Journal for Immunotherapy of Cancer最新文献

Background: Immune checkpoint inhibitors (ICIs) are increasingly used in adolescents and young adults (AYAs) with cancer; however, data on treatment response, the frequency and pattern of immune-related adverse events (irAEs), and the feasibility of ICI rechallenge after irAEs are limited.

Methods: This retrospective study included 136 AYAs (80 males and 56 females) who received ICI therapy for melanoma at our institution from 2013 to 2023. We documented the initial ICI treatment and ICI rechallenge, along with associated irAEs and treatment responses. Kaplan-Meier plots were used to analyze overall survival (OS) and progression-free survival.

Results: At ICI initiation, the median age was 33 (range, 15-39) years, and most patients had stage III or IV disease (93%) and BRAF mutations (63%). Treatment settings included adjuvant (n=70), palliative (n=50), and neoadjuvant (n=16). Compared with those receiving ICI monotherapy (n=77), patients receiving ICI combination therapy (n=59) had significantly higher rates of irAEs of any grade (53% vs 75%, p=0.011) and grade three or four irAEs (12% vs 32%, p=0.003) and higher rates of treatment delay (26% vs 51%, p=0.044), and hospitalization (8% vs 20%, p=0.032). ICI rechallenge was common (n=71), even after prior irAEs (n=48). Colitis and hepatitis were the most common irAEs following initial ICI therapy (26% and 23%, respectively) and ICI rechallenge (31% and 29%, respectively). The adjuvant, palliative, and neoadjuvant ICI therapy groups had 5-year OS rates of 86%, 77%, and 88%, respectively. In the palliative therapy group, the overall response rate and disease control rate were 38% and 42% during initial ICI therapy and 35% and 44% during ICI rechallenge. Elevated baseline lactate dehydrogenase levels were associated with worse OS (adjusted HR, 21.04, 95% CI, 1.35 to 328.29, p=0.030), and colitis and/or hepatitis were strongly associated with better OS (adjusted HR, 0.10, 95% CI 0.01 to 0.83, p=0.033).

Conclusions: AYA patients receiving ICI therapy for melanoma had high incidence of colitis and hepatitis and favorable survival. Initial and rechallenge ICI therapy had similar patterns of irAE severity and efficacy. Colitis and hepatitis were associated with improved OS.

While immune checkpoint inhibition (ICI) has revolutionized therapy across solid tumors, resistance remains an issue. Programmed death ligand-1 immunohistochemistry has limited clinical utility, whereas tumor mutation burden and microsatellite instability are only valuable for a minority of patients and leave room for improvement. Multiomic gene signatures have enhanced prediction of immune response by incorporating interferon-gamma signaling, T-cell dysfunction and exhaustion genes, and myeloid signatures. Single-cell RNA technology has been adopted to further optimize prediction of response to immunotherapy. A novel Immune Profile Score is presented by Zander et al that builds on prior immune signatures, using DNA and RNA profiling to predict outcomes across solid tumors receiving ICIs. While this assay is promising, further prospective validation and refinements will be necessary to realize its full potential in our quest to develop precision immuno-oncology. The incorporation of readily available clinical factors (eg, sites of metastasis), host genetics, orthogonal molecular platforms (microbiome, computational pathology, spatial transcriptomics, epigenetics, proteomics, radiomics) and investigating biomarkers to predict primary refractory disease and severe toxicities may further facilitate precision medicine.

Background: Areca nut is the fourth most addictive substance worldwide and is a known Group 1 carcinogen. Chronic areca nut chewing has been strongly associated with the development of oral squamous cell carcinoma (OSCC), although the underlying carcinogenic mechanisms remain unclear.

Methods: Employing spatial multiomics technology, we recently mapped the immune microenvironment of areca nut-associated OSCC and identified a marked upregulation of the immune checkpoint molecule CD155 in these tumors. Further quantitative reverse transcription-PCR, western blotting, immunofluorescence, animal experiments, etc, explored and verified the reasons for the upregulation of CD155 caused by arecoline and the results of immune escape in OSCC.

