Adoptive T Cell Therapy Research Articles

The Therapeutic Potential of Cytokine-Induced Killer in Patients with Cancer.

Despite the promising results of immunotherapy, further experiments need to be considered because of several factors ranging from physical barriers to off-tumor adverse effects. It is surprising that adoptive cellular immunotherapy, particularly dendritic cell and cytokine-induced killer (DC-CIK) therapy, is far less emphasized in the treatment of cancer diseases. DC-CIK therapy in cancer patients presents auspicious results with low or no side effects, which should not be overlooked. More interestingly, almost all DC-CIK clinical trials are ongoing in China that highlight the limitations of therapeutic strategies and require large-scale research. To date, it is advisable to consider combination therapy with chemotherapy since it has shown promising outcomes with higher efficacy. In this article, the efficacy of DC-CIK therapy in patients with cancer is summarized by underscoring the lack of experiments on soft cancers on an unprecedented scale. In brief, DC-CIK therapy is a safe and effective therapeutic agent for malignant and nonmalignant diseases that enhances short-term and long-term effects.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma.

Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.

Abstract A020: An early determination of patients eligibility for a bladder cancer immunotherapy using a data science approach

Abstract Advanced bladder cancer patients have limited treatment options and, in most cases, limited overall survival. The first clinical trial with adoptive T cell therapy (ACT) that uses bladder cancer patients’ autologous tumor-infiltrating T lymphocytes (TILs) has been recently opened at Moffitt. To help identify which patients could benefit from ACT-TIL we are developing a machine learning predictor that takes advantage of tumor evolution data, such as tumor stages and grades routinely collected in clinic. The first phase of ACT-TIL involves resection of the primary tumor and the growth of TILs followed by a rapid expansion protocol of the reactive T cells. It may take up to 4-5 weeks before bladder cancer patients can get their own expanded TILs. Our predictor aims to determine whether the tumor isolated from a patient will grow TILs. In this work, we present a machine learning predictor of expansion of tumor infiltrating lymphocytes (ML-PETIL) that uses retrospectively collected patient tumor data with either demographic, clinical, or biological sample-related features. The proposed method consists of a suite of algorithms to identify a robust set of predictive features (feature selection algorithms) that are used to discriminate the dataset into two classes-that with successful TIL expansion or with no TIL growth (classification algorithms). Our predictor includes metrics which are used to address data imbalance and handle small to medium-sized datasets that contain features of varying datatypes and magnitudes. The ML-PETIL protocol offers an early determination of patients who would be eligible for ACT-TIL therapy. Citation Format: Kayode D. Olumoyin, Ahmet M. Aydin, Brittany L Bunch, Shari Pilon-Thomas, Michael Poch, Katarzyna A. Rejniak. An early determination of patients eligibility for a bladder cancer immunotherapy using a data science approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A020.

Facts and Hopes in Immunotherapy Strategies Targeting Antigens Derived from KRAS Mutations.

In this commentary, we advance the notion that mutant KRAS (mKRAS) is an ideal tumor neoantigen that is amenable for targeting by the adaptive immune system. Recent progress highlights key advances on various fronts that validate mKRAS as a molecular target and support further pursuit as an immunological target. Because mKRAS is an intracellular membrane localized protein and not normally expressed on the cell surface, we surmise that proteasome degradation will generate short peptides that bind to HLA class I (HLA-I) molecules in the endoplasmic reticulum for transport through the Golgi for display on the cell surface. T-cell receptors (TCR)αβ and antibodies have been isolated that specifically recognize mKRAS encoded epitope(s) or haptenated-mKRAS peptides in the context of HLA-I on tumor cells. Case reports using adoptive T-cell therapy provide proof of principle that KRAS G12D can be successfully targeted by the immune system in patients with cancer. Among the challenges facing investigators is the requirement of precision medicine to identify and match patients to available mKRAS peptide/HLA therapeutics and to increase the population coverage by targeting additional mKRAS epitopes. Ultimately, we envision mKRAS-directed immunotherapy as an effective treatment option for selected patients that will complement and perhaps synergize with small-molecule mKRAS inhibitors and targeted mKRAS degraders.

Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1.

