Abstract Background: Adoptive cell therapy (ACT) has revolutionized outcomes in hematologic malignancies; however, its application in solid tumors remains limited by antigen heterogeneity, manufacturing complexity, and toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Natural killer (NK) cells mediate cytotoxicity without prior antigen exposure. Chimeric antigen receptor (CAR)-NK has emerged as a promising alternative for CAR-T, offering innate cytotoxicity that could mitigate antigen escape, improved “off-the-shelf” feasibility and reduced toxicity. TROP2, a transmembrane glycoprotein overexpressed in multiple epithelial malignancies, including breast cancer and non-small cell lung cancer (NSCLC), is associated with poor prognosis. Its therapeutic relevance is supported by the success of TROP2-directed antibody-drug conjugates.TROP2 CAR-NK is a cord blood-derived NK-cell product transduced with IL-15 to enhance persistence and an inducible caspase-9 (iC9) safety switch. Preclinical studies demonstrated potent and antigen-specific cytotoxicity against TROP2-positive tumors including breast and NSCLC models, without off-tumor toxicity in normal human cell lines. We hypothesize that this approach will be safe and demonstrate preliminary antitumor activity in patients with advanced high TROP2-expressing solid tumors. Methods: TROPIKANA (NCT06066424) is a single-center, open-label, first-in-human phase 1 dose-escalation and expansion study of TROP2 CAR-NK cells in adult patients with advanced TROP2-positive solid tumors. Primary objectives are to evaluate the safety/tolerability, optimal cell dose, maximum tolerated dose, and recommended Phase 2 dose of TROP2-CAR-NK. Secondary objectives are to assess the preliminary efficacy, CAR-NK persistence, and pharmacodynamic immune effects. Approximately 54 patients with advanced or metastatic solid tumors with high TROP2 expression (IHC 2+ or 3+) will be enrolled using a Bayesian Optimal Interval Phase I/II (BOIN12) design. Dose expansion cohorts include patients with NSCLC and HER2-low/negative breast cancer with high TROP2 expression.Patients receive lymphodepleting chemotherapy (cyclophosphamide/fludarabine, days −5 to −3, followed by TROP2 CAR-NK infusion on day 0, up to 4 doses every 8 weeks. Primary endpoints are incidence and severity of adverse events as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Key secondary endpoints include overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, progression-free and overall survival. Exploratory analyses will evaluate longitudinal blood-based biomarkers, ctDNA dynamics, and immune profiling. The first patient on this trial was treated in January 2024 and is actively enrolling patients. Citation Format: Oriol Mirallas, David Marin, Hui Chen, Paula Pohlmann, Bora Lim, Mehmet Altan, Samrina Hussain, Amber Kennon, May Daher, Miriam Gavriliuc, Rafet Basar, Wei-Lien Wang, Ying Yuan, Patrow Kebriaei, Elizabeth J. Shpall, Jordi Rodon, David S Hong, Funda Meric-Bernstam, Katy Rezvani, Ecaterina E Dumbrava. Phase I study of TROP2 CAR engineered IL-15-transduced cord blood-derived NK cells in advanced solid tumors (TROPIKANA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT294.

IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity.

Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.

Diverse soft robotic applications, such as wearable devices, haptic interfaces, artificial muscles, and biomedical systems, require soft actuators to simultaneously deliver large actuation strain (>40%) and high power density (>323Wkg-1) in response to mild, human-safe stimuli. However, no existing soft actuator system has successfully met these combined requirements. To address this critical gap, body-temperature-responsive liquid crystalline elastomer (LCE) films are designed with a thickness direction orientation gradient achieved through macromolecular engineering of lightly crosslinked gels during the initial stage of network formation. Using ultrahigh stretch ratios to 2000% and with controlled entropic recovery, the degree of molecular orientation through the film thickness can be established. As a result, the fully crosslinked monodomain LC soft actuator simultaneously provides a high actuation strain of 88% and a high power density of 1960Wkg-1 under body-temperature stimulation, a level of performance unmatched by existing actuators sensitive to mild stimuli. Device-level demonstrations, including a rotary soft robot and an intelligent safety switch, highlight the actuator's versatility and potential for real-world integration in next-generation soft robotic systems.

