adoptive T cell transfer

Objective: This integrative review article examines the efficacy of adoptive cell therapy using tumor-infiltrating lymphocytes, with a particular focus on the treatment of melanomas and other solid tumors. Methods: The methodology encompasses theme definition, comprehensive database searches, and a critical review of pertinent literature. Of the 1,947 articles initially identified, 15 were meticulously selected based on stringent inclusion and exclusion criteria. Results: The findings suggest that tumor-infiltrating lymphocytes-based therapy is particularly effective in treating metastatic melanomas, as noted by its tailored approach and substantial potential. However, the applicability of these findings to other solid tumor types remains limited. Conclusion: This review indicates that adoptive cell therapy using tumor-infiltrating lymphocytes demonstrates efficacy, especially in the treatment of metastatic melanoma, and shows considerable promise for treating solid tumors.

Chimeric antigen receptor (CAR) T cells are genetically engineered T lymphocytes that express a synthetic receptor that recognizes a tumor cell surface antigen, which causes the T lymphocyte to kill the tumor cell. As of December 2024, the US Food and Drug Administration (FDA) approved six CAR T-cell therapies, with ten CAR T-cell therapies commercially available globally, which target the CD19 and B-cell maturation antigen (BCMA) molecules and with approved indications that include B-cell acute lymphoblastic leukemia (ALL), large B-cell lymphoma (LBCL), follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma. Pharmaceutical and economic forecasts have shown that the global CAR T-cell therapy market was worth USD 4.6 billion in 2024, with a projected USD 25 billion by 2035. However, there are several challenges in treating hematologic malignancies with CAR T-cell therapy, which include reduced treatment efficacy and durability in some patients, acute and long-term adverse effects, lack of effective salvage treatments, limited access to CAR T-cell therapies due to cost and availability, and the rare association with developing myeloid malignancies. A tumor-infiltrating lymphocyte (TIL) therapy, lifileucel, is FDA-approved for advanced melanoma. The T-cell receptor (TCR) therapy, afamitresgene autoleucel, is FDA-approved for advanced synovial sarcoma. The results from ongoing studies and clinical trials are awaited in solid tumors (melanoma, sarcomas, and carcinomas). This article reviews recent developments and ongoing challenges in adoptive T-cell therapies, including CAR T-cell therapies, in lymphoid and solid organ malignancies.

Objective: This integrative review article examines the efficacy of adoptive cell therapy using tumor-infiltrating lymphocytes, with a particular focus on the treatment of melanomas and other solid tumors. Methods: The methodology encompasses theme definition, comprehensive database searches, and a critical review of pertinent literature. Of the 1,947 articles initially identified, 15 were meticulously selected based on stringent inclusion and exclusion criteria. Results: The findings suggest that tumor-infiltrating lymphocytes-based therapy is particularly effective in treating metastatic melanomas, as noted by its tailored approach and substantial potential. However, the applicability of these findings to other solid tumor types remains limited. Conclusion: This review indicates that adoptive cell therapy using tumor-infiltrating lymphocytes demonstrates efficacy, especially in the treatment of metastatic melanoma, and shows considerable promise for treating solid tumors.