The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator. We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored. A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB > = 16(TMB > = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB > = 16 and < 16 are 35.58, and 10.71months respectively with average 12.39months (p < 0.0001). The median months of PFS in the TMB > = 16 and < 16 are not-obtained, and 2.79months respectively with an average of 3.32months (p < 0.0001). The DCR in the TMB > = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB > = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001). The TMB > = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

Adoptive cell transfer therapy with ex vivo primed peripheral lymphocytes in combination with anti-PDL1 therapy effectively inhibits triple-negative breast cancer growth and metastasis

BackgroundAdoptive cell transfer cancer immunotherapy holds promise for treating disseminated disease, yet generating sufficient numbers of lymphocytes with anti-cancer activity against diverse specificities remains a major challenge. We recently developed a novel procedure (ALECSAT) for selecting, expanding and maturating polyclonal lymphocytes from peripheral blood with the capacity to target malignant cells.MethodsImmunodeficient mice were challenged with triple-negative breast cancer cell lines or patient-derived xenografts (PDX) and treated with allogeneic or autologous ALECSAT cells with and without anti-PDL1 therapy to assess the capacity of ALECSAT cells to inhibit primary tumor growth and metastasis.ResultsALECSAT mono therapy inhibited metastasis, but did not inhibit primary tumor growth or prolong survival of tumor-bearing mice. In contrast, combined ALECSAT and anti-PDL1 therapy significantly inhibited primary tumor growth, nearly completely blocked metastasis, and prolonged survival of tumor-bearing mice.ConclusionsCombined ALECSAT and anti-PDL1 therapy results in favorable anti-cancer responses in both cell line-derived xenograft and autologous PDX models of advanced triple-negative breast cancer.

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance. Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.

Application of hydrogels in cancer immunotherapy: a bibliometric analysis.

Cancer immunotherapy has made significant progress in recentyears, with numerous studies worldwide. Immunotherapy has had a transformative impact on oncology and autoimmune diseases. In the biomedical arena, hydrogels with good properties are widely used in cancer immunotherapy. Our study used bibliometrics to analyze the changing trends in using hydrogels for cancer immunotherapy. From 2013 to 2023, a systematic search was conducted in the Web of Science Core Collection database to identify reviews and articles discussing the applications of hydrogels in cancer immunotherapy. The software CiteSpace was used to visually perform the bibliometric analysis in terms of research trends, countries, institutions, authors, journals, and keywords. Individual authors' productivity was assessed with the Lotka's law. The most relevant publication sources were identified by Bradford's law. A total of 422 English-language publications related to hydrogels in cancer immunotherapy were collected. The number of annual publications increased rapidly after 2021 and remained constant for the past two years. China published the most articles in this field. The institution with the maximum number of published articles was the Chinese Academy of Sciences in China. Chen. Q was the most prolific author, and Liu. Z was the second most published author. In terms of journal contributions, the journal "Biomaterials" had the highest number of publications (n = 30). Biomaterials, Advanced Functional Materials and Journal of Controlled Release were the most influential journals. Keyword analysis revealed that cancer immunotherapy, drug delivery, immunogenic cell death, tumor microenvironment, injectable hydrogels, and immune checkpoint blockade were the primary research hotspots. In recent 3 years, adoptive T-cell therapy, black phosphorus, cell capture, adaptive cell therapy, tumor microenvironment, photodynamic therapy, and sustained release were the research hotspots in this field. Our study summarizes the objective of hydrogels in cancer immunotherapy in recent years, providing a reference for potential researchers in related field. This bibliometric analysis shows the progress and trend of research on hydrogels in cancer immunotherapy. This study provides a significant avenue for future investigation into current concerns and trends in research within this field.

Redefining the tumor microenvironment with emerging therapeutic strategies.

The environment surrounding a tumor, known as the tumor microenvironment (TME), plays a role in how cancer progresses and responds to treatment. It poses both challenges and opportunities for improving cancer therapy. Recent progress in understanding the TME complexity and diversity has led to approaches for treating cancer. This perspective discusses the strategies for targeting the TME, such as adjusting networks using extracellular vesicles to deliver drugs and enhancing immune checkpoint inhibitors (ICIS) through combined treatments. Furthermore, it highlights adoptive cell transfer (ACT) therapies as an option for tumors. By studying how components of the TME interact and utilizing technologies like single-cell RNA sequencing and spatial transcriptomics, we can develop more precise and efficient treatments for cancer. This article emphasizes the need to reshape the TME to boost antitumor immunity and overcome resistance to therapy, providing guidance for research and clinical practices in precision oncology.

Piloting a scale-up platform for high-quality human T-cells production.