Results: The investigation revealed that arecoline, a bioactive component of areca nut, induces CD155 expression in OSCC cells. Through interaction with its receptor, TIGIT, CD155 suppresses CD8⁺ T cell function and activity, facilitating immune evasion in OSCC. Mechanistically, arecoline upregulates CD155 via activation of muscarinic acetylcholine receptors on the surface of OSCC cells, leading to RhoA-mediated inhibition of YAP phosphorylation. This promotes YAP nuclear translocation and phase separation, driving CD155 transcription. In both in vitro and in vivo models, blockade of the CD155-TIGIT signaling axis significantly enhanced the efficacy of immunotherapy in OSCC.

Conclusion: This study unveils a novel mechanism by which arecoline promotes immune evasion in OSCC and highlights promising immune therapeutic targets and strategies for the treatment of areca nut-associated OSCC.

Checkpoint inhibitors best perform in neoadjuvant settings for a number of solid malignancies including cutaneous melanoma as compared with adjuvant schemes. A key difference between both treatment settings is the availability of tumor antigens to continuously prime antitumor T lymphocytes. Mounting evidence indicates that priming is a function chiefly performed by a subset of dendritic cells that cross-present tumor antigens rather than by malignant cells themselves. Acting in favor of these mechanisms to foster tumor-antigen priming is proposed to enhance the efficacy of adjuvant schemes.

Adoptive cell therapy (ACT) has shown remarkable success in the treatment of some malignancies, particularly leukemia. However, there are multiple factors that limit the durability of ACT in solid tumors, including dose-limiting toxicities, the immunosuppressive tumor microenvironment, and T-cell exhaustion. As the manufacture and preparation of adoptive T-cell therapies allows time and adequate conditions for ex vivo T-cell engineering, forward genetic screens can identify novel genetic targets that could improve their effectiveness. CRISPR is a commonly used functional genomics tool that has been successfully used to both enhance our understanding of mechanisms of resistance and to discover potential genetic edits to improve ACT. A complementary approach, Sleeping Beauty transposon mutagenesis provides additional opportunities to identify novel genetic edits without being constrained by the annotated human genome. Here, we summarize forward genetic screens and their tools to uncover strategies to enhance ACT. Complementary approaches can be combined and improved on to identify translatable genetic editing strategies through studies that accurately recapitulate disease-specific challenges.

Clinical trials of immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) have largely been unsuccessful despite promising preclinical studies and proven efficacy in other solid tumors. These disappointing clinical outcomes have been attributed to an immunosuppressive tumor microenvironment, a relative lack of infiltrating immune effector cells, and tumor-related and host-related factors, which collectively render prostate cancer a relatively immunologically "cold" tumor. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, induces an immune response targeted against prostatic acid phosphatase. It received approval from the US Food and Drug Administration in 2010, marking the first immunotherapy to show an overall survival benefit in patients with mCRPC in large phase III randomized trials. Unfortunately, subsequent immunotherapy-based strategies have been less efficacious in mCRPC relative to other tumor types. Given the use of sipuleucel-T as a standard of care backbone, there is emerging interest in combining it with other immunotherapies, hormonal therapies, or chemotherapies to improve its clinical efficacy. This review summarizes past experiences and current knowledge of combining sipuleucel-T with other treatments and explores future approaches to enhance such combinatorial strategies.

Background: Compared with conventional chemotherapy, pembrolizumab-based chemoimmunotherapy (Pembro) and nivolumab plus ipilimumab with or without two cycles of platinum-doublet chemotherapy (Nivo+Ipi) improve survival in advanced non-small cell lung cancer (NSCLC). However, biomarkers for selecting optimal immunotherapy remain unclear. This study aimed to assess whether programmed cell death-ligand 1 (PD-L1) expression on tumor and immune cells (ICs) can guide first-line immunotherapy in advanced NSCLC.

Methods: This multicenter, observational study retrospectively reviewed patients with NSCLC treated with first-line Pembro or Nivo+Ipi who had evaluable PD-L1 expression on tumor (Tumor Proportion Score (TPS), 22C3) and ICs score (SP142). In addition, whole-exome and RNA sequencing were performed on treatment-naïve NSCLCs with available PD-L1 expression status by both assays.

