Journal of Immunotherapy最新文献

Immune checkpoint inhibitors (ICIs) have become the standard treatment for many types of cancer. After several years of using these therapies, many adverse events related to ICIs have been observed. Dermatologic toxicities such as nonspecific morbilliform rash, vitiligo, Stevens-Johnson syndrome/toxic epidermal necrolysis, and more rarely, lichenoid eruptions have been described in the literature. We report 2 cases of pustular lichenoid eruptions, 1 in a patient with nonsmall cell lung carcinoma and 1 in a patient with metastatic melanoma, induced by pembrolizumab and nivolumab, respectively. The 2 patients were treated with topical corticosteroids, and complete healing of lesions was slowly obtained. Due to the severity of the cutaneous eruptions, pembrolizumab and nivolumab were discontinued. We identified 6 cases of pustular lichenoid eruptions induced by ICIs in the published literature and in the French Pharmacovigilance Database and reviewed their main clinical features and courses.

The transformation of chronic lymphocytic leukemia to an aggressive lymphoma, called Richter transformation, is often accompanied by resistance to chemotherapy and high mortality. Thus, novel therapeutic strategies are required for the successful treatment of these patients. One possibility is cellular immunotherapy with chimeric antigen receptor T cells. However, the time delay until cells are available and the limited number of effector cells due to the impaired immune system of these patients potentially compromises the efficacy of this approach. Another promising attempt might be the therapy with γδ T cells. Once activated, they exhibit various antitumor effects against several types of malignancies. Furthermore, they can be safely used in an allogeneic setting and can be multiplied in vivo as already demonstrated in clinical studies. In vitro data, in addition, show that the cytotoxicity of γδ T cells can be significantly enhanced by monoclonal antibodies. Here we present a patient, who suffered from Richter transformation and did not respond to several lines of immunochemotherapy. Due to the lack of further therapy options, we conducted an individual therapy with adoptive transfer of haploidentical γδ T cells combined with the application of the monoclonal antibody obinutuzumab. A histologically confirmed complete remission was achieved through this therapy approach, whereby relevant side effects were not seen. This case highlights the potential of γδ T cells and the feasibility of this therapeutic approach for further clinical trials.

Checkpoint inhibitor-related pneumonitis (CIP) is one of the most important immune checkpoint inhibitors side effects, and it is rare but fatal. Identifying patients at risk of refractory CIP before the start of CIP therapy is important for controlling CIP. We retrospectively analyzed the clinical data of 60 patients with lung cancer who developed CIP. Refractory CIP was defined as CIP with poor response to corticosteroid treatment, including CIP not relieved with corticosteroid administration or CIP recurrence during the corticosteroid tapering period. We analyzed clinical characteristics, peripheral blood biomarkers, treatment, and outcomes in nonrefractory and refractory CIP. Risk factors associated with refractory CIP were assessed. Among 60 patients with CIP, 16 (26.7%) had refractory CIP. The median onset time for patients with nonrefractory and those with refractory CIP was 16.57 (interquartile range [IQR], 6.82-28.14) weeks and 7.43 (IQR, 2.71-19.1) weeks, respectively. The level of lactate dehydrogenase (LDH) was significantly higher in the refractory CIP group at baseline (255 [222, 418] vs. 216 [183, 252], P =0.031) and at CIP onset (321.5 [216.75, 487.5] vs. 219 [198. 241], P =0.019). An LDH level >320 U/L at CIP onset was an independent risk factor of refractory CIP (odds ratio [OR], 8.889; 95% confidence interval [CI]: 1.294-61.058; P =0.026). The incidence of refractory CIP is high among patients with CIP. An increased LDH level at CIP onset is independently associated with refractory CIP. Monitoring LDH levels during immune checkpoint inhibitors treatment is recommended.

The project was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Electronic databases were screened to identify relevant trials. The primary endpoints were prognostic parameters and adverse events (AEs) through pooled rate, odds ratio, and hazard ratio (HR) with 95% CI. Totally, 6558 TNBC patients from 41 cohorts were included. The pooled pathologic complete response rate (odds ratio=2.03, 95% CI: 1.35-3.06, P =0.0007) and event-free survival (HR=0.84, 95% CI: 0.73-0.96, P =0.0100) of ICIs plus chemotherapy was higher than that of chemotherapy-alone in early-stage TNBC. For metastatic TNBC, compared with chemotherapy-alone, the addition of ICIs prolonged the progression-free survival (PFS) (HR=0.92, 95% CI: 0.88-0.96, P <0.0001); the improvement also existed in the following 3 subgroups: programmed cell death-ligand 1 positive, race of White and Asian, and patients without previous neoadjuvant or adjuvant chemotherapy; however, the benefit of the combined regimen was not observed in overall survival (OS) (HR=0.95; 95% CI: 0.89-1.03, P =0.2127). In addition, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone. In the safety analysis, compared with chemotherapy-alone, ICIs plus chemotherapy increased immune-related AEs and several serious AE. The regimen of ICIs plus chemotherapy is promising in both early-stage and metastatic TNBC, while the increased serious AE should not be neglected. Furthermore, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone.

