Adoptive Immunotherapy Research Articles

Updated results on multiple antigens stimulating cellular therapy (MASCT-I) in metastatic urothelial carcinoma: A randomized, open-label, phase I trial.

2545 Background: The appropriate treatment for mUC remains unmet medical needs. MASCT-I, an adoptive transfer of dendritic cells (DCs) presenting 15 types of tumor-associated antigens (TAAs), showed valuable treatment in solid tumors. We previously reported the efficacy and safety of MASCT-I alone, or plus camrelizumab or chemotherapy in mUC (NCT03034304). The biomarker analysis and long-term follow-up to for this promising approach was unknown. Methods: All enrolled patients were divided into in five groups (G) as previous reported. Patients in G2 receiving maintenance therapy of MASCT-I after first-line platinum based-chemotherapy were allowed to enter enrolled in G3 and receiving MASCT-I plus camrelizumab when disease progressed. We updated the exploratory endpoint of the IFN-γ ELISPOT assay, which was used to measure activation of the cytotoxic T Lymphocyte (CTL) response in eligible patients. Long-term follow-up results for safety, progression-free survival (PFS) and overall survival (OS) were reported. Results: 39 patients were enrolled. By January 31st, 2024, median follow-up time was 31.1 months. No new safety signals were updated. As previously reported, the most common adverse events (AEs) associated with MASCT-I included grade 1 and 2 flushing, pruritus, rash, muscle cramp, fever, and arthralgia. No MASCT-I-related death occurred. Median PFS and OS for all patients were 2.3 months, and 16.9 months, respectively. Patients in G2 presented superior OS of 41.2 months and duration of response (DOR) of 6.4 months. Nine patients treated with MASCT-I and camrelizumab after progression on MASCT-I in G2 presented a 24-month PFS rate of 55.6% and a 48-month DOR rate of 71.8%. Five patients had prolonged PFS for more than 20 months while two of them had PFS of more than 43 months. To identify the potentially beneficial population, IFN-γ ELISPOT data analysis revealed that patients who had positive TAAs ELISPOT response had significant prolonged PFS and OS compared to the non-responders (median PFS: 10.1 months vs 4.8 months, HR=0.30, 95% CI: 0.14-0.61, P<0.005; median OS: not reached vs 13.6 months, HR=0.16, 95% CI: 0.05-0.57, P<0.005). The Cmax value of INF-γ-positive T cells after cell infusion was also higher in patients with better PFS. In addition, we observed a significant increase in INF-γ-positive T cell activities in patients who progressed from G2 and were subsequently treated with a combination of MASCT-I and camrelizumab (Cmax mean (SD): 72 spots per million bulk PBMCs at G2 to 186 spots per million bulk PBMCs after transfer to G3, P=0.002). Conclusions: MASCT-I alone or in combination with immunotherapy or chemotherapy are safe and well tolerated, with inspiring survival benefit. The combination of PD-1 inhibitors may enhance the antitumor activity of MASCT-I. IFN-γ ELISPOT might be able to predict potentially beneficial populations. Clinical trial information: NCT03034304 .

ATHENA: A phase 1/2 study of AZD5851, a chimeric antigen receptor (CAR) T-cell therapy directed against GPC3 in adult patients with advanced/recurrent hepatocellular carcinoma (HCC).