Precise identification of vulnerable plaque (VAP) is essential for the prevention of acute cardiovascular diseases, yet current molecular probes are hampered by poor VAP lesion penetration and high background. Here, the innate tropism of circulating inflammatory monocytes for VAP, and their differentiation‐driven expression of legumain (Lgmn) in response to the VAP microenvironment is exploited. A monocyte differentiation‐activated fluorescent (MDAF) probe is conceived that hitchhikes monocytes to precisely migrate to VAP and is activated by Lgmn during monocyte differentiation. This activation triggers in situ self‐assembly, resulting in spatiotemporally controlled aggregation‐induced emission (AIE) fluorescence signals, and turning the monocyte itself into an on‐site “scout” that reports plaque instability. In Apoe−/− mice bearing both vulnerable and stable plaques, the MDAF produces a striking OFF/ON fluorescence switch confined to vulnerable lesions, yielding a markedly improved signal‐to‐noise ratio (SNR). By integrating fluorescence emission computed tomography (FLECT), MDAF probe surpasses the depth limitations of conventional fluorescence imaging. Therefore, the AIE signal of the MDAF probe is more than just a “fluorescent read‐out,” and it also acts as a crucial safety switch that transforms the monocyte into a ratiometric immune scout for plaque instability. This innovative strategy offers a translatable approach for the precision diagnosis of VAP.

B cells could be effective immunotherapeutic “drug cells,” but reports of genomic editing to redirect their specificity have not included safety strategies. To address the potential complications of cell therapy, there is a growing demand for integrated safety switches. This is particularly pertinent in the case of B cells, which are prone to malignant transformation. We evaluated in B cells the efficacy of inserting the inducible caspase-9 (iCasp9) suicide gene, together with either a reporter gene or a single-chain immunoglobulin cassette specific for a tumor antigen. We demonstrate that a single edit of the IgH locus enables the expression of both iCasp9 and the cassette hijacking antigen specificity, while preserving B cell functionality. In both primary and malignant lymphoma B cells, activation of iCasp9 using the drug AP1903 readily induced apoptosis of edited cells, both in vitro and in established tumors grafted to immunodeficient animals. Although AP1903 treatment strongly curbed edited cell survival, this was constantly followed by the selection of resistant cells with lowered expression of both iCasp9 and the therapeutic antibody cassette. Therefore, in adoptive immunotherapy protocols, the iCasp9/AP1903 safety switch could stand as an efficient neoadjuvant therapy, as well as a rheostat to modulate the infusion of a therapeutic molecule.

Soft actuators are widely explored as movers in various devices, human–machine interfaces, for medical purposes and other biomedical applications. Among them are soft actuators based on a foamed silicone matrix with the working liquid (WL) captured in its pores that undergo the liquid–gas phase transition. For the first time, to gain the actuation strain of such composites, we added, to the WL, a substance that sublimates during the composite actuation. C1–C3 alcohols were tested as WLs, while the sublimation substance (SS) used was benzoic acid dissolved in the WL. It was found that the rejuvenation procedure is able to fill the composite pores with WL + SS solution. The effect of benzoic acid addition was revealed using the two-stage heating mode. The sublimation substance effectively extends the composite strain for methanol and ethanol as WL for about 20%. For C3 propanols, the strain is left nearly unchanged. In the open-air conditions, the high diffusion of WL + SS in silicone allows only a single actuation that makes it a disposable actuator, i.e., a kind of safety switch is proposed. The results obtained in this work pave the way to future, powerful multipurpose “soft safeties” appliances.