Results: Between 2019 and 2023, 198 patients were included (Pembro/Nivo+Ipi: 137/61). In the Pembro cohort, patients with high TPS (≥ 50%) had significantly longer progression-free survival (PFS) than those with low TPS (< 50%) (median PFS (mPFS, months): 8.1 vs 7.1; p=0.02), while IC score was not predictive. In the Nivo+Ipi cohort, high IC score (≥1) was associated with longer PFS than low IC score (0) (mPFS: 7.7 vs 2.8; p=0.04), while TPS showed no impact. Among patients with low TPS/high IC scores, Nivo+Ipi achieved longer PFS than Pembro (mPFS: 12.4 vs 6.6; restricted mean survival time (RMST)_Nivo+Ipi/RMST_Pembro (24 months)=1.5; p=0.049). Multiomics analysis using 152 NSCLC samples showed that tumors with low TPS/high IC scores exhibited an activated tumor immune microenvironment comparable to that of tumors with high TPS. However, these tumors had significantly highest tumor mutation burden (TMB) and regulatory T cell (T_reg) fraction among the PD-L1 phenotypes (median TMB (mut/Mb): 1.6 in tumors with low TPS/low IC score, 18.2 in low TPS/high IC score, and 1.9 in high TPS/any IC score; median T_reg fraction (×10^-2]: 0.0, 0.2, and 0.0, respectively), supporting a potential benefit of cytotoxic T-lymphocyte-associated antigen 4 blockade in addition to programmed cell death protein 1 (PD-1)/PD-L1 inhibition in this subgroup.

Conclusions: Patients with NSCLC and low TPS/high IC scores may benefit more from Nivo+Ipi than from Pembro due to distinct genomic and immunological features, including high TMB and T_reg fraction.

Background: Colorectal carcinoma exhibits high heterogeneity, comprising subtypes that show poor efficacy of T cell-based immunotherapies, such as programmed cell death protein 1 (PD-1) checkpoint inhibitors. Although natural killer (NK) cells are considered a promising approach for cancer immunotherapy, it remains unclear what molecular mechanisms drive NK cell activation or suppression within the tumor microenvironment. Moreover, limitations in human tumor models that reflect the diversity of individual patient tumors hinder the ability to effectively select patients who would benefit most from NK cell-based therapies.

Methods: Here, we established a co-culture platform of genetically diverse colorectal cancer (CRC) patient-derived organoids (PDOs) with primary allogeneic NK cells. We performed bulk RNA sequencing analysis of sorted NK cells after exposure to PDOs and aligned gene expression signatures derived from our findings with publicly available single-cell RNA sequencing data of NK cells from peripheral blood and CRC tissues of patients. Moreover, we evaluated identified pathways using flow cytometry and IncuCyte live-cell imaging analysis to quantify phenotypic alterations and NK cell-mediated killing of PDOs over time, respectively. Ultimately, we tested CRISPR-Cas9-edited NK cells and PDOs, small molecule compounds, and clinically relevant monoclonal antibodies (mAbs) to increase NK cell potency.

Results: On co-culture, NK cells acquired common transcriptional signatures related to hypoxia and transforming growth factor-beta (TGF-β), similar to NK cells infiltrating CRC tissues of patients. In addition, we observed patient-specific differential PDO susceptibilities to NK cell-mediated lysis. Major histocompatibility complex class I deficiency and natural killer group 2, member D (NKG2D)-ligand expression on PDOs facilitated NK cell-mediated cytotoxicity, and induced phenotypic NK cell diversification related to activation and the acquisition of inflammation and tissue-residency-related transcriptional signatures. Genetic or pharmaceutical targeting of hypoxia-inducible factors HIF1A/EPAS1 or TGF-βR1, or the addition of anti-CEACAM1 mAbs, enhanced NK cell-mediated PDO killing or activation, respectively.

Conclusions: The NK cell/PDO co-culture platform allows the identification of both common and patient-specific impacts of the tumor microenvironment on NK cell function and can aid the development of patient-tailored immunotherapies. The majority of CRC (CMS2/CMS3) PDOs from our cohort were susceptible to NK cell-mediated killing and induced NK cell activation, highlighting the potential of NK cells for CRC immunotherapies.

Purpose: Preoperative characterization of renal mass malignancy, subtype, and immuno-oncologic pathology could inform and improve tailored management decisions. We examine multiparametric MRI (mpMRI) for (1) sensitivity to immuno-oncologic markers of the tumor immune microenvironment and (2) classification of tumor malignancy, subtype, and grade.

