Journal for Immunotherapy of Cancer最新文献

Background: Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy for several tumor indications. However, a substantial fraction of patients treated with CPIs derive no benefit or have short-lived responses to CPI therapy. Identifying patients who are most likely to benefit from CPIs and deciphering resistance mechanisms is therefore essential for developing adjunct treatments that can abrogate tumor resistance.

Patients and methods: In this study, we used a machine learning approach that used the US-based nationwide de-identified Flatiron Health and Foundation Medicine non-small cell lung carcinoma (NSCLC) clinico-genomic database to identify genomic markers that predict clinical responses to CPI therapy. In total, we analyzed data from 4,433 patients with NSCLC.

Results: Analysis of pretreatment genomic data from 1,511 patients with NSCLC identified. Of the 36 genomic signatures identified, 33 exhibited strong predictive capacity for CPI response (n=1150) compared with chemotherapy response (n=361), while three signatures were prognostic. These 36 genetic signatures had in common a core set of four genes (BRAF, BRIP1, FGF10, and FLT1). Interestingly, we observed that some (n=19) of the genes in the signatures (eg, TP53, EZH2, KEAP1 and FGFR2) had alternative mutations with contrasting clinical outcomes to CPI therapy. Finally, the genetic signatures revealed multiple biological pathways involved in CPI response, including MAPK, PDGF, IL-6 and EGFR signaling.

Conclusions: In summary, we found several genomic markers and pathways that provide insight into biological mechanisms affecting response to CPI therapy. The analyses identified novel targets and biomarkers that have the potential to provide candidates for combination therapies or patient enrichment strategies, which could increase response rates to CPI therapy in patients with NSCLC.

Background: Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited.

Methods: This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method.

Results: Among 110 pts, median age at ICI initiation was 65 (IQR: 59-75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients.

Conclusions: Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis.

The share of immune checkpoint inhibitors (ICIs) used in cancer treatment has rapidly increased in recent years. Although ICIs have the potential to provide a durable survival benefit in a subset of patients, many patients do not respond to these costly and often toxic therapies.Recent retrospective clinical data indicate that the time of day of ICI infusion may be a powerful modulator of their efficacy. These observational studies suggest an enhanced efficacy of morning over evening infusion. However, randomized trials have not confirmed in other fields findings obtained by observational studies, possibly because of selection bias and residual confounding factors. Thus, while the data are intriguing, the time dependence of the efficacy of immunotherapy needs to be confirmed in pragmatic randomized clinical trials. Here, we provide an overview of the modulation of ICI efficacy by the timing of immunotherapy infusion and critically discuss the biological rationale for chrono-immunotherapy, the circadian regulation of the immune system, and the need for pragmatic randomized clinical trials to confirm an effect of the timing of immunotherapy infusions on patient outcomes.

Background: No established biomarker exists for specific myeloid cell populations or in gastric cancer. This study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with an immune checkpoint inhibitor and/or cytotoxic chemotherapy.

Methods: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer treated with first-line fluoropyrimidine plus platinum chemotherapy (n=143, cohort 1) and third-line nivolumab (n=165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. External single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics datasets were employed to validate the findings.

Results: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor progression-free survival (PFS) and overall survival (OS) with first-line chemotherapy compared with those with low levels (TCTP-low group) in cohort 1 (HR: 1.73 for PFS; 1.77 for OS). In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/natural killer (NK) cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. scRNA-seq analyses identified a myeloid subset with high TPT1 (encoding TCTP) expression and TCTP-related molecules, enriched with inhibitory myeloid inflammation gene signatures and providing inhibitory signals to T/NK cells (Macrophage-chemokine). Spatial transcriptomics analyses revealed a tumor-cell-enriched cluster co-localized with the Macrophage-chemokine subset, which exhibited the highest TPT1 expression and a positive correlation between its abundance and average TPT1 levels. In nivolumab-treated patients (cohort 2), the high TCTP group was associated with poor survival outcomes (HR: 1.39 for PFS; 1.47 for OS).

