Journal for Immunotherapy of Cancer最新文献

Background: Enhancing antigen cross-presentation is essential for the development of a tumor neoantigen vaccine. One approach is to stimulate antigen-presenting cells (APCs) to uptake neoantigens. Mycobacterium tuberculosis (MTb) contains pathogen-associated molecular patterns (PAMPs) recognized by APCs and adhesion molecules that facilitate MTb invasion of APCs. Therefore, we suggest using MTb as a carrier to enhance APC phagocytosis of neoantigens, thereby promoting antigen cross-presentation.

Methods: The successful preparation of the MTb carrier (phMTb) was confirmed through electron and confocal microscopy. Fluorescence microscopy was used to detect PAMPs and adhesion molecules on phMTb as well as to observe its role in aiding dendritic cells (DCs) in antigen uptake into endosomes or lysosomes. Flow cytometry was used to assess the retention of PAMPs and adhesion molecules on phMTb, investigate antigen uptake by DCs, evaluate their activation and maturation status, examine the presentation of tumor neoantigens, and analyze immune cells in draining lymph nodes and tumor tissues. The efficacy of phMTb vaccine formulations in combination with anti-programmed cell death protein 1 (PD-1) antibody therapy was assessed using the MC38 mouse tumor models. Adverse effects were evaluated through H&E staining of major organs, assessment of reproductive capability and detection of biochemical indices.

Results: The engineered porous hollow phMTb carrier successfully encapsulated model tumor neoantigens, with or without the adjuvant CpG. The phMTb retained PAMPs and adhesion molecules on its surface, similar to the parental MTb, thereby enhancing DC uptake of phMTb and its formulations containing tumor neoantigens and CpG. Vaccines formulated with phMTb facilitated DC maturation, activation, cross-presentation of tumor neoantigens, and promoted migration of phMTb-laden DCs to lymph nodes, enhancing effector and memory CD8⁺ T lymphocyte function. In murine tumor models, immunization with phMTb-formulated neoantigen vaccines elicited a robust tumor-specific cytotoxic T lymphocyte immune response with minimal adverse effects. Additionally, vaccination with phMTb-formulated neoantigen vaccines effectively reversed the tumor's immune-suppressive microenvironment. Concurrent administration of the PD-1 antibody with the phMTb-formulated neoantigen vaccine exhibited significant synergistic therapeutic effects.

Conclusions: The results of our study highlight the potential clinical translation of personalized tumor neoantigen vaccines using the phMTb carrier.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but come with high costs. Alternative ICI dosing strategies could reduce costs without losing efficacy. However, clinical efficacy data are lacking.

Methods: In this retrospective cohort trial, consecutive patients with advanced non-small cell lung cancer (NSCLC) who received ≥1 cycle pembrolizumab±chemotherapy at two tertiary institutions were included. Hybrid dosed patients received either 100, 150 or 200 mg pembrolizumab every 3 weeks or double every 6 weeks depending on their weight: <65 kg, 65-90 kg or >90 kg, respectively. Standard-of-care flat dosed patients received 200 mg every 3 weeks or 400 mg every 6 weeks. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier estimation, compared by log-rank test and HRs were calculated with the Cox proportional hazards model in both unweighted and inverse probability of treatment weighted (IPTW) cohorts. Non-inferiority margin was set at an HR of 1.15.

Results: In total, 375 patients and 391 patients were included and median follow-up was 43.1 and 61.0 months in the hybrid and flat dose cohort, respectively. OS was non-inferior in the hybrid dose cohort compared with the flat dose cohort: median 17.7 months (95% CI 14.9 to 20.9) vs 11.8 months (95% CI 9.3 to 13.8, HR 0.76, 95% CI 0.65 to 0.90, p<0.0001 for non-inferiority). After correcting for confounders by IPTW, OS remained non-inferior (HR 0.76, 95% CI 0.63 to 0.91, p<0.0001 for non-inferiority). PFS in the hybrid cohort was also non-inferior to the flat dose cohort with a median of 6.4 months (95% CI 5.7 to 7.7) vs 4.6 months (95% CI 3.9 to 5.5, HR 0.82, 95% CI 0.70 to 0.96, p<0.0001 for non-inferiority). In total, 26.2% (or 52.5 mg per cycle, p<0.0001) pembrolizumab was saved in the hybrid dose cohort accounting to US$36 331.36 per patient.

Conclusions: In this retrospective analysis of a large cohort of advanced NSCLC patients treated with pembrolizumab±chemotherapy, OS of hybrid dosed patients was non-inferior to flat dosed patients. OS remained non-inferior after correcting for possible confounding factors. This hybrid regimen resulted in significant savings of pembrolizumab and costs.

