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Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials. Invariant natural killer T (iNKT) cells recognize abnormal cells, but their T cell receptor is not variable and kill cancerous or infected target cells without MHC I restriction. Here, the authors show that in a clinical trial, donor-unrestricted allogeneic iNKT cells could be safely administered to human COVID-19 patients suffering from acute respiratory distress syndrome and trigger an anti-inflammatory response.

Despite significant advances in cancer therapies, many malignancies remain resistant to current treatments due to complex immunosuppressive mechanisms, limited neoantigen expression, and dynamic tumor adaptations, underscoring the need for innovative therapeutic strategies. Adoptive cell therapy (ACT), particularly with chimeric antigen receptors (CARs and recombinant TCRs) targeting cancer-associated antigens, has emerged as a transformative strategy. However, conventional CAR-T cell therapies face substantial limitations such as manufacturing challenges, severe toxicities, and limited efficacy against solid tumors. Invariant natural killer T (iNKT) cells, a unique lymphocyte subset bridging innate and adaptive immunity, have emerged as a compelling alternative platform for CAR-based therapies, due to their distinctive ability to persist, penetrate in and remodel the tumor microenvironment (TME). Unlike conventional T cells, iNKT cells exhibit rapid activation without priming, potent cytotoxicity, and extensive immunomodulatory functions. Furthermore, the inherent immunomodulatory properties of iNKT cells through interactions with the monomorphic antigen-presenting molecule CD1d or stress ligands augment endogenous anti-tumor immunity by activating NK cells and cytotoxic T lymphocytes, promoting dendritic cell maturation, and reducing immunosuppressive myeloid cells, unlike other Innate T cells. CAR-engineered iNKT (CAR-iNKT) cells therefore leverage multiple targeting mechanisms through their native semi-invariant T-cell receptor (TCR), NK receptors (NKRs) and engineered CARs, enabling broader and more effective tumor recognition while actively reshaping immunosuppressive TME. Notably, iNKT cells lack alloreactivity, circumventing the risk of graft-versus-host disease (GvHD), positioning CAR-iNKT cells as ideal candidates for “off-the-shelf” allogeneic therapies that can overcome the limitations of existing immunotherapies.

The PD-L1 immune checkpoint ligates the PD-1 immune checkpoint, and antibodies against either are effective in treating selected human cancers. Although PD-L2 also ligates PD-1, αPD-L2 is little studied as cancer immunotherapy. We previously showed that αPD-L1 treated young B16-bearing mice but failed in aged. We show here that αPD-L2 fails in young B16-bearing mice but is effective in aged. αPD-L2 increases tumour-infiltrating interferon-γ + immune cell prevalence and interferon-γ production in aged but not young melanoma-bearing hosts in an unexpectedly IL-17-dependent manner. We also show improved αPD-L2 efficacy with advancing age in another tumour type, and αPD-L2-responsive tumours in young hosts, but without IL-17 dependence. The immune B16 microenvironment in aged IL-17-deficient hosts resembles that of young hosts, and exogenous IL-17 elicits αPD-L2 melanoma efficacy in young hosts, demonstrating IL-17 influence on aged immune outcomes. Mechanistic insights into age-related αPD-L2 efficacy could improve immune checkpoint blockade efficacy including in younger patients, address immune checkpoint blockade-resistant tumours and improve understanding of age effects on anti-cancer immunity. PD-L2 can bind the immune checkpoint PD-1. However, its potential as a therapeutic target for immune checkpoint blockade in cancer has not been extensively explored. Here, the authors demonstrate that αPD-L2 is effective in aged, but not young, melanoma murine models.

BackgroundPatients with platinum-resistant/refractory ovarian cancer (PROC) experience suboptimal outcomes, highlighting an immediate need for novel therapies. This phase 1b study investigated the safety and efficacy of botensilimab (BOT), a fragment crystallizable (Fc)-enhanced anti–cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action from first-generation CTLA-4 inhibitors, plus balstilimab (BAL; anti–programmed cell death protein 1 antibody), in an expanded cohort of patients with treatment-refractory ovarian cancer.MethodsBOT was administered intravenously at 1 mg/kg or 2 mg/kg every 6 weeks in combination with BAL intravenously at 3 mg/kg every 2 weeks (up to 2 years). The primary objectives were to assess safety and tolerability. Efficacy end points included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. Overall survival (OS) was an exploratory end point.ResultsOverall, 44 patients were evaluable for safety (with a median of 3 prior lines of therapy; median follow-up 9.6 months (range, 0.6—36.6)), and 35 for efficacy. The most common treatment-related adverse event was diarrhea/colitis (43%; 16% grade 3) with no treatment-related deaths. RECIST-confirmed ORR was 23% (8/35; 95% CI 10% to 40%; one complete (CR), seven partial responses (PRs)) and clinical benefit rate (CR, PR, or stable disease ≥24 weeks) was 31% (11/35; 95% CI 17% to 49%). Median DOR was 9.7 months (95% CI 2.8 to not reached (NR)), median PFS was 2.8 months (95% CI 1.4 to 5.5), median OS was 14.8 months (95% CI 12.1 to NR), and 12-month OS was 75% (95% CI 55% to 86%). Immune phenotypic analyses and biomarker data revealed significantly higher FcγRIIIA+CD11c+ cells and higher programmed death-ligand 1 expression in responding patients, a strong association between T-cell infiltrated tumors and clinical benefit, and differences in immune architecture across histologic subtypes.ConclusionThe BOT/BAL combination demonstrated deep, durable responses and complete remissions in patients with treatment-refractory ovarian cancer where no standard treatments are currently available. RECIST under-represented clinical benefit with 11 patients achieving prolonged/clinically meaningful stable disease (or better) for ≥24 weeks. Toxicities were manageable and reversible. The encouraging clinical activity of BOT/BAL in heavily pretreated patients, as well as biomarker associations, warrants further investigation of this combination.