Introduction: Our previous results demonstrated a considerable antitumor effect of doxorubicin loaded in PLGA nanoparticles (Dox-PLGA NPs) coated with poloxamer 188 (P188) against the intracranial 101.8 glioblastoma in rats [1,2]. As a high-grade breast cancer is a common cause of brain metastases occurring in at least 10-16% patients [3] and doxorubicin is widely used against breast cancer, the aim of the present study was to evaluate the efficiency of Dox-PLGA NPs against 4T1 metastatic breast cancer in Balb/c mice. Methods: Dox-PLGA NPs were prepared by a double emulsion solvent evaporation technique. Chemotherapy: 4T1 murine breast cancer cells were previously modified by firefly luciferase gene transfection (4Т1-Luc2) and inoculated intracardially (1  10 5) into the cavity of a left ventricle of female Balb/c mice. On days 7, 10, 13, 16, and 19 after intracardial injection the tumor-bearing animals received i.v. the following formulations in the dose of 2 mg/kg (as doxorubicin): 1) Doxorubicin solution (Dox-sol), 2) Dox-PLGA NPs in PBS (DOX-PLGA), 3) Dox-PLGA NPs coated with 1% poloxamer 188 (Dox-PLGA/P188). For coating the NPs were resuspended in 1% P188 30 min before injection. Animals treated with 1% P188 solution and untreated group were used as controls 1 and 2, respectively. Organ bioluminescence intensity was assessed using an intravital fluorescence imaging system Ivis Spectrum CT on days 14 and 28 after tumor inoculation. Additionally, the presence of metastases in surviving animals was confirmed by MRI on days 21 and 28. Results: The average particle diameter was 120-130 nm, and the drug loading was 84%. The mean survival time of tumour-bearing mice was increased by >40% after treatment with Dox-PLGA NPs, as compared to control (23 days versus 15-16 days, respectively). As shown by intravital fluorescence imaging, the improved survival in the nanoparticle-treated groups also correlated with significantly lower fluorescence intensity of metastases as compared to the group treated with Dox-sol and control groups. The difference between the groups treated with DOX-PLGA and Dox-PLGA/P188 was not significant; however, in the animals treated with P188-coated NPs a somewhat lower bioluminescence of metastases was observed. Importantly, administration of nanoparticulate formulations was associated with a significantly improved tolerance of chemotherapy, as compared to free doxorubicin. Conclusion: Binding of doxorubicin to PLGA nanoparticles considerably enhanced its antitumour efficacy against 4T1 metastatic breast cancer in mice providing more pronounced inhibition of metastatic spread and higher increase of animal lifespan , as compared to the free drug. Moreover, Dox-PLGA NPs appeared to be less toxic which is most probably due their altered biodistribution pattern.

BackgroundNexImmune is developing highly differentiated immunotherapies to target, activate and expand tumor antigen-specific T cells using the proprietary Artificial Immune Modulation (AIM™) nanotechnology platform. The AIM nanoparticle (AIM-np) technology functions as synthetic dendritic cells capable of directing a specific T cell-mediated immune response. By mimicking natural T cell biology, NexImmune’s non-genetically engineered cellular therapy product candidates (AIM ACT) are designed to combine the attributes of cellular precision, potency, and persistence with reduced potential for undesired toxicities.MethodsHere we present an example of AIM ACT expanded MART-1 specific T cells and their phenotypic and functional characterization in vitro and in vivo. Leukopaks from healthy donors were used to produce AIM ACT T cell products with our proprietary AIM ACT enrichment and expansion (E+E) manufacturing process and antigen peptide-loaded AIM-nanoparticles.ResultsThe final MART1 ...

SummaryRegulatory cells play a crucial role in the induction and maintenance of tolerance by controlling T cell as well as B and natural killer (NK) cell-mediated immunity. In transplantation, CD4+CD25+forkhead box P3+ T regulatory cells are instrumental in the maintenance of immunological tolerance, as are several other T cell subsets such as NK T cells, double negative CD3+ T cells, γδ T cells, interleukin-10-producing regulatory type 1 cells, transforming growth factor-β-producing T helper type 3 cells and CD8+CD28- cells. However, not only T cells have immunosuppressive properties, as it is becoming increasingly clear that both T and non-T regulatory cells co-operate and form a network of cellular interactions controlling immune responses. Non-T regulatory cells include tolerogenic dendritic cells, plasmacytoid dendritic cells, mesenchymal stem cells, different types of stem cells, various types of alternatively activated macrophages and myeloid-derived suppressor cells. Here, w...