TPS2675 Background: Checkpoint inhibitor therapy is the standard first-line treatment for advanced/recurrent HCC, but there is a significant unmet therapeutic need for patients (pts) who progress after first-line treatment. Adoptive cellular immunotherapy may provide a novel treatment option. Glypican-3 (GPC3), a heparan sulfate proteoglycan, is overexpressed by tumor cells in HCC and virtually absent in healthy tissues, making it an ideal target for CAR-T therapy. AZD5851 is an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine. Early clinical data with C-CAR031, a CAR-T product with the same GPC3-specific CAR and dnTGFβRII-armoring transgene as AZD5851, showed promising tolerability and antitumor activity in pts with HCC [1]. ATHENA (NCT06084884) is a first-in-human, single-arm, open-label, multicenter phase 1/2 study to evaluate the safety, tolerability, and antitumor activity of AZD5851 in pts with GPC3+ advanced/recurrent HCC, for whom ≥1 prior line of standard therapy failed or was not tolerable. Methods: Eligible pts are aged ≥18 years with histologically confirmed advanced/recurrent or metastatic and/or unresectable HCC, GPC3+ tumor sample as determined by immunohistochemistry, ≥1 prior line of standard systemic therapy, ≥1 measurable lesion per RECIST 1.1, Child-Pugh A, ECOG PS 0/1, and adequate organ and bone marrow function. Approximately 24 pts will be enrolled in Part A (Phase I, dose escalation) and 50 in Part B (Phase II dose expansion). Pts will undergo apheresis to collect peripheral blood mononuclear cells for AZD5851 production, after which they may receive approved bridging therapy for disease control. Upon successful generation of AZD5851 product, pts will undergo lymphodepletion before receiving a single dose of IV AZD5851. Subsequent follow-up is divided into 3 stages: Stage 1, active follow-up of all pts through 6 months post AZD5851 infusion; Stage 2, further evaluation of pts who have not progressed or started a new anticancer regimen during Stage 1; Stage 3, long-term follow-up for all pts who have received AZD5851. The primary endpoints are to assess the safety/tolerability of AZD5851 (both study parts), and to determine the recommended dose(s) of AZD5851 for expansion and phase 2 trials (Part A). Secondary endpoints include efficacy (objective response rate, best overall response, duration of response, disease control rate, durable response rate, time to response, progression-free survival, and overall survival) and pharmacokinetics. Exploratory endpoints include pharmacodynamic biomarkers and immunogenicity. Enrollment began Nov 2023. 1. Zhang et al. AACR 2023. Abstract CT097. Clinical trial information: NCT06084884 .

OS-113 Adoptive natural killer cell immunotherapy can increase the recurrence-free survival following transarterialchemoembolization in patients with intermediate stage hepatocellular carcinoma

OS-113 Adoptive natural killer cell immunotherapy can increase the recurrence-free survival following transarterialchemoembolization in patients with intermediate stage hepatocellular carcinoma

Pelareorep driven blood TIL expansion in patients with pancreatic, breast and colon cancer.

e14625 Background: Tumor infiltrating lymphocytes (TILs) represent a major immunological tumor control mechanism that is associated with better prognosis in cancer. One emerging cancer treatment approach to leverage the therapeutic potential of TILs is the expansion and adoptive cell transfer of autologous TILs, commonly referred to as autologous adoptive therapy (ACT). ACT clinical studies have shown encouraging results. While the majority of these trials have targeted melanoma, impressive clinical benefit has also been observed in cervical cancer, with preliminary efficacy in colorectal cancer (CRC), cholangiocarcinoma, non-small cell lung cancer, and breast cancer. Pelareorep (pela) is a live, replication competent reovirus (T3D) that selectively replicates in cancer cells and represents a new class of immunotherapy currently being explored in multiple clinical settings. To examine the effect of pela therapy on TIL expansion we applied T cell receptor sequencing of matched tumor tissue and whole blood pre- and post-treatment in a subset of breast, pancreatic, and (CRC) subjects receiving chemotherapy and atezolizumab, an anti-PD-L1 therapy, and intravenous treatment with pela. Methods: Identification of TIL clones was performed by immunosequencing of the CDR3 regions of human T-cell receptor-β (TCRβ) chains (ImmunoSEQ Assay, Adaptive Biotechnologies). DNA was isolated from tissue and blood at baseline and from blood collected post-treatment. TCRβ CDR3 regions were amplified by a multiplex, bias-controlled PCR with primers targeting the V and J genes of T cells as well as primers targeting housekeeping genes to quantitate the total nucleated cells in each sample. PCR products were sequenced on an Illumina NextSeq. Results: Pela treatment was observed to increase the expansion of pre-existing and new TIL clones in the blood in from all tumor samples after one cycle of treatment. We also observed that pre-existing TIL clonal expansion in the blood seemed to correlate with reductions in tumor volume in pancreatic cancer and to a lesser extent in CRC patients who received multiple cycles of therapy. Interestingly, unlike atezolizumab, pela’s clinical activity was lost when combined with avelumab, a PD-LI inhibitor capable of binding Fc receptors and inducing ADCC. The addition of avelumab eliminated pre-existing TIL expansion in the blood highlighting the importance of TIL expansion following pela therapy. Conclusions: These findings, while preliminary, suggest that the clinical benefits observed following pela immunotherapy may be mechanistically analogous to ACT. Accordingly, pela therapy may offer a means to directly expand TILs without the need for tumor resection, ex vivo TIL expansion, T cell ablation and IL-2 therapy. Clinical trial information: Eudra-CT: 2020-003996-16 .

Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.

A phase 2, multicenter study of TILs treatment in advanced tumors with alterations in the SWI/SNF complex: The TILTS study.

TPS2674 Background: Tumors associated with SWI/SNF complex (SWI/SNFc) mutations, mainly SMARCA4 and SMARCB1 loss, are a heterogeneous group of malignancies with rhabdoid features that typically affect young patients (pts). These are aggressive malignancies with poor prognosis for which no standard treatment is available. Despite not having a high tumor mutation burden, tumor infiltrating lymphocytes (TILs) are usually present in high numbers. The biologic reasons for this feature are not clearly understood but might be associated to changes in gene expression due to aberrant chromatin remodeling. However, these TILs indicate that tumor antigens are recognized by lymphocytes unveiling a vulnerability that can be exploited by immunotherapy. The objective of the TILTS study is to develop a personalized adoptive cell therapy using TILs in pts affected by these tumors. Methods: Single arm, multi center, phase 2 study of TILs in pts with advanced tumors associated with SWI/SNFc mutations. Pts are treated at 3 centers in Spain: Catalan Institute of Oncology (ICO), Barcelona, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, and Centro Integral Oncológico Clara Campal (HM CIOCC), Madrid. Primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include toxicity evaluation, duration of response (DOR), progression-free survival (PFS) or overall survival (OS). After informed consent is obtained, tumor resection is performed. Total volume of tumor resected should be at least 1.5 cc to assure TIL isolation. Eligible pts enter the treatment phase. TILs are produced under GMP conditions. During the TILs manufacturing process, pts are allowed to receive standard treatment if clinically indicated. Before TIL infusion, pts receive non-myeloablative preconditioning lymphodepletion with daily intravenous (IV) cyclophosphamide (60 mg/kg; IV x2 doses) and daily fludarabine (25 mg/m2; IV x5 doses). Infusion of autologous TILs is given on Day 0 followed by administration of IL-2 at 600,000 international units (IU)/kg every 8-12 hours for a maximum of 6 doses. After 4 weeks, a new tumor biopsy is optional. First image evaluation is performed after 8 weeks from TIL infusion. Pts without progression enter the follow-up phase. An ancillary translational study will explore mechanisms of immunogenicity, antigen recognition, TILs anti-tumor activity, and changes in the stool microbiome and specific TCR population during treatment. Also, tumor immune microenvironment will be analyzed. Clinical trial information: 2023-504632-17-00 . [Table: see text]

Phase 1 study of GT101 as an autologous tumor infiltrating lymphocyte (TIL) therapy in advanced solid tumors.

