Journal for Immunotherapy of Cancer最新文献

γδ T cells are unconventional lymphocytes that bridge innate and adaptive immunity by combining recognition of stress-induced ligands independently of classical major histocompatibility complex molecules with the capacity to undergo clonal expansion and long-term adaptation. Their unusual ability to detect malignant transformation using semi-invariant T-cell receptors, butyrophilin recognition and natural killer-like receptors positions them as powerful effector cells in tumors that evade classical immune escape mechanisms. Furthermore, distinct γδ subsets have distinct phenotyping and specific tissue-residencies, which could be leveraged to modulate immunological responses. We evaluate engineered therapies and different experimental platforms for studying γδ T cell biology. We conclude that next-generation cancer treatments should strategically integrate γδ T cells into synthetic immunology, individualized modeling, and combinatorial regimes.

B-cell maturation antigen (BCMA) was recently identified as a target of T-cell-directed therapy for acute myeloid leukemia (AML), based on the study reporting high BCMA abundance in AML cells using the flow cytometry anti-BCMA antibody clone 19F2 (BCMA-19F2). However, our independent investigation demonstrated limited BCMA levels in both AML patient samples and AML cell lines through the analysis of established transcriptome profiles. The low BCMA expression in AML cells was validated by flow cytometry using an alternative anti-BCMA antibody (clone REA315) and western blotting. Importantly, we unveiled that the BCMA-19F2 could bind non-specifically to AML cells via its non-antigen-binding fragment, as evidenced by the isotype control experiment and Fc receptor blocking assay. Furthermore, cytotoxicity assay confirmed that the leukemic cell lysis was minimal on the treatment of anti-BCMA CAR T cells. Our data suggest that BCMA expression is restricted in AML, and the BCMA-19F2 is unsuitable for BCMA detection in the context of AML samples. It underscores that the accurate assessment of tumor antigen is paramount for therapeutic target design.

Immunotherapy has been a pillar of the renal cell carcinoma (RCC) treatment landscape for over three decades. Some of the earliest cancer immunotherapies available, such as interleukin 2 and interferon-alpha, have resulted in complete responses, but only in a small number of patients. Immune checkpoint inhibitors (ICIs), however, have demonstrated improved response rates and prolonged survival for a greater number of patients, fully transforming the standard of care in first-line and subsequent-line settings. More recently, ICIs are also being used in the adjuvant setting for high-risk patients. However, treatment with ICIs requires a nuanced understanding of topics such as patient selection, histology and risk considerations, and integration with local therapies. As such, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline (CPG) on immunotherapy for the treatment of RCC. Drawing from published data and clinical experience, the Expert Panel developed evidence-based and consensus-based recommendations. Topics include therapy selection in the adjuvant and metastatic settings, considerations for special patient populations, response monitoring, and patient education and quality of life considerations, among others, with the goal of improving patient care by providing guidance to the oncology community.

Background: The discovery and therapeutic application of immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in cancer treatment. However, the response rate is still low in gastrointestinal (GI) cancers. The gut microbiome's impact on immune modulation is a promising area for overcoming resistance to immunotherapy.

Methods: This study (NCT04130763) is an open-label, single-arm, single-center, phase I study assessing the safety and efficacy of fecal microbiota transplantation (FMT) from healthy donors in 10 patients with advanced GI cancer resistant to anti-programmed death-ligand 1 (PD-(L)1) treatment. 10 patients with histologically confirmed, unresectable, or metastatic GI cancers (8 gastric, 2 colorectal) who were refractory to anti-PD-(L)1 treatment were enrolled. Patients received initial FMT treatment via oral capsules (60 capsules), followed by a combination therapy phase, where maintenance FMT (10 capsules per treatment) was paired with nivolumab at 3 mg/kg every 2 weeks for six cycles. Serial biomarker assessments were conducted through both fecal and blood sampling.

Results: The combination of FMT and anti-PD-1 treatment was well tolerated with no serious adverse events. The objective response rate was 20% and the disease control rate was 40%. Clinical benefits were associated with colonization of donor-derived immunogenic microbes, and an activated immune status reflected by peripheral immune cell populations. Moreover, microbial signatures were identified for anti-programmed cell death protein-1 (PD-1) responsiveness and validated in an independent cohort.