Background: Cancer is one of the most lethal diseases worldwide. Traditional approaches such as chemotherapy have toxic side e!ects. New therapies on the rise are more target specific. One such therapy, immunotherapy, has become increasingly attractive in the field. However, to ensure the modulated and controlled manipulation of the immune system, delivery methods for drugs cells and biomaterials must be developed.Methods: In this review, we analyze the literature to discuss the recent advances in T cell immunotherapy as well as four delivery technologies that address the issues of safety and efficacy associated with this treatment.Summary: We conclude that the CAR-T approach could be a step towards overcoming the inaccessibility of poorly vascularized tumors and the evasion mechanisms of tumor cells. Delivery methods such as surface conjugated nanoparticles, DNA nanocarriers, scafolds and artifcial antigen-presenting cells aim for a more tumor-targeted approach rather than a system...

Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of 46000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.

Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of 46000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.

Immunotherapy holds tremendous promise for improving cancer treatment in which an appropriate stimulator may naturally trigger the immune system to control cancer. Up-to-date, adoptive T-cell therapy has received two new FDA approvals that provide great hope for some cancer patient groups. Nevertheless, expense and safety-related issues require further study to obtain insight into targets for efficient immunotherapy. The development of material science was largely responsible for providing a promising horizon to strengthen immunoengineering. In this review, we focus on T-cell characteristics in the context of the immune system against cancer and discuss several approaches of exploiting engineered particles to manipulate the responses of T cells and the tumor microenvironment.

Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO 91-99), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO 91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO 91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO 91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO 91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO 91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

Immunotherapy for cancer has been a focus 50 years ago. At the time, this treatment was developed prior to cloning of the cytokines, no knowledge of regulatory T-cells, and very little information that mesenchymal stem cells (MSCs) (originally colony forming unit-fibroblasts [CFU-F]) could be licensed by the inflammatory microenvironment to suppress an immune response. Given the information available at that time, mononuclear cells from the peripheral blood were activated ex vivo and then replaced in the patients with tumor. The intent was to harness these activated immune cells to target the cancer cells. These studies did not lead to long-term responses because the activated cells when reinfused into the patients were an advantage to the resident MSCs, which can home the tumor and then become suppressive in the presence of the immune cells. The immune suppression caused by MSCs would also expand regulatory T-cells, resulting instead in tumor protection. As time progressed, these d...

Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages an...

A subset of CD1c-restricted T lymphocytes exhibits strong reactivity against leukemia cells. These T cells recognize methyl-lysophosphatidic acid (mLPA), a novel lipid antigen produced by acute leukemia cells. Considering that CD1crestricted T cells display efficacious anti-leukemia activities in a mouse model, this lipid antigen thus represents a novel target in the immunotherapy of hematological malignancies.

Background NexImmune's artificial immune modulation (AIM™) technology is designed to direct T cell function and drive a T cell-mediated response. AIM antigen-specific immunotherapies rely on a nanoparticle-based artificial antigen presenting cell (aAPC) platform. The off-the-shelf injectable nanoparticles (INJ) are developed using biodegradable PLGA-PEG or PLA-PEG core materials and designed to mimic the function of natural APCs. AIM INJ nanoparticles present (i) an antigen-specific recognition signal delivered by an MHC molecule loaded with an antigenic peptide (Signal 1), and (ii) a co-stimulatory signal (anti-CD28, Signal 2) to induce expansion of the T cells activated through Signal 1. Methods AIM INJ nanoparticles were synthesized by nanoprecipitation method on the Ignite NanoAssemblr TM microfluidic system. Murine AIM INJ nanoparticles were formulated by conjugating murine protein Signal 1 and 2, and then loading with tumor-specific peptides. Physicochemical characterization, stability, and in vitro functional tests were performed to assess antigen-specific CD8 + T cell proliferation, expansion, and cytokine production upon nanoparticle exposure. In vivo biodistribution and efficacy studies were performed in B16-F10 melanoma model by s.c. injection of AIM INJ nanoparticles. Biodistribution studies were conducted using 89 Zr radiolabeled nanoparticles. For the efficacy study, on day 7 after nanoparticle injection, tumor tissues were harvested and stimulated ex vivo to measure the expression of CD107a and cytokines IFN-g, TNF-a, IL-2 by the tumor infiltrating lymphocytes (TILs). Results PLGA-PEG based AIM INJ nanoparticles, with 100nm diameter, PDI < 0.2, and close-to-neutral surface charge, have round morphology and were stable in liquid formulation over 6-months. The peptide-loaded murine AIM INJ nanoparticles activated CD8 + T cells in antigen-specific manner by promoting cell proliferation, expansion, and poly-functionality. The biodistribution studies showed a significantly higher amount of AIM INJ nanoparticle accumulation in the tumor (24 hours) and draining lymph node (96 hours) compared to naked nanoparticles (no proteins/peptides). In an in vivo treatment study, we demonstrated that the peptide-loaded AIM INJ nanoparticles induced significant amounts of polyfunctional CD8 + TILs in a B16-F10 melanoma model. In addition, we will present data from ongoing studies using different sizes and formulations of AIM INJ nanoparticles. Conclusions We demonstrated that biodegradable AIM INJ nanoparticles can activate and expand multiple antigen-specific CD8 + T cells in vitro and in vivo to induce anti-tumor activity. These studies along with other in vivo pre-clinical characterization will be used to support multiple INDs and advance AIM INJ into Phase 1 studies for various solid tumors.