2548 Background: Adoptive cell therapy utilizing autologous TIL has demonstrated efficacy and durable long-term responses in patients with certain advanced solid tumors progressed after conventional therapies. We present data from 14 patients enrolled in the study of GT101, a Phase 1, open-label, single-arm, multicenter trial (NCT05430373) of autologous TIL therapy, aiming to investigate the safety profile, efficiency trend and the duration of response. Methods: The trial was designed with the primary endpoint on evaluating DLT and characterizing the safety profile of GT101 in solid tumor patients measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs). The secondary endpoints were to assess efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) according to RECIST v1.1. Results: As of November 10, 2023, a cohort of 14 patients received treatment with a median age of 46.9 and a median of 2.6 lines of prior therapies. Following a standard FC-based lymphodepletion, patients underwent GT101 infusion at doses ≥ 5x109 cells with median dose of 3.7x1010 cells, followed by high-dose IL-2 administration. Most of observed Grade ≥ 3 AEs were related to the FC conditioning regimen and IL-2, including decreased lymphocyte count, decreased white blood cell count, decreased neutrophil count, anemia, pyrexia and decreased platelet count. The majority of these AEs were recovered within 14 days, while a few were downgraded to ≤ Grade 2 within 4 weeks. Among 14 enrolled patients across various indications (small-cell-lung cancer, melanoma, cervical cancer), the ORR was 35.7%. Specifically, 4 pts (28.6%) had a confirmed partial response (PR), 1 pt (7.1 %) achieved complete response (CR), and 8 pts (57.1 %) had stable disease (SD) as their best response. One pt had unconfirmed disease progression (PD). Notably, among 11/14 patients with cervical cancer, the ORR was 45.5% (5/11) with 4 pts (36.4%) achieving PR and 1 pt (9.1 %) achieving CR. Disease control was observed in 10/11 pts (90.9%), and the median PFS was 4.2 months for this cohort. The CR patient underwent a long-term follow-up and the duration of CR and PFS (estimated by Kaplan-Meier) was 24 weeks and 36 weeks, respectively. Post GT101 infusion, T cell expanded robustly in the peripheral blood of all patients with median Tmax 6.83 days and average 15.9 days. Conclusions: In the GT101 Phase 1 study, no treatment-related SAEs and DLT were observed. In patients with heavily pretreated advanced or metastatic solid tumors, GT101 exhibited a manageable safety profile under the treatment protocol of lymphodepletion and high-dose IL-2 and a favorable clinical profile, particularly in cervical cancer, with an encouraging ORR and sustained response duration. Clinical trial information: NCT05430373 .

Immunomodulatory alpha neutrophils: The first-in-class neutrophil progenitor-based allogeneic immuno-cell therapy with cytotoxic and immunomodulatory functionality for the treatment of solid tumours.

e14523 Background: Adoptive cell therapy for the treatment of cancer has largely focused on the administration of autologous engineered αβ T cells. Although successful in some haematological malignancies, the solid tumour microenvironment (TME) poses significant challenges to the efficacy of CAR-T cells, including physical barriers, heterogeneous antigen expression or antigen escape and immunosuppressive mediators. Remodeling the immunosuppressive solid TME is pivotal to the success of immunotherapies. Recent studies have highlighted key roles for neutrophils in tumour control and in facilitating successful responses to cancer immunotherapy, with neutrophil functional heterogeneity within the TME becoming increasingly appreciated. Methods: At LIfT Biosciences we have developed the first-in-class, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties called Immunomodulatory Alpha Neutrophils (IMANs). IMANs are derived from CD34+ stem cells expanded and differentiated in proprietary media compositions in a simple and scalable GMP-compliant manufacturing process. IMANs are designed to recapitulate those neutrophil states that are both cytotoxic and capable of immunomodulating the solid TME for long-lasting tumour control. Off-the-shelf, allogeneic, innate IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Results: IMANs multimodal mechanisms of action (MoA) have been demonstrated in different state-of-the-art solid tumour models, including co-culture with patient-derived xenograft organoids (PDX-O) and with 3D ex vivo patient tissues (tumour-on-a-chip). Direct antigen-independent cytotoxicity towards PDX-O from a range of solid tumour indications has been demonstrated. Additionally, and fundamental to IMANs MoA is their ability to migrate to the solid TME and recruit and activate recipients’ anti-tumour immune responses. We have demonstrated IMANs ability to rapidly migrate into the solid TME and promote recruitment of patients’ immune cells leading to enhanced tumour cell death using tumour-on-a-chip technology accompanied by daily live cell imaging. Mechanistically, co-culture with IMANs enhanced expression of co-stimulatory receptors on T and NK cells, such as OX40 and 4-1BB, as well as promoting secretion of TME-modulating factors, such as CXCL10. Furthermore, co-culture with IMANs enhanced secretion of IFN-γ by activated tumour-infiltrating lymphocytes. Conclusions: These cytotoxic and immunomodulatory functions enable IMANs to remodel the TME, leaving the solid tumour more susceptible to host immune responses.