A novel and highly effective truncated BCMA safety switch for adoptive cell therapy

CD19 antigen: From tumor target to safety switch able to improve the safety profile of CAR T cell therapy

Abstract Background "In PDAC, overexpression of B7-H3 on tumor cells frequently correlates with fewer tumor-infiltrating lymphocytes, faster cancer progression, and poor clinical outcomes. Treatments targeting B7-H3 correlate with tumor response in preclinical and phase I studies. Specifically, a B7-H3 CAR-T in a PDAC patient derived xenograft (PDX) model yielded some complete responses. This makes B7-H3 CAR-T therapy a promising therapeutic strategy in patients with chemotherapy refractory PDAC; however, CAR-T therapy is associated with life-threatening cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). The use of an inducible caspase 9 “safety switch” can abrogate these toxic effects, if necessary. Methods We are conducting a phase I study of (iC9)-CAR.B7-H3 T cells in subjects with refractory PDAC using a modified 3+3 dose escalation design with doses selected from previous T cell therapy studies in solid tumors. Fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2, administered intravenously (IV), is used as a conditioning regimen, and rimiducid is used to activate the iCas9 safety switch as needed. Disease assessment is performed six weeks after CAR T cell therapy using RECIST criteria. Results We have enrolled a total of five patients with four collected for product manufacturing, and three patients treated at dose level 1 (1×106 transduced cells/kg with a max dose of 1×108 cells). All five patients were Caucasian, non-Hispanic males, aged 63, 66, 68, 72, and 76, all with two prior lines of therapy. No DLTs were observed. Although two patients experienced grade 3 CRS requiring tocilizumab, they did not require treatment with rimiducid. Of the three patients treated, two had progressive disease at the first follow up and one had stable disease. Of the patient with stable disease, one target lesion was noted to have decreased in size by 25%. We have enrolled the next patient at dose level 2 (2.5×106 transduced cells/kg with a max dose of 2.5×108 cells), and have a planned dose level 3 (5×106 transduced cells/kg with a max dose of 5×108 cells) if tolerated. Conclusions The use of iC9-CAR.B7-H3 T cells therapy in patients with refractory PDAC is safe at DL1. Continued dose escalation and longitudinal follow-up are ongoing to determine the safety, tolerability, recommended dose and early evidence of efficacy." Citation Format: Ashwin Somasundaram, Natalie S. Grover, Clarissa A. Urban, Hannah Ratzlaff, Faith B. Buchanan, Catherine J. Cheng, Kaitlin Morrison, Leila V. Kiefer, Allison Camp, Jonathan S. Serody, Barbara Savoldo, Gianpietro Dotti. A Phase I Study of Autologous CAR-T Cells Targeting the B7-H3 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects with Refractory Pancreatic Ductal Adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A075.

Human induced pluripotent stem cells (iPSCs) are gaining momentum as a powerful starting material in cell therapy. To fully harness their potential, CRISPR technology permits endogenous gene modifications as well as the introduction of advanced features, to increase the immune compatibility of the cells or insert suicide genes for enhancing therapeutic safety, for instance. However, genetic manipulation of iPSCs, in particular the generation of knock-in lines, remains relatively inefficient. Conventional mitigation strategies, such as enriching for positive cells using antibiotic selection or complex instrumentation, may, however, cause conflicts with good manufacturing practice (GMP) requirements. To address this challenge, we have systematically optimized a basic gene editing procedure using both Cas9 and Cas12a-based ribonucleoprotein (RNP) complexes. Based on the sequential delivery of RNPs and donor plasmids as a critical hallmark, this virus-free approach permits knock-ins of full-length transgenes at above 30% efficiency, while readily identifying positive clones through random screening at small scale. We exemplify these advances by creating and characterizing homozygous iPSC lines depleted of HLA class I and carrying an inducible caspase-9 suicide gene. Isolated clones from independent GMP iPSC lines retained genomic integrity, differentiation capability, and functionality of the safety switch in the differentiated state. This improved methodology will form a flexible platform for custom gene editing universally applicable both in basic iPSC research and therapy.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-17876-4.