Conclusions: Plasma TCTP is a prognostic biomarker, reflecting clinically relevant immunosuppressive myeloid signals in patients with gastric cancer.

Background: Hypoxia is associated with the evasion of triple-negative breast cancer (TNBC) from immune surveillance. Hypoxia increases the subpopulation of putative TNBC stem-like cells (TNBCSCs) through activating Wnt/β-Catenin signaling. The shedding of MHC class I-related chain A (MICA) is particularly noteworthy in cancer stem cells (CSCs), promoting the resistance of CSCs to natural killer (NK) cell cytotoxicity. To reestablish MICA/NKG2D-mediated immunosurveillance, we proposed the design of a fusion protein (SHH002-hu1-MICA) which consists of Frizzled-7 (Fzd7)-targeting antibody and MICA, serving as an engager retargeting NK cells against TNBCs, especially TNBCSCs.

Methods: Opal multicolor immunohistochemistry staining was used to validate the expression of membrane MICA (mMICA) and existence of NK cells in TNBC tumors; flow cytometry (FCM) assay was used to detect the expression of Fzd7/mMICA on TNBCs. Biolayer interferometry (BLI) and surface plasmon resonance (SPR) assays were executed to assess the affinity of SHH002-hu1-MICA towards rhFzd7/rhNKG2D; near-infrared imaging assay was used to evaluate the targeting capability. A cytotoxicity assay was conducted to assess the effects of SHH002-hu1-MICA on NK cell-mediated killing of TNBCs, and FCM assay to analyze the effects of SHH002-hu1-MICA on the degranulation of NK cells. Finally, TNBC cell-line-derived xenografts were established to evaluate the anti-tumor activities of SHH002-hu1-MICA in vivo.

Results: The expression of mMICA is significantly downregulated in hypoxic TNBCs and TNBCSCs, leading to the evasion of immune surveillance exerted by NK cells. The expression of Fzd7 is significantly upregulated in TNBCSCs and exhibits a negative correlation with the expression of mMICA and infiltration level of NK cells. On accurate assembly, SHH002-hu1-MICA shows a strong affinity for rhFzd7/rhNKG2D, specifically targets TNBC tumor tissues, and disrupts Wnt/β-Catenin signaling. SHH002-hu1-MICA significantly enhances the cytotoxicity of NK cells against hypoxic TNBCs and TNBCSCs by inducing the degranulation of NK cells and promotes the infiltration of NK cells in CD44^high regions within TNBC xenograft tumors, exhibiting superior anti-tumor activities than SHH002-hu1.

Conclusions: SHH002-hu1-MICA maintains the targeting property of SHH002-hu1, successfully activates and retargets NK cells against TNBCs, especially TNBCSCs, exhibiting superior antitumor activities than SHH002-hu1. SHH002-hu1-MICA represents a promising new engager for NK cell-based immunotherapy for TNBC.

We read with great interest the article by Bernatowicz et al Despite the promising findings, we would like to highlight several concerns regarding the methodology and interpretation of the results that warrant further discussion, including the stability of radiomic features across pan-cancer types, the optimal threshold for CT-TIME (tumor immune microenvironment) scores, the biological interpretability of radiomic models, and the survival tail effect of immunotherapy responses.

Background: Higher levels of tumor-infiltrating lymphocytes (TILs) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers, decreasing myeloid-derived suppressor cells (MDSCs) and increasing T lymphocyte responsiveness. We have shown that the DNMTi decitabine augments the effectiveness of immunotherapy using murine triple-negative breast cancer (TNBC) models. The primary objective was to determine whether DNMTi+immune checkpoint blockade would increase stromal TIL (sTIL) in primary breast cancers before neoadjuvant chemotherapy (NCT).