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

BackgroundAnti-PD-1 therapies have achieved durable clinical responses in a wide range of malignancies, but responses are limited to a small subset of patients. Expression of PD-L1 on tumor cells by immunohistochemistry (IHC) has been applied as a companion diagnostic for anti-PD-1 therapy. However, recent studies have called in to question the reliability of this method to predict response.MethodsHere we developed a novel platform that integrates in vitro pharmacogenomic and functional data with clinical pharmacodynamic responses to immunotherapy using proprietary in silico approaches. The data originate from a long-term co-culture of primary antigen-specific T cells and cancer cells which drives T cells to a terminally dysfunctional, PD-1 refractory state. T cell effector functions and gene expression changes were monitored in the presence or absence of anti-PD-1 antibody or genetic knockouts. RNA expression signatures were refined with a randomized sliding window approach to generate a deep learning neural network for PD-1 response prediction.ResultsWe defined five T cell states associated with distinct phenotypic and molecular features - naïve, active, effector, transition and dysfunction. Among the genes that were selectively expressed in the dysfunction state, we identified a 96-gene signature that is closely associated with clinical outcomes to anti-PD-1 therapy. In PD-1 treated patients across multiple solid tumor indications, this signature correlates with objective response rate and outperforms traditional metrics such as tumor mutation burden or PD-L1 IHC signal. Moreover, this signature combines with tumor sequencing data to generate a powerful machine-learning model that predicts anti-PD-1 responses in metastatic melanoma patients with significantly higher accuracy than PD-L1 IHC. Having established that the T cell states in our co-culture relate to clinical outcomes, we leveraged the system to investigate the molecular basis for PD-1 responses. Single cell mapping of transition state T cells in the presence of anti-PD-1 revealed an expanded population of T cells that co-expresses PD-1, TIGIT and activation markers. Likewise, PD-L1 knockout on cancer cells identified the TIGIT ligand, CD155, as a potential tumor escape mechanism to anti-PD-1 therapy. Consistent with this, the combination of PD-1 and TIGIT blockade enhanced T cell cytotoxicity of tumor cells relative to monotherapies.ConclusionsAgenus’ T cell dysfunction platform combines deep in vitro profiling and AI-based approaches to predict clinical outcomes. Here, we defined a predictive biomarker signature that outperforms standard PD-L1 IHC. Further, we identified known (TIGIT) and potentially novel combination partners predicted to enhance the durability of anti-PD-1 responses.Ethics ApprovalNot ApplicableConsentNot Applicable

BackgroundHarnessing both the innate and adaptive immune system could increase the efficiency of current cancer immunotherapies and promote durable anti-tumor immunity. Invariant natural killer T (iNKT) cells are innate-like lymphocytes that bridge innate and adaptive immune responses and promote anti-cancer immunity. iNKT cells are activated and respond rapidly via multiple signals such as recognition of lipid antigens through the invariant T cell receptor (TCR), pro-inflammatory cytokines or recognition of stress ligands. Here we describe, AgenT-797, a novel, allogeneic and ‘off-the shelf’ iNKT cell therapy, designed to promote effective anti-cancer immunity against a wide range of malignancies.Methods iNKT cells isolated from healthy donors were expanded by stimulation of the invariant TCR with alpha-Galactosylceramide (αGalCer) and cytokines using the AgenTus manufacturing protocol. The phenotype and functional activity of the expanded unmodified iNKT cells, AgenT-797, were characterized by flow cytometry. The cytotoxic potential of AgenT-797 was assessed in tumor co-culture assays against CD1d-expressing cancer cell lines. To further direct anti-tumor responses, iNKT cells were engineered to express Chimeric Antigen Receptors (CARs), and the cytotoxic potential assessed against antigen-expressing cancer cells.Results iNKT cells were rapidly expanded up to 2 × 1010 cells in 30 days, with over 99% purity. Expanded, unmodified iNKT cells, AgenT-797, were found to secrete both Th1 (IFNγ, TNFa, GM-CSF) and Th2 (IL4, IL13) type cytokines. After rapid expansion, AgenT-797, retained their inherent cytotoxic capacity against CD1d-expressing tumor cell lines. Further, killing of tumor target cells, in vitro, was mediated through their endogenous invariant TCR or engineered CAR receptor.ConclusionsAgenT-797 is an ‘off-the-shelf’ and allogenic cell therapy with effective cancer killing properties. Strategies to engineer iNKT cells using CAR technology further enhance the tumor killing potential of iNKT therapy.