Objectives Atherosclerosis, a progressive condition characterised by the build-up of plaque due to the accumulation of low-density lipoprotein and fibrous substances in the damaged arteries, is the major underlying pathology of most cardiovascular diseases. Despite the evidence of the efficacy of the present treatments for atherosclerosis, the complex and poorly understood underlying mechanisms of atherosclerosis development and progression have prevented them from reaching their full potential. Novel alternative treatments like usage of nanomedicines and theranostics are gaining attention of the researchers worldwide. This review will briefly discuss the current medications for the disease and explore potential future developments based on theranostics nanomaterials that may help resolve atherosclerotic cardiovascular disease. Key findings Various drugs can slow the effects of atherosclerosis. They include hyperlipidaemia medications, anti-platelet drugs, hypertension and hyperglyc...

Checkpoint blockade immunotherapy enhances systemic antitumor immune response by targeting T cell inhibitory pathways; however, inadequate T cell infiltration has limited its anticancer efficacy. Radiotherapy (RT) has local immunomodulatory effects that can alter the microenvironment of irradiated tumors to synergize with immune checkpoint blockade. However, even with high doses of radiation, RT has rarely elicited systemic immune responses. Herein, we report the design of two porous Hf-based nanoscale metal-organic frameworks (nMOFs) as highly effective radioenhancers that significantly outperform HfO, a clinically investigated radioenhancer in vitro and in vivo. Importantly, the combination of nMOF-mediated low-dose RT with an anti-programmed death-ligand 1 antibody effectively extends the local therapeutic effects of RT to distant tumors via abscopal effects. Our work establishes the feasibility of combining nMOF-mediated RT with immune checkpoint blockade to elicit systemic anti...

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34 +) and normal (CD3 +) cells isolated from the patients' blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4 + response and 11 (34%) induced a CD8 + response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients.

Purpose Current response assessment systems for cancer patients receiving immunotherapy are limited. This is due to the associated inflammatory response that may confound the conventional morphological response evaluation criteria in solid tumors and metabolic positron emission tomography (PET) response criteria in solid. Recently, novel PET imaging techniques using radiolabeled antibodies and fragments have emerged as a particularly sensitive and specific modality for quantitative tracking of immune cell dynamics. Therefore, we sought to investigate the utility of Cu-64 labeled F(ab)′2 fragments for in vivo detection of CD8a+ T cells as a prognostic imaging biomarker of response to immunotherapy in an immunocompetent mouse model of colorectal cancer. Procedures [64Cu]NOTA-CD8a was produced by enzymatic digestion of rat-anti-mouse CD8a antibody (clone YTS169.4), purified yielding isolated CD8a-F(ab)′2 fragments and randomly conjugated with the 2-S-(isothiocyanatbenzyl)-1,4,7-triazac...