Methods: In a phase 2 study (NCT02957968), patients with human epidermal growth factor receptor 2-negative breast cancer received window immunotherapy-decitabine (15 mg/m²×4 doses over 5 days) followed by 2 doses of pembrolizumab (200 mg, 2 weeks apart)-before starting NCT. Biopsies before and after window immunotherapy quantified TILs and programmed death-ligand 1 (PD-L1) expression. Patients proceeded to NCT and tumor resection per standard of care. Mid-study, results of the KEYNOTE 522 trial led to patients with TNBC receiving additional pembrolizumab concurrently with standard NCT and in the adjuvant setting.

Results: 46 patients (median age 54.5 years, range 28-72; 71.7% white, 28.3% black; 100% female) were treated. 21 patients had TNBC and received neither neoadjuvant pembrolizumab concurrently with NCT nor adjuvant pembrolizumab (Cohort A), 7 patients had TNBC and did receive concurrent and/or adjuvant pembrolizumab (Cohort A2), and 18 patients were estrogen receptor positive and/or progesterone receptor positive and received neither concurrent nor adjuvant pembrolizumab (Cohort B). Blood samples collected after decitabine administration before pembrolizumab showed a 59% decrease (p<0.01) in monocytic MDSCs compared with baseline. 38 patients had paired biopsies for sTIL and 37 for PD-L1 evaluation. Cohorts A/A2 experienced an sTIL increase of 6.1% (p<0.008); Cohort B experienced an sTIL increase of 8.3% (p=0.006). PD-L1 expression increased by 73.9% (p<0.01). 14 of 43 patients (32.6%) who proceeded to resection achieved pCR (n=11 of 27 (40.1%) in Cohorts A/A2 and n=3 of 16 (18.8%) in Cohort B). The most frequently reported immune-related adverse events were adrenal insufficiency (AI) (n=6, 13.0%), maculopapular rash (n=3, 6.5%), and hypothyroidism (n=3, 6.5%). Five of the six AI instances were at least partially attributable to hypophysitis/pituitary dysfunction, and one remains uncertain.

Conclusions: Treatment in the pre-neoadjuvant window with decitabine and pembrolizumab could sensitize breast cancers to standard NCT by recruitment of TILs to the tumor tissue. The treatment was well-tolerated.

Trial registration number: NCT02957968.

Background: The increased expression of programmed cell death ligand 1 (PD-L1) on a subset of immune cells in the peripheral blood has been frequently observed in patients with cancer, suggesting a relationship with PD-L1 expression in tumor tissues. In this study, we investigated the mechanisms underlying PD-L1 expression on various types of immune cells in the peripheral blood of patients with cancer.

Methods: PD-L1 expression on various immune cell populations was analyzed in peripheral blood mononuclear cells of 112 patients with non-small cell lung cancer (NSCLC) using flow cytometry. A mouse model of X-ray-induced acute thrombocytopenia was used to investigate the relationship between thrombopoiesis and PD-L1-expressing platelet generation. The clinical significance of PD-L1-expressing platelets was analyzed in a cohort of patients with stage IV NSCLC who received a combination of anti-programmed cell death 1 (PD-1) therapy and chemotherapy.

Results: All immune cell populations, including monocytes, T cells, B cells, and NK cells, showed higher PD-L1 expression in patients with cancer than in healthy controls. However, this increased frequency of PD-L1-expressing cells was not attributed to the expression of the cells themselves. Instead, it was entirely dependent on the direct interaction of the cells with PD-L1-expressing platelets. Notably, the platelet-dependent acquisition of PD-L1 on circulating immune cells of patients with lung cancer was observed in various other cancer types and was mechanistically associated with a surge in thrombopoiesis, resulting in the increased production of PD-L1-expressing reticulated platelets. Clinically, patients with enhanced thrombopoiesis and concurrently high PD-L1-expressing platelets exhibited a better response to anti-PD-1 therapy.

Conclusions: These findings highlight the role of tumor-associated thrombopoiesis in generating PD-L1-expressing platelets that may serve as a resource for PD-L1-positive cells in the circulation and act as a predictive biomarker for anti-PD-1/PD-L1 therapy.