo (in a CDX mouse model), and ex vivo (using patient-specific primary cells and patient-specific organoids), in which MSLN surface expression was confirmed. Our CDX study results indicated that MSLN-NK cells effectively killed MDA-MB-231 (MD231) cells in vitro, reduced tumor growth in the CDX mouse model of TNBC, and lysed patient-specific primary cells and patient-specific organoids derived from the tumor samples of TNBC patients. Our data demonstrated that MSLN-NK cells had high efficacy on killing TNBC cells in in vitro, in vivo, and ex vivo. Therefore, MSLN-NK could be a promising treatment option for TNBC patients.