Conclusions: This phase I study demonstrates the feasibility and safety of combining FMT with anti-PD-1 therapy in patients with ICI-refractory gastric cancer. The observed preliminary efficacy signals and identified microbial signatures generate hypotheses for future trials to investigate microbiome-based approaches to enhance immunotherapy efficacy.

Trial registration number: NCT04130763.

Background: Uveal melanoma is a rare melanoma subtype characterized by a liver-dominant pattern of metastasis which is associated with a lack of durable responses to immunotherapies. Adoptive cell transfer of autologous tumor-infiltrating lymphocytes (TILs) has been shown to induce responses in a subset of patients with metastatic uveal melanoma. The safety and feasibility of locoregional administration of TIL therapy via hepatic arterial infusion (HAI) have not previously been evaluated.

Patients and methods: This prospective, open-label, phase I trial investigated the safety and feasibility of one-time TIL therapy administered via HAI in patients with liver metastases of uveal melanoma. Preconditioning chemotherapy with melphalan (1 mg/kg, intravenous) was administered on day -5. TILs were delivered via percutaneous catheterization of the hepatic artery according to a dose escalation scheme (0.1, 0.3, or 1×10⁹ cells) on day 0. Patients received daily subcutaneous interleukin-2 (IL-2, 2 MIU) up to 14 days after TIL administration. The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included clinical efficacy and the feasibility of TIL production using a semiautomated manufacturing system.

Results: Six patients received TIL therapy manufactured using the CliniMACS Prodigy platform; five were treated according to protocol, while one received a lower TIL dose than planned. All had received prior systemic treatment. No AEs related to the HAI procedure were observed. All patients experienced grade ≥3 hematologic AEs related to preconditioning chemotherapy, and two patients experienced grade ≥3 AEs attributed to TIL/IL-2. Best overall response was stable disease in all patients (100%). Median progression-free survival was 4 months, and median overall survival was 14 months.

Conclusions: TILs can be manufactured using the CliniMACS Prodigy. Administration of TIL via HAI was safe and feasible in patients with liver-dominant metastatic uveal melanoma. The used regimen appears insufficient to achieve durable clinical efficacy and implies a need for further testing to obtain conclusive results.

Trial registration numbers: NCT04812470, EUCT number: 2024-512877-28-00, EudraCT number: 2020-006126-31.

Background: Identifying effective therapeutic drugs in the intricate tumor microenvironment (TME) is challenging, further complicated by the lack of a systematic framework for analyzing TME perturbations in response to therapeutic interventions.

Methods: To address this, we established the single-cell RNA sequencing repository of immunomodulatory drugs resource and used the L1000 platform for unbiased screening of 739 immune-modulating compounds across various cancers.

Results: Drug responses in mouse model revealed 12 distinct meta-programs associated with TME remodeling, enriched in biological processes such as antigen presentation, tissue repair, and salt stress response. Notably, myeloid-derived suppressor cells were markedly reduced in responsive TMEs compared with other cell types, underscoring their key immunosuppressive role. We developed an MP scoring algorithm to quantify TME responsiveness, which successfully identified allopurinol-a gout medication-as a potent enhancer of anti-programmed cell death protein-1 therapy. This combination led to significant tumor-free outcomes (4/6) in vivo.

Conclusions: This work provides a robust framework for assessing TME remodeling that uncovers genes and compounds that significantly modulate immunotherapeutic efficacy.

Background: T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) is an inhibitory receptor linked to decreased antitumor activity of immune cells. S095018 is a human anti-TIM-3 IgG2 antibody that blocks the binding of phosphatidyl serine to TIM-3. Sym021 is a humanized IgG1 antibody that inhibits the binding of programmed cell death protein-1 (PD-1) to its ligands programmed death-ligand 1 (PD-L1) and PD-L2.

Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancers (BTC) whose disease progressed under treatment with at least 1 line of systemic therapy and who had not received prior treatment with PD-(L)1 inhibitors (NCT04641871). Patients received 3 mg/kg of Sym021 and 10 mg/kg of S095018 once every 2 weeks. Primary endpoints included overall response rate and incidence/severity of adverse events. Key secondary endpoints included pharmacokinetics, immunogenicity assessment, progression-free survival (PFS) and overall survival (OS).