The influence of antacids use on immune checkpoint inhibitor (ICI) efficacy remains unclear. A systematic review and meta-analysis was performed to evaluate the effect of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) on ICI efficacy in advanced solid cancer patients. A systematic literature search in PubMed, EMBASE, and Web of Science was performed to retrieve studies investigating the effect of antacid use on ICI efficacy. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse events were measured using hazard ratios (HRs) or odds ratios (ORs). Thirty studies enrolling 16,147 advanced cancer patients receiving ICI treatment were included. The pooled analysis indicated that PPI use was associated with shorter OS (HR=1.40, 95% CI, 1.25-1.57) and PFS (HR=1.34, 95% CI, 1.19-1.52) in advanced cancer patients treated with ICIs. PPI use did not show effect on ORR or immune-related adverse event of advanced cancer patients receiving ICI treatment. OS, PFS, and ORR did not differ between H2RA users and non-H2RA users. In subgroup analyses, PPI use was associated with shorter OS and PFS in NSCLC and urothelial carcinoma patients and in patients treated with anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy. In addition, ICI efficacy was different in the antacid exposure time frame subgroups. In conclusion, PPI use has a negative effect on OS and PFS among advanced cancer patients receiving ICI treatment. PPIs should be cautiously administered among advanced cancer patients treated with ICI. The safety of H2RAs and the influence of H2RAs on ICI efficacy need further investigation.

Pregnancy and cancer share CTLA-4 and PD-1/PD-L1 as some of the immunomodulatory pathways that reshape the immune system from a destructive response to a state of tolerance to the fetus and the tumor, respectively. Ipilimumab (anti-CTLA-4 inhibitor) and nivolumab (anti-PD-1 inhibitor) are used in combination for the treatment of metastatic renal cell carcinoma, and their use could theoretically result in an immune response against the fetus. Furthermore, these immune checkpoint inhibitors are immunoglobulin G antibodies that transfer from the mother to the fetus and may cause a direct toxicity. We present the first report of a metastatic renal cell carcinoma patient in which ipilimumab and nivolumab were successfully used starting in her first trimester of pregnancy, with sufficient follow-up to show favorable outcomes for both the mother and the child. We describe our management of this challenging case and we review the available evidence, coming from Developmental and Reproductive Toxicology Studies and case reports of metastatic melanoma patients.

T-cell immunoglobulin and mucin domain 3 (TIM3) is emerging as a potential target for antibody-based checkpoint blockade. However, the efficacy of TIM3 blockade in combination with other treatment modalities, has not been extensively studied. In the current work we combined TIM3 blockade with myxoma virus-based oncolytic virotherapy (OV). Our results demonstrate that myxoma virus's ability to initiate an immense antitumor immune response complements the ability of TIM3 blockade to shift the tumor microenvironment to a more proinflammatory state. As a result, the combination of TIM3 blockade and OV is able to completely eradicate established disease, while neither monotherapy is effective. These data represent the first demonstration that OV can enhance the efficacy of TIM3 blockade and suggest that this treatment may need to be incorporated into more aggressive, combinatorial regimens in order to fulfill its potential as an immunotherapeutic.

Immunotherapy has been approved for stage III non-small cell lung cancer (NSCLC) as consolidation therapy after chemoradiation in patients whose disease does not progress after chemoradiation. However, many patients do not receive chemoradiation due to either the drugs' side effects or poor performance status. This study's objective is to investigate the association of immunotherapy combined with chemotherapy or Radiotherapy (RT) with the overall survival (OS) of stage III NSCLC patients who do not receive chemoradiation. Patients with stage III NSCLC who received either chemotherapy or RT with or without immunotherapy were identified from NCDB. The Cox proportional hazard regression analysis was implied to assess the effect of immunotherapy on survival after adjusting the model for age at diagnosis, race, sex, education, treatment facility type, insurance status, comorbidity score, histology year of diagnosis, and treatment types, such as chemotherapy and radiation therapy. The final analysis included 32,328 patients, among whom 3,205 (9.9%) received immunotherapy. In the multivariable analysis adjusted for all the factors previously mentioned, immunotherapy was associated with significantly improved OS (HR: 0.76, CI: 0.71-0.81) compared with no immunotherapy. Treatment with chemotherapy plus immunotherapy was significantly associated with improved OS (HR: 0.83, CI: 0.77-0.90) compared with chemotherapy without immunotherapy. Further, RT plus immunotherapy was associated with significantly improved OS (HR: 0.62, CI: 0.54-0.70) compared with RT alone. In this comprehensive analysis, the addition of immunotherapy to chemotherapy or radiotherapy was associated with improved OS compared with chemotherapy or radiation therapy without immunotherapy in stage III NSCLC patients.

Higher γδ T cell counts in patients with malignancies are associated with better survival. However, γδ T cells are rare in the blood and functionally impaired in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and interleukin-2 (IL-2). Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a Good Manufacturing Practice (GMP) compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of coculture with aAPC, which exhibited central (47%) and effector (43%) memory phenotypes. In addition, >90% of the expanded γδ T cells expressed NKG2D, although they have low cell surface expression of PD1 and LAG3 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded γδ T cells were effective in killing target cells. Our results demonstrate that large-scale ex vivo expansion of donor-derived γδ T cells in a GMP-like setting can be achieved with the use of quadruplet aAPC and zol/IL-2 for clinical application.

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.