Adoptive Cell Therapy for Solid Tumors: Current Status in Melanoma and Next-Generation Therapies.

Lifileucel or TIL has recently been FDA approved for metastatic melanoma patients as first cell therapy for a solid tumor. We discuss roll-out of TIL as new SOC and other upcoming new cell therapies.

Combination therapy with the oncolytic virus CF33-CD19 and blinatumomab for the treatment of advanced solid tumors.

TPS2687 Background: CF33-CD19 is a novel chimeric vaccinia virus that selectively replicates in tumor cells and can provoke anti-tumor immunity. CF33-CD19 expresses a truncated and non-signaling CD19 protein on the surface of infected tumor cells before virus-mediated tumor lysis, labeling them for CD19-targeted therapies. Preclinical studies with CF33-CD19 have shown that combination therapy with CD19 targeting chimeric antigen receptor T cells is more effective than either monotherapy in murine xenograft and syngeneic models [1]. Likewise, combination therapy with bispecific T-cell engagers (BiTE)s that bind CD3-positive T cells and infected solid tumor cells that express de novo CD19, showed pronounced recruitment of T cells to the tumor microenvironment, resulting in tumor growth inhibition in mouse models. CD19xCD3 targeting BiTEs such as blinatumomab may offer an off-the-shelf alternative to adoptive cell therapies. This phase I study, called OASIS, dose escalates CF33-CD19 administered intravenously (IV) or intratumorally (IT) combined with blinatumomab in adults with advanced or metastatic solid tumors. Methods: The OASIS study (NCT06063317) is enrolling patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy. Patients who have received prior treatment with a poxvirus based oncolytic virus or a bispecific CD19-directed CD3 T-cell engager are excluded. A safety run-in will evaluate the safety of CF33-CD19 monotherapy administered IT or IV before initiating the combination therapy regimen. Combination therapy will be administered in 28-day cycles with CF33-CD19 on days 1 and 15. Following viral transduction to promote de novo CD19 expression, blinatumomab is given on days 2-9 and 16-23 via a 7-day continuous infusion. Patients > 45 kg will receive 9 mcg of blinatumomab during the first week of cycle 1, then 28 mcg during the third week of cycle 1 and subsequent cycles. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independently of each route of CF33-CD19 administration (IT and IV) with dose levels of CF33-CD19 ranging from 1.0x107 to 3.0x109 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST. Enrollment began in October 2023. 1. Park et al. Sci Transl Med. 2020 Sep 2;12(559):eaaz1863. doi: 10.1126/scitranslmed.aaz1863. PMID: 32878978. Clinical trial information: NCT06063317 .

Immunotherapy with genetically engineered T cells holds promise for the treatment of nonmalignant diseases in the dog.

The ability to genetically redirect the antigenic specificity of T cells using chimeric antigen receptors (CAR) has led to unprecedented durable clinical remissions in human patients with relapsed/refractory hematological malignancies. This remarkable advance in successful immune cell engineering has now led to investigations into the application of CAR-T-cell technology to treat nonmalignant diseases. The use of CAR-T cells to target and eliminate specific cell subsets involved in the pathogenesis of autoimmunity, fibrosis, senescence, and infectious disease represents a new direction for adoptive cell therapies. While the use of CAR-T cells for nonmalignant disease is still in its infancy, early reports of dramatic clinical responses to CAR-T cells targeting CD19+ B cells in patients with severe autoimmune disease raise the possibility that this approach could lead to durable remissions, eliminating the need for ongoing conventional immunosuppressive therapies. Excitingly, nonmalignant disease processes that may be addressed by CAR-T-cell therapy in humans also occur in our canine populations. Given that technologies for developing canine CAR constructs are now available, robust protocols have been described for generating canine CAR-T cells, and experience is being gathered with their clinical use in oncology, it is anticipated that CAR-T cells will soon enter the veterinary clinics for the treatment of debilitating nonmalignant diseases. Here, we provide a broad overview of CAR-T-cell therapies for nonmalignant diseases and extrapolate these advances into the veterinary space, highlighting areas in which canine CAR-T cells are poised to enter the clinics for the treatment of nonmalignant disease.