Cell and gene therapies are an innovative solution to various severe diseases and unfulfilled needs. Adoptive cell therapy (ACT), a form of cellular immunotherapies, has been favored in recent years due to the approval of chimeric antigen receptor CAR-T products. Market research indicates that the industry's value is predicted to reach USD 24.4 billion by 2030, with a compound annual growth rate (CAGR) of 21.5%. More importantly, ACT is recognized as the hope and future of effective, personalized cancer treatment for healthcare practitioners and patients worldwide. The significant global momentum of this therapeutic approach underscores the urgent need to establish it as a practical and standardized method. It is essential to understand how cell culture conditions affect the expansion and differentiation of T-cells. However, there are ongoing challenges in ensuring the robustness and reproducibility of the manufacturing process. The current study evaluated various adoptive T-cell culture platforms to achieve large-scale production of several billion cells and high-quality cellular output with minimal cell death. It examined factors such as bioreactor parameters, media, supplements and stimulation. This research addresses the fundamental challenges of scalability and reproducibility in manufacturing, which are essential for making adoptive T-cell therapy an accessible and powerful new class of cancer therapeutics.

Immunotherapy for canine cancer

Cancer in dogs is a serious and prevalent disease that has drawn significant attention in the field of veterinary medicine, representing the most common cause of death in adult dogs. Traditional treatments such as chemotherapy and surgery have many limitations and side effects and have not been able to completely eliminate cancer, and challenges still remain in improving the survival rate and life quality in dogs. The development of a new therapeutic methodology for canine cancer to improve treatment effectiveness and survival rate has become the focus of many scientists. Immunotherapy, as a new treatment strategy, is one of the important research directions in the field of cancer treatment in canine animals. Adoptive T-cell therapy, checkpoint inhibitors, and oncolytic virus therapy, as important immunotherapy approaches, have shown promising treatment effects. This article will introduce the background of canine cancer, the background of immunotherapy, and discuss the application prospects of adoptive T-cell therapy, checkpoint inhibitors, oncolytic virus therapy, and other related topics in the treatment of canine cancer.

Engineered Adoptive T-Cell Therapies for Breast Cancer: Current Progress, Challenges, and Potential.

Breast cancer remains a significant health challenge, and novel treatment approaches are critically needed. This review presents an in-depth analysis of engineered adoptive T-cell therapies (E-ACTs), an innovative frontier in cancer immunotherapy, focusing on their application in breast cancer. We explore the evolving landscape of chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies, highlighting their potential and challenges in targeting breast cancer. The review addresses key obstacles such as target antigen selection, the complex breast cancer tumor microenvironment, and the persistence of engineered T-cells. We discuss the advances in overcoming these barriers, including strategies to enhance T-cell efficacy. Finally, our comprehensive analysis of the current clinical trials in this area provides insights into the future possibilities and directions of E-ACTs in breast cancer treatment.

Evaluation of the Anti-Oxidative Effects of Monocyte Cells Treated with Bone Marrow Mesenchymal Stem Cells Supernatant on Experimental Colitis in BALB/c Mice

Background: Alternate activation of monocytes could induce anti-inflammatory impacts. This study aimed to investigate whether monocyte cells treated with bone marrow mesenchymal stem cells supernatant (MSC-Sp) could improve anti-inflammatory responses as a cell transfer therapy for colitis. Materials and Methods: The induction of experimental colitis was done by acetic acid in four groups of male BALB/c mice, including the control colitis, treated-monocytes, non-treated-monocytes, and mesalazine groups. Following MSCs culture, the supernatant was harvested, and then 50% conditioned media, or negative control media was added to the monocytes for 24 h. After ten days, peritoneal injection of treated or non-treated-monocytes (105 cells/100µL) was performed in animals' relevant groups of colitis. Ten days later, the oxidative stress profile and histopathological evaluation of colon tissue were assessed. Results: Treated monocytes showed a significant improvement in the oxidative stress profile, namely myeloperoxidase (0.126±0.008), nitric oxide (0.153±0.01), and malondialdehyde (0.148±0.014) compared to the control colitis group (P&lt;0.05). Also, histopathological results revealed that the rate of damage in the treated-monocytes group was less than in normal mice. Conclusion: Our study indicated that the treated monocytes had anti-oxidative potential in colitis mice and were usable as a complementary therapy. [GMJ.2021;10:e2131]

Photothermal Prussian blue nanoparticles generate potent multi-targeted tumor-specific T cells as an adoptive cell therapy.

Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in >80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.

(Invited) Lab-in-a-Tube Design Enables a Rapid Diagnosis of Infectious Disease

Disease diagnosis increasingly relies on molecular tests that are often limited by infrastructure constraints. For example, tuberculosis (TB) remains a leading cause of death from infectious disease, but an estimated 4.2 million (39.6%) new TB cases were not diagnosed in 2021 and only 57% were confirmed by gold-standard sputum culture or PCR-based tests, partially due to limited accessibility. New point-of-care tests are thus urgently needed to address coverage disparities for chronic, malignant, and infectious diseases.We have developed two smartphone-based assays that can address two diagnostic shortfalls: an on-chip interferon-gamma release assay (IGRA) that detects a T-cell activation response induced by pathogen antigens in fingerstick blood samples, and a lab-in-tube assay that employs CRISPR to sensitively detect pathogen DNA in sputum. Both approaches translate current diagnostic approaches to point-of-care devices that require minimal equipment, user expertise, and time.Results from our on-chip IGRA also correlated with clinical IGRA results when we employed two proteins associated with TNF-alpha receptor signaling (4-1BB and OX-40) to analyze T-cell activation, indicating this approach could detect infections in individuals with compromised interferon-gamma responses; as observed in HIV patients, who are at increased risk for TB. On-chip IGRA results from a SARS-CoV-2-specific assay also corresponded with both infection and vaccination history, suggesting this data could be employed as a high-throughput, high-capacity test to evaluate the effect of vaccination or previous infection to confer a protective immune response, evaluate its change over time, and predict the response to new variant strains to guide healthcare decisions. Mitogen-induced results could also guide immunotherapy decisions, as reduced IGRA values in patients receiving immune checkpoint inhibitors predict poor treatment response, reduced progression-free survival, and increased risk for interstitial pneumonia, while their change after adoptive T-cell therapy can be an independent predictor for overall survival. Results from our lab-in-tube TB DNA assay also had robust diagnostic performance when compared to gold-standard clinical assays but lacked their more extensive personnel, workflow, and infrastructure requirements and were performed in a closed-tube system that protected user from exposure to infectious material. This lab-in-tube approach also permits parallel multiplex analyses to be performed in a single tube, and thus can be employed to detect mutations associated with drug-resistance to guide treatment decisions. For example, we found that an assay with an optimized guide RNA accurately detected a single-nucleotide polymorphism (rpoB S450L) responsible for the majority of rifampin-resistant TB cases.Both these self-contained handheld devices can employ lyophilized reagents to limit cold-chain concerns, can be readily adapted to diagnose other disease conditions by substituting other disease-specific antibodies or guide RNAs, use rechargeable batteries to avoid infrastructure limitations, and can directly transmit results to central sites to improve disease control efforts.

LTX-315 and adoptive cell therapy using tumor-infiltrating lymphocytes generate tumor specific T cells in patients with metastatic soft tissue sarcoma

ABSTRACTLTX-315 is an oncolytic peptide that elicits both local and systemic immune responses upon intratumoral injection. In the present pilot trial, we treated patients with metastatic soft tissue sarcoma with the combination of LTX-315 and adoptive T-cell therapy using in vitro expanded tumor-infiltrating lymphocytes. Six heavily pretreated patients were included in the trial and treated with LTX-315 of which four patients proceeded to adoptive T-cell therapy. Overall, the treatment was considered safe with only expected and manageable toxicity. The best overall clinical response was stable disease for 208 days, and in this patient, we detected tumor-reactive T cells in the blood that lasted until disease progression. In three patients T-cell reactivity against in silico predicted neoantigens was demonstrated. Additionally, de novo T-cell clones were generated and expanded in the blood following LTX-315 injections. In conclusion, this pilot study provides proof that it is feasible to combine LTX-315 and adoptive T-cell therapy, and that this treatment can induce systemic immune responses that resulted in stabilization of the disease in sarcoma patients with otherwise progressive disease. Further optimization of the treatment protocol is warranted to increase clinical activity. ClinicalTrials.gov Identifier: NCT03725605

A dual-receptor T-cell platform with Ab-TCR and costimulatory receptor achieves specificity and potency against AML