Sézary syndrome (SS) is a leukemic form of cutaneous T cell lymphoma (CTCL), distinguished from mycosis fungoides by the presence of cancerous lymphocytes in the blood and often bears very poor prognoses. SS treatment is palliative, and thus novel therapies are needed. The CD7 surface antigen is highly expressed and confined to the surface of T cells, therefore when present, serves as a promising target for immunotherapy. Herein we describe the preclinical validation and clinical application of our non-gene editing CD7 targeted chimeric antigen receptor (CAR) T therapy to treat relapsed/refractory (r/r) CD7 expressing SS. The CD7 CAR construct possesses a "safety switch" (RTX) to enable rapid depletion of the CAR T treatment with administration of rituximab. Preclinical evaluation of the CD7-RTX CAR T cells demonstrated >99% depletion of target cells in both co-cultures, at 1:1 and 2:1 effector: target (E:T) ratios, and mouse models. In a mouse model, "safety switch" testing resulted in rapid elimination of CAR T cells with rituximab infusion. RTX, in our CD7 therapy, has not yet been clinically validated. A 53-year-old male diagnosed with r/r SS, expressing CD7, was treated with 2×106 CD7-RTX CAR T cells/kg of body weight, as compassionate use. The patient achieved medication and symptom free complete remission (CR) within 28 days post-CAR. The patient remained in CR at 18-month follow-up. The treatment was well tolerated and without severe adverse events (SAEs). Our CD7-RTX CAR T therapy demonstrates exceptional safety and efficacy in one patient with CD7+ r/r SS. This was the first recorded use of CD7 targeted CAR T therapy to treat SS. SS is prototypically CD7-, thus despite its efficacy in this patient, this treatment approach is likely not generalizable to most SS patients. However, this study supports the importance of thorough tumor characterization and the potential use of CD7-RTX CAR T cells to treat a variety of malignancies expressing CD7. Future clinical trials are required to characterize the safety and efficacy of CD7-RTX CAR T cells.

Abstract Background: Triple-negative breast Cancer (TNBC) accounts for 15-20% of all breast cancers, among which it has the worst prognosis and limited therapeutic options. B7-H3, a type I transmembrane protein, is expressed in 75% to 85% of breast cancer, with the highest expression found in TNBC. Preclinical studies have demonstrated significant anti-tumor activity of B7-H3 CAR-T cells in cell lines and patient-derived xenograft (PDX) models. Preliminary data from an ongoing phase 1 clinical trial of B7-H3 CAR-T cells for patients with relapsed ovarian cancer (NCT04670068) at our institution has shown a tolerable safety profile. Additionally, the implementation of an inducible Caspase 9 safety switch aims to mitigate the risk of severe complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), enhancing the clinical application potential of B7-H3 targeted CAR-T cell therapy in TNBC. Based on these premises, we will conduct the first phase 1 study of B7-H3 CAR-T cells in patients with previously treated metastatic TNBC to establish the safety of this novel treatment modality and identify a recommended dose for further study in this population of patients with poor prognosis and unmet clinical need. Methods: This is a Phase I, single-center, open-label study designed to evaluate the safety of escalating doses of CAR T cells targeting the B7-H3 antigen, incorporating an inducible caspase 9 safety switch (iC9-CAR.B7-H3 T cells) in patients with previously treated metastatic TNBC. The study utilizes a modified 3+3 dose-escalation design, starting with a dose of 1 × 106 transduced cells/kg. Patients with TNBC who meet eligibility criteria will undergo leukapheresis for the collection of cells to manufacture iC9-CAR.B7-H3 T cells. During the time period necessary to manufacture the iC9-CAR.B7-H3 T cells, patients will be allowed to receive standard-of-care bridging therapy at the discretion of their local physician. Eligible patients will then receive lymphodepletion chemotherapy with cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) administered intravenously for three consecutive days, followed by the infusion of iC9-CAR.B7-H3 T cells. The primary objective is to evaluate the safety and tolerability of iC9-CAR.B7-H3 T cell administration. Safety assessments will include monitoring for adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Secondary objectives include identifying the recommended Phase II dose (RP2D), determining the objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Patients will be monitored for 15 years post-treatment completion in accordance with guidelines for gene transfer studies. This extended follow-up will evaluate the long-term safety and persistence of the genetically modified T cells. The trial is currently enrolling patients, NCT06347068. Citation Format: Yara Abdou, Barbara Savoldo, Natalie S. Grover, Gianpietro Dotti, Felicia Cao, Catherine J. Cheng, J. Kaitlin Morrison, Jonathan S. Serody, Lisa A. Carey, E. Claire Dees. Phase I Study of B7-H3 Specific Chimeric Antigen Receptor (CAR) T Cell Therapy in Patients with Triple-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-22.

Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Claudin18.2 is highly expressed in PC tissue and could serve as a suitable target for CAR-T therapy. In the present study, we reported the utilization of tEGFR-expressing claudin18.2-targeted CAR-T cells to treat 3 patients with advanced PC. Intriguingly, all 3 patients achieved disease remission after CAR-T cell infusion, with 1 complete remission (CR) and 2 partial remissions (PRs). However, gastric mucosal injury was observed, which was recognized as on-target off-tumor toxicity (OTOT) and may be due to the expression of claudin18.2 on normal gastric tissues. To control the severe OTOT in patient 3, cyclophosphamide and cetuximab were administered to deplete CAR-T cells, and they successfully controlled OTOT. Single-cell transcriptome and T cell receptor sequencing revealed the objective alterations of CAR-T cell clones after cetuximab treatment. Collectively, the present study showed the robust anti-tumor activity of claudin18.2-targeted CAR-T cells against PC and reported the feasibility of the antibody-dependent safety switch strategy to control the OTOT caused by CAR-T cells in patients. Our study may pave the way for the development of a novel strategy to treat patients with advanced PC in the future.

Donor lymphocyte infusion (DLI) is employed to either treat or prevent relapse in patients with hematologic malignancies, as well as to accelerate recovery of adaptive immunity, after allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the increased use of DLI, there is renewed interest in the development of approaches able to prevent graft-versushost disease (GVHD). In this study, we describe a novel and effective safety switch represented by the truncated form of the human CD19 antigen (ΔCD19) used to transduce T lymphocytes (hΔCD19 T cells). We demonstrated that the exposure of ΔCD19 T cells to an anti-hCD19-hCD3 T cell bi-specific T-cell engager (BiTE) molecule (structurally identical to blinatumomab, an agent largely used in the treatment of B-cell acute lymphoblastic leukemia) resulted into a prompt elimination of hCD19+/CD3+ cells both in vitro and in an in vivo animal model of mice developing a xenograft reaction mimicking GVHD after infusion of in vitro-activated/expanded human T cells. Importantly, the administration of the anti-hCD19-hCD3 BiTE molecule in the animal model, on one hand led to the improvement of signs and symptoms of GVHD, as well as of the overall-survival of the mice, and on the other hand, after a drug washout, was associated with the resurge of ΔCD19 T cells without re-occurrence of GVHD. Our study provides evidence that the ΔCD19 suicide gene used in combination with an anti-hCD19-hCD3 T-cell BiTE molecule could represent a valid and effective strategy to control GVHD occurring after the infusion of donor T lymphocytes.

Abstract Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR)-based immunotherapies. Transgenic cytokine expression has been shown to enhance the potency of cellular immunotherapies, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this hypothesis, we generated retroviral constructs expressing IL-15 and/or IL-18 with the inducible caspase 9 (iC9) safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased GD2.CAR-NKTin vitrocytotoxicity, proliferation, and cytokine secretion compared to IL-15 alone. In a metastatic neuroblastoma model, GD2.CAR-NKTs expressing constructs with IL-18 controlled tumor growth better than cells expressing IL-15 only, but mice in the IL-15/IL-18 group developed severe toxicities not observed in the IL-18-only group. Mechanistically, we found that IL-18 drives a distinct transcriptional profile from IL-15 in CAR-NKTs marked by lower expression of exhaustion gene signatures and enrichment of metabolism-related processes. Finally, targeted metabolomics revealed that IL-18 induces broad metabolic reprogramming in CAR-NKTs including enhancement of oxidative phosphorylation, glycolysis, glutaminolysis and purine metabolism. These results support the use of IL-18 in developing the next generation of cytokine-armed CAR-NKT cancer immunotherapy.