Effect of indole 3-propionic acid from microbiota on the immunity of CD8+ T cell to improve chemotherapy of colorectal cancer.

e15194 Background: Sensitivity of chemotherapy is a great challenge to improve the treatment efficacy in patients with colorectal cancer (CRC). Increasing study has revealed the role of microbiota in the modulation of chemotherapy sensitivity. However, the mechanism how microbiota regulates the efficacy of 5-fluorouracil (5-FU) is far from clear. Methods: We used germ-free mice and antibiotic-treated mice to demonstrate the impact of the gut microbiota on 5-FU sensitivity. Metabolomics analysis of serum from patients with CRC or mice experiments were applied to identify the key metabolite, indole 3-propionic acid (IPA). Specific pattern of microbiota with capability to produce IPA was revealed by metagenomics analysis of the mice feces. Single-cell RNA (scRNA) sequencing was subsequently used and antibody blockade experiments as well as T cell adoptive transfer experiment were conducted to confirm the role of CD8+ T cells in 5-FU treatment. AHR KO mice model was used to reveal how IPA regulate the immunity of CD8+ T cells. Engineering Escherichia coli strain BL21 with capability to produce IPA was constructed to modulate the chemotherapy sensitivity. Results: Decreased sensitivity of 5-FU chemotherapy was observed in both germ-free mice and antibiotic-treated mice models. Accumulation of serum IPA was found in mice with vancomycin intervention and verified in CRC patient with chemotherapy resistance. Additionally, metagenomic analysis of mice feces revealed that Clostridium sporogenes capable of producing IPA, are crucial for 5-FU chemotherapy sensitivity. Supplementation with IPA or Clostridium sporogenes could obviously improve the sensitivity of 5-FU chemotherapy. Subsequently scRNA sequencing analysis of tumor tissue revealed a higher infiltration of CD8+ T cells after IPA intervention. The role of IPA-induced CD8+ T cells in 5-FU treatment was confirmed by antibody blockade experiments and T cell adoptive transfer experiment. Further, improved therapeutic sensitivity by IPA and the infiltration of CD8+ T cells were vanished in AHR KO mice model. Biosynthesis of IPA by engineering bacteria was found to enhance the sensitivity of 5-FU chemotherapy. Conclusions: Indole 3-propionic acid from microbiota enhances the immunity of CD8+ T cell via activation of AHR signaling pathway, thus providing potential therapeutic strategies to improve the efficacy of chemotherapy in colorectal cancer.

Double-negative T cells have a reparative role after experimental severe ischemic acute kidney injury.

T cells mediate organ injury and repair. A proportion of unconventional kidney T cells called double-negative (DN) T cells (TCR+ CD4- CD8-), with anti-inflammatory properties, were previously demonstrated to protect from early injury in moderate experimental acute kidney injury (AKI). However, their role in repair after AKI has not been studied. We hypothesized that DN T cells mediate repair after severe AKI. C57B6 mice underwent severe (40 min) unilateral ischemia-reperfusion injury (IRI). Kidney DN T cells were studied by flow cytometry and compared with gold-standard anti-inflammatory CD4+ regulatory T cells (Tregs). In vitro effects of DN T cells and Tregs on renal tubular epithelial cell (RTEC) repair after injury were quantified with live-cell analysis. DN T cells, Tregs, CD4, or vehicle were adoptively transferred after severe AKI. Glomerular filtration rate (GFR) was measured using fluorescein isothiocyanate (FITC)-sinistrin. Fibrosis was assessed with Masson's trichrome staining. Profibrotic genes were measured with qRT-PCR. Percentages and the numbers of DN T cells substantially decreased during repair phase after severe AKI, as well as their activation and proliferation. Both DN T cells and Tregs accelerated RTEC cell repair in vitro. Post-AKI transfer of DN T cells reduced kidney fibrosis and improved GFR, as did Treg transfer. DN T cell transfer lowered transforming growth factor (TGF)β1 and α-smooth muscle actin (αSMA) expression. DN T cells reduced effector-memory CD4+ T cells and IL-17 expression. DN T cells undergo quantitative and phenotypical changes after severe AKI, accelerate RTEC repair in vitro as well as improve GFR and renal fibrosis in vivo. DN T cells have potential as immunotherapy to accelerate repair after AKI.NEW & NOTEWORTHY Double-negative (DN) T cells (CD4- CD8-) are unconventional kidney T cells with regulatory abilities. Their role in repair from acute kidney injury (AKI) is unknown. Kidney DN T cell population decreased during repair after ischemic AKI, in contrast to regulatory T cells (Tregs) which increased. DN T cell administration accelerated tubular repair in vitro, while after severe in vivo ischemic injury reduced kidney fibrosis and increased glomerular filtration rate (GFR). DN T cell infusion is a potential therapeutic agent to improve outcome from severe AKI.