Methods and materials: In a prospective, institutional review board-approved single-center study, 40 patients (13 female/27 males, 60.4±10.7 years) scheduled to undergo surgical management of solid renal masses underwent preoperative 1.5T MRI. This included T1, multi-b-value diffusion-weighted imaging (DWI as intravoxel incoherent motion (IVIM), and apparent diffusion coefficient (ADC)), R2*, arterial spin labeling (ASL), and dynamic contrast-enhanced (DCE-)MRI. Clear cell likelihood scores (ccLS) were assigned using clinical MR images. Tumor diagnoses were extracted from the surgical histopathology. Logistic regression models were built with leave-one-out cross-validation and bootstrapping. Interobserver measurements were obtained in a subset of 27 patients, and tests-retests were run for 2 patients. Tumors from 18 patients with clear cell renal cell carcinoma (ccRCC) underwent immunohistochemistry for CD3, CD4, CD8, CD68, PD-L1, NKp46, HIF-1α, and CD31. MR biomarkers of immunohistochemistry stains were identified with Pearson's r correlation, and diagnostic OR for >5% or >15% cells stained positive, by cross-validated univariate logistic regression.

Results: Of the 40 solid renal masses (mean (range)=32 (8-68) mm), 22 were clear cell, 9 non-clear cell and 9 benign, with 10 Grade 1. IVIM f, D*, and fD* correlated with T cells (CD4, CD3, CD8), while R2* correlated positively with macrophage presence (CD68) and negatively with angiogenesis (CD31). DCE-MRI and ASL negatively correlated with CD68. ASL negatively correlated with CD8 T cells. IVIM D* returned a significant OR for CD68-positive stains (OR=55.0, p<0.001), while ASL renal blood flow returned a significant OR for CD8-positive stains (OR=24.0, p=0.03). mpMRI tumor volume and IVIM D heterogeneity returned the highest [Formula: see text]) for malignancy. ccLS had the highest [Formula: see text] for overall detection of ccRCC, and mpMRI distinguished ccRCC from non-ccRCC with increased IVIM D and ADC with [Formula: see text].

Conclusion: In this pilot study, mpMRI was sensitive to immuno-oncologic biomarkers supporting preoperative MRI as a method of characterizing tumor immune microenvironment, malignancy, and subtype for informed and tailored treatment management.

Background: Adoptive cell transfer-based immunotherapy holds promise for treating advanced cancer. However, a key challenge remains: generating sufficient numbers of lymphocytes capable of recognizing and targeting a broad range of cancer antigens. We recently developed Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT), a novel procedure for selecting, expanding and maturing polyclonal lymphocytes from peripheral blood with the capacity to target cancer cells. In this single-center phase Ib trial, we evaluated the safety, tolerability, and preliminary efficacy of ALECSAT in combination with standard carboplatin and gemcitabine in patients with locally advanced or metastatic triple-negative breast cancer (mTNBC).

Methods: This clinical study enrolled 15 patients with mTNBC. The patients received three ALECSAT doses, administered every 28 days. Subsequently, ALECSAT doses were given at 6-week intervals. Carboplatin and gemcitabine were administered on days 1 and 8 in 3-week cycles. The cell composition of ALECSAT preparations was analyzed using flow cytometry. Additionally, patient-derived xenograft (PDX) mouse models were generated and treated with ALECSAT to assess treatment responses.

Results: 14 patients with mTNBC, who had received one to four prior treatment lines, were treated with 1-10 doses of ALECSAT. The combination of ALECSAT with carboplatin and gemcitabine was well tolerated and demonstrated a favorable safety profile. Common adverse events (AEs), including fatigue, nausea, and hematological abnormalities, were consistent with the known toxicity profiles of carboplatin and gemcitabine. Notably, grade ≥3 AEs were predominantly hematological, with manageable durations of neutropenia and thrombocytopenia. Among treated patients, one achieved a complete response, four had partial responses, five had stable disease, and four had progressive disease. The objective response rate was 36% (95% CI 12.8% to 64.9%). Median progression-free survival was 4.3 months (95% CI 1.6 to 7.0), while median overall survival was 8.7 months (95% CI 5.1 to 12.4). A positive correlation was observed between the total number of administered ALECSAT cells (particularly CD8+T cells) and time to progression. Additionally, ALECSAT treatment outcomes in patients correlated with responses observed in their corresponding PDX models.

Conclusion: ALECSAT, in combination with carboplatin and gemcitabine, was safe, well tolerated, and demonstrated promising antitumor activity in mTNBC. These findings support further investigation in larger clinical trials.

Trial registration number: NCT00891345.