Abstract B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy has shown high initial response rates in relapsed/refractory multiple myeloma (RRMM), but most patients eventually relapse with progressive disease. Previous studies have identified a less differentiated, CD19-positive progenitor subpopulation of MM cells that contributes to resistance and poor survival. Furthermore, anti-CD19 CAR-T cells given after high-dose melphalan and stem cell transplantation have shown to improve patient survival and can eliminate MM progenitor cells that are resistant to BCMA-directed CAR-T cells. P-BCMACD19-ALLO1 is a fully allogeneic CAR-T therapy designed to target BCMA and CD19. Additionally, P-BCMACD19-ALLO1 is a T stem cell memory (TSCM)-rich product derived from healthy donor T cells using a nonviral, transposon-based system for transgene delivery, with knockout of TRBC1/2 and B2M to prevent graft-versus-host disease and reduce host T-cell mediated rejection, respectively. TSCM -rich CAR-Ts, including our BCMA-targeting allogeneic P-BCMA-ALLO1 CAR-T for RRMM (NCT04960579), have shown favorable efficacy and safety in the clinic. To develop P-BCMACD19-ALLO1, we constructed the BCMA CAR using two fully human, single-domain, heavy-chain variable domains (VHs) that independently bind BCMA and are joined together by a G4S linker in tandem. The tandem anti-BCMA VHs binds to all clinical escape mutants, including teclistamab-resistant R27P mutation. The anti-CD19 CAR binder comprises of a fully human VH against CD19. Both CARs are expressed from a single, multi-cistronic transgene that also contains an inducible Caspase-9 safety switch and a dihydrofolate reductase mutein. Herein, we show enhanced in vivo potency of P-BCMACD19-ALLO1against BCMA/CD19-double positive RPMI-8226 MM xenograft model using an optimized ICD combination that incorporates a novel co-stimulatory domain derived from the tumor necrosis factor receptor family member transmembrane activator and CAML interactor (TACI) in the CD19 CAR and the standard 4-1BB in the BCMA CAR. P-BCMACD19-ALLO1 demonstrates target-specific, in vitro cytotoxicity against tumor cells expressing BCMA, CD19, or both antigens but lacks activity against antigen-negative tumor cells. P-BCMACD19-ALLO1 also demonstrates potent, in vitro killing of tumor cells expressing R27P, P33Del, P33S and S30Del escape mutants. Lastly, P-BCMACD19-ALLO1 effectively eliminates primary bone marrow CD81+CD19+ progenitor cells as well as colony-forming cells derived from MM patient samples, suggesting that P-BCMACD19-ALLO1 may increase the depth and the durability of response. Taken together, our data underscore the therapeutic potential of P-BCMACD19-ALLO1 and support its application for treating RRMM to be further evaluated in clinical trials. Citation Format: Steven Wang, Iris Pang, Claudia Chang, Michelle Burrascano, Nick DeMarco, Danny Mendoza-Reyes, Sonia Reyes, Arturo Barcenas, Pastor Nieto, Jose Diaz, Garret Arauz, Chris Lynn, Tony Nguyen, Connor Reed, Mona Connerney, Quy Le, Julia Coronella, Devon J. Shedlock. Enhanced potency of BCMA/CD19 dual-targeting allogeneic CAR-T cells for relapsed/ refractory multiple myeloma with 4-1BB/TACI intracellular domains [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4811.