Background:: Tumours are no longer regarded as isolated masses of aberrantly proliferating epithelial cells. Rather, their properties depend on complex interactions between epithelial cancer cells and the surrounding stromal compartment within the tumour microenvironment. In particular, leukocyte infiltration plays a role in controlling tumour development and is now considered one of the hallmarks of cancer. Thus, in the last few years, immunotherapy has become a promising strategy to fight cancer, as its goal is to reprogram or activate antitumour immunity to kill tumour cells, without damaging the normal cells and provide long-lasting results where other therapies fail. However, the immune-related adverse events due to the low specificity in tumour cell targeting, strongly limit immunotherapy efficacy. In this regard, nanomedicine offers a platform for the delivery of different immunotherapeutic agents specifically to the tumour site, thus increasing efficacy and reducing toxicity...

For the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen prediction technologies provides opportunities for further development of personalized immunotherapies. In this study, we present a novel strategy to deliver in silico predicted neoantigens to autologous dendritic cells (DCs) using paramagnetic beads (EpiTCer beads). DCs pulsed with EpiTCer beads are superior in enriching for healthy donor and patient blood-derived tumor-specific CD8+ T cells compared to DC loaded with whole-tumor lysate or 9mer neoantigen peptides. A dose-dependent effect was observed, with higher EpiTCer bead per DC being favorable. We concluded that CD8+ T cells enriched by DC loaded with EpiTCer beads are tumor specific with limited tumor cross-reactivity and low recognition of autologous non-activated monocytes or CD8+ T cells. Furthermore, tumor specificity and recognition were improved and preserved after additional expansion using our Good Manufacturing Process (GMP)-compatible rapid expansion protocol. Phenotypic analysis of patientderived EpiTCer DC expanded CD8+ T cells revealed efficient maturation, with high frequencies of central memory and effector memory T cells, similar to those observed in autologous expanded tumor-infiltrating lymphocytes. These results indicate that DC pulsed with EpiTCer beads enrich for a T-cell population with high capacity of tumor recognition and elimination, which are features needed for a T-cell product to be used for personalized adoptive cell therapy.

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34 +) and normal (CD3 +) cells isolated from the patients' blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4 + response and 11 (34%) induced a CD8 + response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients.

As professional antigen presenting cells (APCs) capable of eliciting primary immune responses among naïve T cells, dendritic cells (DCs) offer an attractive target for immune intervention. While some strategies for vaccination have sought to deliver antigens direct to DCs in vivo, others have pulsed DCs with target antigens ex vivo prior to administration. Indeed, numerous clinical studies of cancer immunotherapy have been conducted over the past two decades based on this approach, most of them benefitting from the ease with which DCs may be differentiated in vitro from the peripheral blood monocytes of individual patients. Nevertheless, while therapies exploiting monocyte-derived DCs (moDCs) have been shown to be safe, clinical outcomes have been disappointing, efficacy having been limited by factors including the type of DCs used and the source of tumor antigens. Here we review recent developments in identifying DC subsets with more favorable properties for use in cancer vaccination, with particular emphasis on CD141 + DCs capable of antigen cross-presentation and discuss alternative sources, such as induced pluripotent stem cells (iPSCs), amenable to manufacture at scale. Furthermore, we assess how different sources of tumor antigens may complement this approach for the design of next generation DC vaccines.

Immunotherapy has yielded impressive results, but only for a minority of patients with cancer. Therefore, new approaches that potentiate immunotherapy are a pressing medical need. Ferroptosis is a newly described type of programmed cell death driven by iron-dependent phospholipid peroxidation via Fenton chemistry. Here, we developed iron oxide-loaded nanovaccines (IONVs), which, chemically programmed to integrate iron catalysis, drug delivery, and tracking exploiting the characteristics of the tumor microenvironment (TME), improves immunotherapy and activation of ferroptosis. The IONVs trigger danger signals and use molecular disassembly and reversible covalent bonds for targeted antigen delivery and improved immunostimulatory capacity and catalytic iron for targeting tumor cell ferroptosis. IONV-and antibody-mediated TME modulation interfaced with imaging was important toward achieving complete eradication of aggressive and established tumors, eliciting long-lived protective antitumor immunity with no toxicities. This work establishes the feasibility of using nanoparticle iron catalytic activity as a versatile and effective feature for enhancing immunotherapy.