Programmable cancer treatments: Engineering biology approaches for living cures.

Living cures are cell-based, programmable therapies that integrate the latest learnings in immunology and synthetic biology. Although Adoptive Cell Therapies (ACTs) have transformed the treatment landscape of haematological malignancies by harnessing the powerful anti-tumour properties of immune cells, commercialisation and ensuring access is challenging. Their application in solid tumour treatment has been hindered by the immunosuppressive tumour microenvironment (TME) and its associated physical barriers. Conversely, bacterial immunotherapies offer cost-effective solutions by utilising tumour-colonising bacteria that trigger localised inflammatory responses within the TME. The authors briefly examine advancements in ACT and propose bacterial immunotherapies as an alternative or complementary treatment modality with potential use either as standalone therapies or in conjunction with other treatments.

Dopamine β-hydroxylase shapes intestinal inflammation through modulating T cell activation

BackgroundInflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined. MethodsCD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function. ResultsInhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells. ConclusionModulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.

Transfer of micro-organisms from dry surface biofilms and the influence of long survival under conditions of poor nutrition and moisture on the virulence of Staphylococcusaureus

Biofilms on dry hospital surfaces can enhance the persistence of microorganisms on dry harsh clinical surfaces and can potentially act as reservoirs of infectious agents on contaminated surfaces. This study was conducted to quantify the transfer of viable Staphylococcus aureus cells from dry biofilms through touching and to investigate the impact of nutrient and moisture deprivation on virulence levels in S. aureus. Dry biofilms of S. aureus ATCC 25923 and a defective biofilm-forming ability mutant, S. aureus 1132 were formed in 24 well plates under optimised conditions mimicking dry biofilm formation on clinical surfaces. Microbial cell transfer was induced through the touching of the dry biofilms, which were quantified on nutrient agar. To investigate the impact of nutrient and moisture deprivation on virulence levels, dry and standard biofilms as well as planktonic cells of S. aureus ATCC 25923 were inoculated into Galleria mellonella and their kill rates compared. Results of this study showed that viable cells from dry biofilms of S. aureus ATCC 25923 were significantly more virulent and readily transferrable from dry biofilms through a touch test, therefore representing a greater risk of infection. The biofilm-forming capability of S. aureus strains had no significant impact on their transferability with more cells transferring when biofilm surfaces were wet. These findings indicate that dry biofilms on hospital surfaces may serve as a reservoir for the dissemination of pathogenic microorganisms in hospitals, thus highlighting the importance of regular cleaning and adequate disinfection of hospital surfaces.