Results: 35 patients with stage IV BTC received S095018 in combination with Sym021. A partial response was achieved in 2 patients (5.7%) and stable disease in 11 patients (31.4%) for a disease control rate of 37%; 4 patients were not evaluable for response. Median PFS and OS were 1.9 months (90% CI 1.8 to 3.7) and 13.4 months (90% CI 8.2 to 27.1), respectively. The most common treatment-emergent adverse events of any grade included fatigue, pruritus, infusion-related reaction, and increases in amylase (8.6% each). Exploratory biomarker analyses in paired tumor biopsies showed an increase in intratumoral CD8 T-cell density and an upregulation of gene signatures related to interferon-γ signaling, antigen presentation, and T-cell activation with treatment without, however, clear association with efficacy endpoints.

Conclusions: Dual PD-1/TIM-3 inhibition was tolerable but exhibited modest antitumor activity in patients with advanced/metastatic recurrent BTC who had not received prior anti-PD-(L)1 treatment.

Cancer poses serious health risks to humans. The solute carrier (SLC) family is crucial for cancer development regulation. As a member of this family, SLC7A7 forms a heterodimer with SLC3A2 to transport cationic and neutral amino acids (AA) across the membrane, thereby maintaining cellular AA homeostasis. A recent study resolved the crystal structure of SLC7A7 and identified the key residues involved in substrate binding of SLC7A7, providing important experimental evidence for the future development of small-molecule inhibitors of SLC7A7. In addition, multiple studies have revealed the expression regulation mechanism of SLC7A7 in human, mouse, and porcine cells, providing a basis for studying the regulatory mechanism of SLC7A7 expression in cancer cells. SLC7A7 is dysregulated in multiple cancers, including bladder cancer, non-small cell lung cancer, and hepatocellular carcinoma. SLC7A7 is involved in cancer proliferation and metastasis, with a notable impact on shaping the tumor microenvironment (TME) across multiple cancer types, making it a valuable target for further investigation. In this review, we discuss recent advances in understanding the structure, expression, and regulatory mechanisms of SLC7A7, focusing on its role in cancer development and the current research limitations. Furthermore, this review emphasizes the role of SLC7A7 in promoting cancer immune escape by influencing innate and adaptive immune cells in the TME and discusses its potential mechanisms of immune cell regulation.

The complement system, a key component of the immune response, plays a dual role in cancer, influencing both tumor suppression and progression. Its three activation pathways (classical, alternative, and lectin) initiate immune processes, including opsonization and cell lysis. Within the tumor microenvironment, however, complement activation can paradoxically support immune-mediated tumor control or contribute to immune evasion and tumor growth. Therapeutic interventions such as radiation and certain chemotherapies can trigger complement activation by inducing immunogenic cell death and the release of damage-associated molecular patterns. This activation leads to the generation of anaphylatoxins C3a and C5a, which recruit immune cells to the tumor site and promote antitumor immunity. However, these same fragments may also foster an immunosuppressive microenvironment by attracting regulatory T cells and myeloid-derived suppressor cells, thereby limiting the efficacy of immunotherapies. Additionally, tumor cells often upregulate membrane complement regulatory proteins, including CD46, CD55, and CD59, to escape complement-mediated cytotoxicity and immune surveillance. Recent insights indicate that the complement system is a critical barrier to effective immunotherapy. Complement inhibition, particularly by targeting C3a receptor and C5a receptor 1, has been shown to synergize with immune checkpoint inhibitors (eg, anti-programmed cell death protein-1/programmed death-ligand 1), reversing complement-driven immunosuppression and enhancing T cell-mediated tumor rejection. Combining complement blockade with proimmunogenic therapies such as radiation or chemotherapy may further amplify these effects by uncoupling therapy-induced complement activation from its immunosuppressive consequences. Thus, the interplay between complement activation and cancer therapeutics presents a promising avenue for treatment innovations. Strategic modulation of complement, whether through genetic, pharmacologic, or antibody-based approaches, could sensitize tumors to immunotherapy and help overcome resistance mechanisms. Continued investigation into this crosstalk will be essential for designing effective combination strategies that maximize antitumor immunity while minimizing immune escape.