AbstractChimeric antigen receptor T-cell (CAR T) therapy has produced remarkable clinical responses in B-cell neoplasms. However, many challenges limit this class of agents for the treatment of other cancer types, in particular the lack of tumor-selective antigens for solid tumors and other hematological malignancies, such as acute myeloid leukemia (AML), which may be addressed without significant risk of severe toxicities while providing sufficient abundance for efficient tumor suppression. One approach to overcome this hurdle is dual targeting by an antibody–T-cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to 2 different antigens, in which both antigens are found together on the cancer cells but not together on normal cells. To explore this proof of concept in AML, we engineered a new T-cell format targeting Wilms tumor 1 protein (WT1) and CD33; both are highly expressed on most AML cells. Using an AbTCR comprising a newly developed TCR-mimic monoclonal antibody against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a single-chain variable fragment directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T-cell cytotoxicity to the AML cells while sparing healthy hematopoietic cells, including CD33+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T-cell therapy in AML.

Antigen-specific T cell activation through targeted delivery of in-situ generated antigen and calcium ionophore to enhance antitumor immunotherapy

Recent advances in adoptive T-cell therapy have delivered impressive therapeutic outcomes by instigating enduring anti-tumor responses. Nonetheless, achieving specific T-cell activation remains a challenge due to several factors. Some cancer cells evade T-cell recognition due to the scarcity of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC) presentation. Notably underestimated is the impact of waning T-cell receptor (TCR) expression and the constrained formation of immune synapses (IS) between dendritic cells (DCs) and T cells, impairing T-cell activation. Addressing these complexities, we introduce a pioneering approach featuring the deployment of a gel implant. This implant establishes an on-site antigen reservoir, efficiently targets DCs in lymph nodes, and facilitates calcium ion (Ca2+) delivery. Engineered with controlled swelling, poroelasticity, and resilience, the gel is suitable for surgical implantation. Its ample encapsulation capacity accommodates both photosensitizers and nanoparticles. Upon in situ photothermal irradiation, the gel generates tumor-specific antigens. Furthermore, cationic albumin nanoparticles (cNPs) co-loaded with monophosphoryl lipid A (MPLA) and ionomycin are released, guiding antigens to tumor-draining lymph nodes for DCs maturation. This meticulous process fosters the formation of IS thereby amplifying antigen-specific T-cell activation.

A replicating LCMV-based vaccine for the treatment of solid tumors

Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging. Here, we systematically investigate viral-vector-based cancer vaccines encoding a tumor-associated self-antigen (TRP2) for the treatment of established melanomas in preclinical mouse models, alone or in combination with adoptive T-cell therapy. We reveal that, unlike foreign antigens, tumor-associated antigens require replication of LCMV-based vectors to break tolerance and induce effective antigen-specific CD8+ T-cell responses. Immunization with a replicating LCMV vector leads to complete tumor rejection when combined with adoptive TRP2-specific T-cell transfer. Importantly, immunization with replicating vectors leads to extended antigen persistence in secondary lymphoid organs, resulting in efficient T-cell priming, which renders previously “cold” tumors open to immune infiltration and reprograms the tumor microenvironment to “hot”. Our findings have important implications for the design of next-generation immunotherapies targeting solid cancers utilizing viral vectors and adoptive cell transfer.

Magnetic Cellular Backpacks for Spatial Targeting, Imaging, and Immunotherapy.

Adoptive cell transfer (ACT) therapies are growing in popularity due to their ability to interact with diseased tissues in a specific manner. Disc-shaped particles, or "backpacks", that bind to cellular surfaces show promise for augmenting the therapeutic potential of adoptively transferred cells by resisting phagocytosis and locally releasing drugs to maintain cellular activity over time. However, many ACTs suffer from limited tumor infiltration and retention and lack a method for real-time spatial analysis. Therefore, we have designed biodegradable backpacks loaded with superparamagnetic iron oxide nanoparticles (SPIONs) to improve upon current ACT strategies by (i) controlling the localization of cell-backpack complexes using gradient magnetic fields and (ii) enabling magnetic particle imaging (MPI) to track complexes after injection. We show that magnetic backpacks bound to macrophages and loaded with a proinflammatory drug, resiquimod, maintain anticancer phenotypes of carrier macrophages for 5 days and create cytokine "factories" that continuously release IL-12. Furthermore, we establish that forces generated by gradient magnet fields are sufficient to displace cell-backpack complexes in physiological settings. Finally, we demonstrate that MPI can be used to visualize cell-backpack complexes in mouse tumors, enabling a potential strategy to track the biodistribution of ACTs in real time.