BackgroundCD137 (4-1BB) represents a costimulatory pathway that promotes T, NK, and dendritic cell effector functions favorable for antitumor immunity. The extracellular domain of CD137, comprised of four cysteine-rich domains (CRD-I, CRD-II, CRD-III, CRD-IV), trimerizes upon binding to CD137 ligand (CD137L) to induce cell stimulatory transcriptional and epigenetic changes.1 2 The investigation of CD137-targeting agonist antibody, urelumab (CRD-I-binding, IgG4), in human subjects showed immunologic and pharmacodynamic effects, but poor efficacy due to dose-limiting liver toxicity.3 Preclinical studies using a murine surrogate antibody, clone 3H3 (CRD-I-binding, rIgG2a), also demonstrated hepatotoxicity that correlated with activation of CD137-expressing myeloid cells and memory CD8+ T cells.4 5 In contrast, utomilumab (CRD-II/III-binding, IgG2) showed acceptable tolerability, but limited clinical efficacy.6 7 These and more recent findings implicate epitope and Fc gamma receptor (FcγR)-dependent antibody cross-linking as critical factors for CD137 therapeutic antibody design.MethodsWe investigated the molecular and cellular effects of AGEN2373 (CRD-IV-binding, IgG1), a conditionally active CD137-targeting agonist antibody designed to bind and induce CD137 signaling upon FcγR cross-linking while permitting ligand binding to CD137. The role of epitope and FcγR binding as critical factors for anti-CD137 therapeutic activity were elucidated in primary cell-based assays and syngeneic tumor-bearing mouse models using anti-mouse antibody clones S3B1 (CRD-IV-binding) and 3H3, surrogates of AGEN2373 and urelumab, respectively. In an ongoing phase 1 trial (NCT04121676), we evaluated the safety and tolerability of AGEN2373.ResultsAGEN2373 bound with high-affinity to CD137 CRD-IV and promoted potent agonist activity of CD137 that was conditionally dependent on Fc-dependent antibody cross-linking. AGEN2373 surrogate, S3B1, showed comparable binding and cross-link dependent agonist activity. In CT26 tumor-bearing mice, S3B1 and 3H3 demonstrated complete tumor control that was not reproducible with a Fc-silent S3B1 antibody. The Fc-dependent activity of S3B1 correlated with induced immunologic changes in the TME including CD8 T cell expansion, NK cell activation, and Treg depletion. Patients with advanced solid cancers, treated with AGEN2373 up to 1 mg/kg every 4 weeks, demonstrate clinical activity with no evidence of hepatotoxicity.ConclusionsConditional and potent agonist activity of AGEN2373 is dependent on binding to CD137 CRD-IV and FcγR. Preclinically, our data demonstrate that AGEN2373-like murine surrogate antibodies promote potent immune activation and anti-tumor immunity. Phase 1 clinical trials investigating the safety and efficacy of AGEN2373, alone or combination with balstilimab (anti-PD-1), are underway.Trial RegistrationNCT04121676ReferencesWen TJ, Bukczynski and Watts TH. 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J Immunol 2002;168(10): p. 4897–906.Bitra A, et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. J Biol Chem 2018;293(26): p. 9958–9969.Segal NH, et al., Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8): p. 1929–1936.Bartkowiak T, et al., Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27-dependent pathway. Clin Cancer Res 2018;24(5): p. 1138–1151.Lin GH, et al., GITR-dependent regulation of 4-1BB expression: implications for T cell memory and anti-4-1BB-induced pathology. J Immunol 2013;190(9): p. 4627–39.Segal, N.H., et al., Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018;24(8): p. 1816–1823.Li Y, et al., Limited Cross-Linking of 4-1BB by 4-1BB ligand and the agonist monoclonal antibody utomilumab. Cell Rep 2018;25(4): p. 909–920 e4.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1–confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population ( n  = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10–26%), and DCR was 61% (62/101; 95% CI, 51–71%). Median DOR was not reached (NR; 95% CI, 5.7 months–NR), and median PFS was 3.5 months (95% CI, 2.7–4.1 months), at a median follow-up of 10.3 months (range, 0.5–42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 . In an ongoing phase 1 trial, the combination of two new immunotherapies targeting CTLA-4 and PD-1 was overall well tolerated and elicited encouraging clinical responses in patients with relapsed/refractory microsatellite stable colorectal cancer, a tumor type typically unresponsive to immune checkpoint blockade.