Immunotherapy has yielded impressive results, but only for a minority of patients with cancer. Therefore, new approaches that potentiate immunotherapy are a pressing medical need. Ferroptosis is a newly described type of programmed cell death driven by iron-dependent phospholipid peroxidation via Fenton chemistry. Here, we developed iron oxide-loaded nanovaccines (IONVs), which, chemically programmed to integrate iron catalysis, drug delivery, and tracking exploiting the characteristics of the tumor microenvironment (TME), improves immunotherapy and activation of ferroptosis. The IONVs trigger danger signals and use molecular disassembly and reversible covalent bonds for targeted antigen delivery and improved immunostimulatory capacity and catalytic iron for targeting tumor cell ferroptosis. IONV-and antibody-mediated TME modulation interfaced with imaging was important toward achieving complete eradication of aggressive and established tumors, eliciting long-lived protective antitumor immunity with no toxicities. This work establishes the feasibility of using nanoparticle iron catalytic activity as a versatile and effective feature for enhancing immunotherapy.

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Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO 91-99), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO 91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO 91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO 91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO 91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO 91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

This study investigates the effect of PD1 blockade on the therapeutic efficacy of novel doxorubicin-loaded temperature-sensitive liposomes. Herein, we report photothermally-activated, low temperature-sensitive magnetoliposomes (mLTSL) for efficient drug delivery and magnetic resonance imaging (MRI). The mLTSL were prepared by embedding small nitrodopamine palmitate (NDPM)-coated iron oxide nanoparticles (IO NPs) in the lipid bilayer of low temperature-sensitive liposomes (LTSL), using lipid film hydration and extrusion. Doxorubicin (DOX)-loaded mLTSL were characterized using dynamic light scattering, differential scanning calorimetry, electron microscopy, spectrofluorimetry, and atomic absorption spectroscopy. Photothermal experiments using 808 laser irradiation were conducted. In vitro photothermal DOX release studies and cytotoxicity was assessed using flow cytometry and resazurin viability assay, respectively. In vivo DOX release and tumor accumulation of mLTSL(DOX) was assessed using fluorescence and MR imaging, respectively. Finally, the therapeutic efficacy of PD1 blockade in combination with photothermally-activated mLTSL(DOX) in CT26-tumor model was evaluated by monitoring tumor growth, cytokine release and immune cell infiltration in the tumor tissue. Interestingly, efficient photothermal heating was obtained by varying the IO NPs content and the laser power, where on-demand burst DOX release was achievable in vitro and in vivo. Moreover, our mLTSL exhibited promising MR imaging properties with high transverse r2 relaxivity (333 mM-1 s-1), resulting in superior MR imaging in vivo. Furthermore, mLTSL(DOX) therapeutic efficacy was potentiated in combination with anti-PD1 mAb, resulting in a significant reduction in CT26 tumor growth via immune cell activation. Our study highlights the potential of combining PD1 blockade with mLTSL(DOX), where the latter could facilitate chemo/photothermal therapy and MRI-guided drug delivery.

The development of strategies capable of eliminating metastasized cancer cells and preventing tumor recurrence is an exciting and extremely important area of research. In this regard, therapeutic approaches that explore the synergies between nanomaterial-mediated phototherapies and immunostimulants/immune checkpoint inhibitors have been yielding remarkable results in pre-clinical cancer models. These nanomaterials can accumulate in tumors and trigger, after irradiation of the primary tumor with near infrared light, a localized temperature increase and/or reactive oxygen species. These effects caused damage in cancer cells at the primary site and can also (i) relieve tumor hypoxia, (ii) release tumor-associated antigens and danger-associated molecular patterns, and (iii) induced a pro-inflammatory response. Such events will then synergize with the activity of immunostimulants and immune checkpoint inhibitors, paving the way for strong T cell responses against metastasized cancer cell...