Background: There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).

Methods: Patients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.

Results: 8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.

Conclusions: Across >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.

Immunotherapy has progressed significantly in cancer treatment; however, several factors influence its outcomes. Abnormal lipid metabolism, which is frequently observed in cancers, promotes tumor proliferation, invasion, and metastasis. Li et al from the Medical Oncology Department of Chongqing University Cancer Hospital constructed a lipid metabolism scoring system and reported that MK1775 inhibited fatty acid oxidation in tumor-associated macrophages and reduced T-cell infiltration, further enhancing the efficacy of immunotherapy. This study demonstrated the critical role of lipid metabolism scoring system and lipid metabolism in immunotherapy. Currently, the metabolism of lipids, such as fatty acids, phospholipids, and cholesterol, has been reported to affect the tumor microenvironment by regulating immune cells, including T cells, natural killer cells, and macrophages. These metabolic changes can impair the efficacy of immunotherapy, resulting in tumor progression. Consequently, lipid metabolism emerges as an important immune regulator for improving immunotherapeutic outcomes and provides a novel and powerful strategy for tumor combination therapy.

Background: Our study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC.

Methods: This is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers.

Results: 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%-91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%-94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively.

Conclusions: Perioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.

Background: CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma.

Methods: This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts.

Results: Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses.

Conclusions: IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor.

Trial registration number: NCT03291002.

Background: Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse.

Methods: This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y. Individual patient-level data (IPD) from the experimental arm of the KEYNOTE-024 trial were extracted (KN024 IPD cohort) to compare the long-term outcomes between the two cohorts. To further assess the reproducibility of clinical trial results, we reconstructed the "KN024 look-alike" cohort by excluding patients with an Eastern Cooperative Oncology Group-performance status (ECOG-PS)≥2, those requiring corticosteroids with doses ≥10 mg of prednisolone/equivalent, patients with positive/unknown epidermal growth factor receptor/anaplastic lymphoma kinase genotype, and those with pre-existing autoimmune disease. We additionally provided a hierarchical organization of determinants of long-term benefit through a conditional inference tree analysis.

Results: The study included 1050 patients from 61 institutions across 14 countries, with a median follow-up of 70.3 months. The 5-year survival rate was 26.9% (95% CI: 23.8% to 30.2%), and median OS was 21.8 months (95% CI: 19.1 to 25.7), while 32 (3.0%) patients who achieved a complete response remained progression-free at the data cut-off. The KN024 look-alike cohort had a 5-year survival rate of 29.3% (95% CI: 25.5% to 33.6%) and a median OS of 27.5 months (95% CI: 22.8 to 31.3). Neither the overall study population nor the KN024 look-alike cohort exhibited significantly different OS compared with the KN024 IPD cohort. By the data cut-off, 1015 patients (96.7%) had permanently discontinued treatment: 659 (64.9%) due to progressive disease, 156 (15.4%) due to toxicity, 77 (7.6%) due to treatment completion, and 106 (10.4%) due to other reasons. Overall, 222 participants (21.1%) were treated for a minimum period of 24 months, among them the 5-year survival rates were: 31.7%, 72.7%, 78.6%, 84.2% for patients who discontinued treatment due to progressive disease, toxicity, treatment completion, and other reasons, respectively.

Conclusion: This study provides valuable real-world evidence that confirms the long-term efficacy of pembrolizumab outside of clinical trials. Hierarchical organization indicates ECOG-PS, age and PD-L1-TPS as the most important predictors of 5-year survival, potentially informing clinical practice.

The discovery that natural killer (NK) cells can retain features of "memory" from previous stimulation and pathogen exposure was a landmark advance highlighting one of many ways in which NK cells of the innate immune system resemble T cells of the adaptive immune system. This ability to "remember" prior stimulation to bring about enhanced protection of the host sparked significant excitement regarding potential therapeutic applications. Yet, how closely the features of naïve and memory NK cells recapitulate those of T cells remains unclear. Nonetheless, despite unresolved questions about the immunobiology of naïve and memory NK cells, the application of memory NK cells to the clinic for cancer and other indications has gathered steam to meet the unmet need for novel immunotherapies. Recent work from Arellano-Ballestero et al highlights this evolving field and the current state of the art with memory NK cells. Application of these cells to the clinic is progressing with promising results, but important questions remain about the essential molecular, phenotypic, and functional characteristics that define a memory NK cell.