Modeling the Nonmonotonic Immune Response in a Tumor–Immune System Interaction

Tumor–immune system interactions are very complicated, being highly nonlinear and not well understood. A large number of tumors can potentially weaken the immune system through various mechanisms such as secreting cytokines that suppress the immune response. In this paper, we propose a tumor–immune system interaction model with a nonmonotonic immune response function and adoptive cellular immunotherapy (ACI). The model has a tumor-free equilibrium and at most three tumor-presence equilibria (low, moderate and high ones). The stability of all equilibria is studied by analyzing their characteristic equations. The consideration of nonmonotonic immune response results in a series of bifurcations such as the saddle-node bifurcation, transcritical bifurcation, Hopf bifurcation and Bogdanov–Takens bifurcation. In addition, numerical simulation results show the coexistence of periodic orbits and homoclinic orbits. Interestingly, along with various bifurcations, we also found two bistable scenarios: the coexistence of a stable tumor-free as well as a high-tumor-presence equilibrium and the coexistence of a stable-low as well as a high-tumor-presence equilibrium, which can show symmetric and antisymmetric properties in a range of model parameters and initial cell concentrations. The new findings indicate that under ACI, patients can possibly reach either a stable tumor-free state or a low-tumor-presence state in the presence of nonmonotonic immune response once the immune system is activated.

Limited Immunogenicity of an HLA-A*03:01-restricted Epitope of Erv-k-env in Non-hiv-1 Settings: Implications for Adoptive Cell Therapy in Cancer.

Repetitive elements (REs) are often expressed at higher levels in tumor cells than normal cells, implicating these genomic regions as an untapped pool of tumor-associated antigens. In ovarian cancer (OC), protein from the RE ERV-K is frequently expressed by tumor cells. Here we determined whether the targeting of a previously identified immunogenic epitope in the envelope gene (env) of ERV-K resulted in target antigen specificity in non-HIV-1 settings. We found that transducing healthy donor T cells with an ERV-K-Env-specific T cell receptor construct resulted in antigen specificity only when co-cultured with HLA-A*03:01 B lymphoblastoid cells. Furthermore, these transduced T cells were not specific for HLA-A*03:01 + OC cells nor for the cognate peptide in HLA-matched systems from multiple healthy donors. These data suggest that the ERV-K-Env epitope recognized by this T cell receptor is of low immunogenicity and has limited potential as a T cell target for OC.

Surface-Functionalized Microgels as Artificial Antigen-Presenting Cells to Regulate Expansion of T Cells.

Artificial antigen-presenting cells (aAPCs) are currently used to manufacture T cells for adoptive therapy in cancer treatment, but a readily tunable and modular system can enable both rapid T cell expansion and control over T cell phenotype. Here, it is shown that microgels with tailored surface biochemical properties can serve as aAPCs to mediate T cell activation and expansion. Surface functionalization of microgels is achieved via layer-by-layer coating using oppositely charged polymers, forming a thin but dense polymer layer on the surface. This facile and versatile approach is compatible with a variety of coating polymers and allows efficient and flexible surface-specific conjugation of defined peptides or proteins. The authors demonstrate that tethering appropriate stimulatory ligands on the microgel surface efficiently activates T cells for polyclonal and antigen-specific expansion. The expansion, phenotype, and functional outcome of primary mouse and human T cells can be regulated by modulating the concentration, ratio, and distribution of stimulatory ligands presented on microgel surfaces as well as the stiffness and viscoelasticity of the microgels.

Nanomaterial-Driven Precision Immunomodulation: A New Paradigm in Therapeutic Interventions.

Immunotherapy is a rapidly advancing field of research in the treatment of conditions such as cancer and autoimmunity. Nanomaterials can be designed for immune system manipulation, with precise targeted delivery and improved immunomodulatory efficacy. Here, we elaborate on various strategies using nanomaterials, including liposomes, polymers, and inorganic NPs, and discuss their detailed design intricacies, mechanisms, and applications, including the current regulatory issues. This type of nanomaterial design for targeting specific immune cells or tissues and controlling release kinetics could push current technological frontiers and provide new and innovative solutions for immune-related disorders and diseases without off-target effects. These materials enable targeted interactions with immune cells, thereby enhancing the effectiveness of checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. Moreover, they allow for fine-tuning of immune responses while minimizing side effects. At the intersection of nanotechnology and immunology, nanomaterial-based platforms have immense potential to revolutionize patient-centered immunotherapy and reshape disease management. By prioritizing safety, customization, and compliance with regulatory standards, these systems can make significant contributions to precision medicine, thereby significantly impacting the healthcare landscape.