Metastatic spread is the mechanism in more than 90 percent of cancer deaths and current therapeutic options, such as systemic chemotherapy, are often ineffective. Here we provide a proof of principle for a novel two-pronged modality referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) having the potential to safely eradicate both primary tumors and distant metastatic foci. Using a combination of immune-checkpoint inhibition and plasmonic gold nanostar (GNS)-mediated photothermal therapy, we were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice implanted with the MB49 bladder cancer cells. Delayed rechallenge with MB49 cancer cells injection in mice that appeared cured by SYMPHONY did not lead to new tumor formation after 60 days observation, indicating that SYMPHONY treatment induced effective long-lasting immunity against MB49 cancer cells.

The versatility and nanoscale size have helped nanoparticles (NP) improve the efficacy of conventional cancer immunotherapy and opened up exciting approaches to combat cancer. This review first outlines the tumor immune evasion and the defensive tumor microenvironment (TME) that hinders the activity of host immune system against tumor. Then, a detailed description on how the NP based strategies have helped improve the efficacy of conventional cancer vaccines and overcome the obstacles led by TME. Sustained and controlled drug delivery, enhanced cross presentation by immune cells, co-encapsulation of adjuvants, inhibition of immune checkpoints and intrinsic adjuvant like properties have aided NPs to improve the therapeutic efficacy of cancer vaccines. Also, NPs have been efficient modulators of TME. In this context, NPs facilitate better penetration of the chemotherapeutic drug by dissolution of the inhibitory meshwork formed by tumor associated cells, blood vessels, soluble mediators and extra cellular matrix in TME. NPs have shown to achieve this by suppression, modulation, or reprogramming of the immune cells and other mediators localised in TME. In this review, we summarize applications of NPs used to enhance the efficacy of cancer vaccines and modulate the TME to improve cancer immunotherapy. Finally, the hurdles faced in commercialization and translation to clinic have been discussed and intriguingly, NPs owe great potential to emerge as clinical formulations for cancer immunotherapy in near future.

Cancer immunotherapy has emerged as a promising strategy for the treatment of many forms of cancer by stimulating body&#39;s own immune system. This therapy not only eradicates tumor cells by inducing strong anti-tumor immune response but also prevent their recurrence. The clinical cancer immunotherapy faces some insurmountable challenges including high immune-mediated toxicity, lack of effective and targeted delivery of cancer antigens to immune cells and off-target side effects. However, nanotechnology offers some solutions to overcome those limitations, and thus can potentiate the efficacy of immunotherapy. This review focuses on the advancement of nanoparticle-mediated delivery of immunostimulating agents for efficient cancer immunotherapy. Here we have outlined the use of the immunostimulatory nanoparticles as a smart carrier for effective delivery of cancer antigens and adjuvants, type of interactions between nanoparticles and the antigen/adjuvant as well as the factors contro...

Abnormal cell metabolism with vigorous nutrition consumption is one of the major physiological characteristics of cancers. As such, the strategy of cancer starvation therapy through blocking the blood supply, depleting glucose/oxygen and other critical nutrients of tumors has been widely studied to be an attractive way for cancer treatment. However, several undesirable properties of these agents, such as low targeting efficacy, undesired systemic side effects, elevated tumor hypoxia, induced drug resistance, and increased tumor metastasis risk, limit their future applications. The recent development of starving-nanotherapeutics combined with other therapeutic methods displayed the promising potential for overcoming the above drawbacks. This review highlights the recent advances of nanotherapeutic-based cancer starvation therapy and discusses the challenges and future prospects of these anticancer strategies.

Metastatic spread is the mechanism in more than 90 percent of cancer deaths and current therapeutic options, such as systemic chemotherapy, are often ineffective. Here we provide a proof of principle for a novel two-pronged modality referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) having the potential to safely eradicate both primary tumors and distant metastatic foci. Using a combination of immune-checkpoint inhibition and plasmonic gold nanostar (GNS)-mediated photothermal therapy, we were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice implanted with the MB49 bladder cancer cells. Delayed rechallenge with MB49 cancer cells injection in mice that appeared cured by SYMPHONY did not lead to new tumor formation after 60 days observation, indicating that SYMPHONY treatment induced effective long-lasting immunity against MB49 cancer cells.