Abstract Cytokine-induced memory-like NK cells have garnered a lot of attention as cellular therapeutic agents due to their much-increased lifespan in patients and their enhanced memory response upon re-challenge by cytokines or target cells. A key part of this memory recall feature is the increased secretion of interferon gamma (IFNγ). This potent immune stimulator can trigger upregulation of MHC-I molecules expression on the surface of tumor cells, thereby pushing the tumor towards an immunologically “hot” status. However, IFNγ also triggers expression of the immune checkpoint molecule PD-L1. We show here that the Natural Killer cell line NK-92®, or ‘activated’ NK (aNKTM), can acquire a memory-like phenotype upon overnight induction with IL-12, IL-18, and the IL-15 superagonist N-803, as evidenced by increased steady-state IFNγ secretion (>50-fold increase) and up-regulation of CD25. Although the initial increase in IFNγ secretion subsides after 48hrs, memory-like NK-92 cells display memory recall for several days post-activation, as evidenced by an enhanced IFNγ response upon challenge with K562, Raji, and THP-1 cells compared to non-memory-like cells (2.3, 6.9, and 3.8-fold increases after 1 week, respectively). Further, NK-92 cells engineered to express a high-affinity Fc receptor and an anti-PD-L1 Chimeric Antigen Receptor (PD-L1 t-haNK) maintained their susceptibility to memory-like cytokine induction. Exposure of the NK-resistant cells lines THP-1 and SK-ES-1 to culture supernatant from memory-like PD-L1 t-haNK triggered expression of PD-L1 on their surface, rendering them highly sensitive to PD-L1 CAR-mediated targeted killing by the PD-L1 t-haNK cells in a 4-hour in vitro cytotoxicity assay (respectively 91% and 88% killing at E:T ratio of 1.25:1, compared to 54% and 41% for target cells exposed to regular PD-L1 t-haNK supernatant), while not affecting their resistance to NK-92 cells. Infusion of a cellular therapy product that constitutively secretes high IFNγ may cause detrimental side effects. Memory-like PD-L1 t-haNK cells may circumvent this problem through their memory recall ability and deliver increased amount of IFNγ specifically at the tumor site when locally engaging with tumor cells. This increase would then drive upregulation of PD-L1 expression on neighboring tumor cells, creating an expanding wave of targets sensitized to killing by PD-L1 t-haNK cells. A next generation, memory-like PD-L1 t-haNK cell line equipped with inducible safety switch features to remove the need for irradiation and extend their half-life in patients is being developed and would constitute a promising “off-the-shelf” cellular therapy against immunologically cold cancers. Citation Format: Dustin Elwood, Devapriya Segaran, Joseph Thibault, Vidya Godbole, Manju Saxena, Hans Klingemann, Laurent Boissel, Patrick Soon-Shiong. Generation of cytokine-induced memory-like PD-L1 t-haNK (NK-92®) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 894.

Abstract Solvents in liquid and gel polymer electrolytes are recognized for contributing to high ionic conductivity in high‐energy‐density lithium metal batteries. However, parasitic reactions involving solvents and lithium metal induce safety risks under thermal abuse conditions and poor lifespan during room‐temperature cycles, which are rarely investigated. This study introduces a thermoresponsive mono‐solvent electrolyte as a built‐in safety switch. The mono‐solvent electrolyte polymerizes at elevated temperatures, creating a passivate polymer network without residue solvents. The polymer exhibits high thermal stability with 91% mass retention at 200 °C and significantly suppresses side reactions between lithium metal and the electrolyte, reducing thermal runaway risks. Ah‐level Li||LiNi0.8Co0.1Mn0.1O2 pouch batteries employing this electrolyte can efficiently improve the critical temperature of thermal runaway by 75 °C compared to the thermoresponsive gel polymer electrolyte. At ambient temperatures, the electrolyte promotes the formation of a stable solid electrolyte interphase (SEI) rich in LiF and Li2O, effectively reducing side reactions and dendrite growth on the lithium anode. Consequently, Li||LiNi0.5Co0.2Mn0.3O2 cells retain 91% capacity after 152 cycles, even under high‐loading cathodes (19.7 mg cm−2, 3 mAh cm−2). This research offers valuable insights into inhibiting parasitic reactions during the electrochemical cycle and thermal runaway, enhancing the lifespan and safety of high‐energy‐density batteries.

The rapid growth of the photovoltaic industry necessitates the development of innovative solutions to ensure the safe operation of these systems. One of the most critical challenges in photovoltaic installations is ensuring protection against electric shock under both operational and emergency conditions, as well as minimizing the risk of fire spread in case of an installation fire. Existing safety measures do not provide a sufficient level of protection, particularly in terms of fire safety. To address these shortcomings, a comprehensive safety system has been developed. This system includes a photovoltaic panel shutter and a safety switch device, which enables the short-circuiting of individual panel outputs while also providing a break in the DC circuit. The proposed solution can be classified as part of the Balance of System (BoS). The effectiveness of this safety system has been validated through both numerical simulations and experimental investigations. Furthermore, an economic analysis indicates that implementing this system will not significantly impact the overall cost of a photovoltaic system.