The efficacy of immunotherapy was demonstrated to be compromised by reduced immunogenicity of tumor cells and enhanced suppressive properties of the tumor microenvironment in cancer treatment. There is growing evidence that low-dose chemotherapy can modulate the immune system to improve the anti-tumor effects of immunotherapy through multiple mechanisms, including the enhancement of tumor immunogenicity and reversal of the immunosuppressive tumor microenvironment. Here, we fabricated thermosponge nanoparticles (TSNs) for the co-delivery of chemotherapeutic drug paclitaxel (PTX) and immunostimulant interleukin-2 (IL-2) to explore the synergistic anti-tumor effects of chemotherapy and immunotherapy. The distinct temperature-responsive swelling/deswelling character facilitated the effective post-entrapment of cytokine IL-2 in nanoparticles by a facile non-solvent mild incubation method with unaffected bioactivity and favorable pharmacokinetics. PTX and IL-2 co-loaded TSNs exhibited sig...

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity.

Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-b...

Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-f producing CD8+ T cells, when compared to monotherapy controls (all p...

Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen–targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule ...

Le traitement des leucémies myéloïdes et lymphoblastiques aiguës a connu des avancées importantes dans la dernière décennie. Malgré ces progrès, le taux de rechutes reste élevé et le besoin médical est réel. Ces leucémies sont caractérisées par une expression aberrante d’antigènes qui peuvent provenir de protéines mutées, mais aussi de séquences rapportées comme non codantes. Les réponses contre ces néoantigènes tumoraux « cryptiques » demeurent non caractérisées. Afin de définir l’existence d’un répertoire varié de récepteurs des lymphocytes T (TCR) qui reconnaitraient ces néoantigènes, des cellules mononuclées du sang périphérique de patients sains sont isolées puis enrichies en cellules T CD8+ naïves. L’expansion et l’activation de ces cellules sont ensuite réalisées avec des cellules dendritiques autologues chargées avec l’antigène d’intérêt puis triées à l’aide de multimères HLA-peptides spécifiques. L’ARN des cellules avec TCR spécifiques aux antigènes spécifiques des tumeurs ...

Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies.

Background: To predict the behavior of biological systems, mathematical models of biological systems have been shown to be useful. In particular, mathematical models of tumor-immune system interactions have demonstrated promising results in prediction of different behaviors of tumor against the immune system. Methods: This study aimed at the introduction of a new model of tumor-immune system interaction, which includes tumor and immune cells as well as myeloid-derived suppressor cells (MDSCs). MDSCs are immune suppressor cells that help the tumor cells to escape the immune system. The structure of this model is agent-based which makes possible to investigate each component as a separate agent. Moreover, in this model, the effect of low dose 5-fluorouracil (5-FU) on MDSCs depletion was considered. Results: Based on the findings of this study, MDSCs had suppressive effect on increment of immune cell number which consequently result in tumor cells escape the immune cells. It has also been demonstrated that low-dose 5-FU could help immune system eliminate the tumor cells through MDSCs depletion. Conclusion: Using this new agent-based model, multiple injection of low-dose 5-FU could eliminate MDSCs and therefore might have the potential to be considered in treatment of cancers.

Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBreg) can block metastasis despite MDSC expan-sion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations that expand in cancer have only partially primed regulatory function and limited prometastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying, in part, on TgfbR1/TgfbR2 signaling.MDSC fully educated in this manner exhibit an increased production of reactive oxygen species and NO and more efficiently suppress CD4þ and CD8þ T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfbR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regul...

Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBregs) can block metastasis despite MDSC expansion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations which expand in cancer have only partially primed regulatory function and limited pro-metastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying in part on TgfβR1/TgfβR2 signaling. MDSC fully educated in this manner exhibit an increased production of ROS and NO and more efficiently suppress CD4+ and CD8+ T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfβR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are imp...