Journal Articles

Immunocytokines with target cell-restricted IL-15 activity for treatment of B cell malignancies

Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short half-life, poor accumulation at the tumor site, and severe toxicity due to unspecific immune activation. We here report modified immunocytokines consisting of Fc-optimized CD19 and CD20 antibodies fused to an IL-15 moiety comprising an L45E-E46K double mutation (MIC(+) format). The E46K mutation abrogated binding to IL-15R_, thereby enabling substitution of physiological trans-presentation by target binding and thus conditional IL-15R__ stimulation, whereas the L45E mutation optimized IL-15R__ agonism and producibility. In vitro analysis of NK activation, anti-leukemia reactivity, and toxicity using autologous and allogeneic B cells confirmed target-dependent function of MIC(+) constructs. Compared with Fc-optimized CD19 and CD20 antibodies, MIC(+) constructs mediated superior target cell killing and NK cell proliferation. Mouse models using luciferase-expressing human NALM-6 lymphoma cells, patient acute lymphoblastic leukemia (ALL) cells, and murine EL-4 lymphoma cells transduced with human CD19/CD20 as targets and human and murine NK cells as effectors, respectively, confirmed superior and target-dependent anti-leukemic activity. In summary, MIC(+) constructs combine the benefits of Fc-optimized antibodies and IL-15 cytokine activity and mediate superior NK cell immunity with potentially reduced side effects. They thus constitute a promising new immunotherapeutic approach shown here for B cell malignancies.

Author Info: (1) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. C

Author Info: (1) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (2) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. (3) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. (4) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. (5) School of Medical Sciences, University of Sydney, 2050 NSW, Australia. (6) Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (7) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (8) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (9) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. (10) Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department for Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University TŸbingen, 72076 TŸbingen, Germany. (11) Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department for Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University TŸbingen, 72076 TŸbingen, Germany. (12) Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (13) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. (14) Childrens University Hospital, University Hospital TŸbingen, 72076 TŸbingen, Germany. (15) Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (16) Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany. Department of Immunology, Institute for Cell Biology, Eberhard Karls UniversitŠt TŸbingen, Germany. DKFZ Partner Site TŸbingen, German Cancer Consortium (DKTK), 72076 TŸbingen, Germany. (17) Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TŸbingen, 72076 TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of TŸbingen, 72076 TŸbingen, Germany.

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers

BACKGROUND: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T(_)), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T(_) that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (F(H)AB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted. METHODS: SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101. RESULTS: Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T(_) of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFN_). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines. CONCLUSION: SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFN_ response, which may be important for tumor control in patients. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.

Author Info: (1) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (2) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (3) Sonnet BioTherapeutics, Inc, Princeton, NJ, United

Author Info: (1) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (2) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (3) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (4) Sonnet BioTherapeutics, Inc, Princeton, NJ, United States. (5) Momentum Metrix, LLC, Dublin, CA, United States. (6) Momentum Metrix, LLC, Dublin, CA, United States. (7) Sarcoma Oncology Center, Santa Monica, CA, United States. (8) Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia. InClin, Inc, San Mateo, CA, United States. (9) Nucleus Network Pty Ltd, Melbourne, VIC, Australia. (10) Nucleus Network Pty Ltd, Melbourne, VIC, Australia.

Exosomes Derived from Heat-shocked Tumor Cells Promote In vitro Maturation of Bone Marrow-derived Dendritic Cells

Dendritic cells (DCs), professional antigen-presenting cells that process and deliver antigens using MHC II/I molecules, can be enhanced in numerous ways. Exosomes derived from heat-shocked tumor cells (HS-TEXs) contain high amounts of heat-shock proteins (HSPs). HSPs, as chaperons, can induce DC maturation. This study aimed to investigate whether HS-TEXs can promote DC maturation. To generate DC, bone marrow-derived cells were treated with Interleukin-4 and GM-CSF. Exosomes were isolated from heat-treated CT-26 cells. The expression level of HSP in exosomes was checked by western blot and the increase in the expression of this protein was observed. Then, HS-TEXs were co-cultured with iDCs to determine DC maturity, and then DCs were co-cultured with lymphocytes to determine DC activity. Our results showed that DCs treated with HS-TEXs express high levels of molecules involved in DC maturation and function including MHCII, CD40, CD83, and CD86. HS-TEXs caused phenotypic and functional maturation of DCs. In addition, flow cytometric results reflected a higher proliferative response of lymphocytes in the iDC / Tex + HSP group. HS-TEXs could be used as a strategy to improve DC maturation and activation.

Author Info: (1) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. nh.he21@yahoo.com. (2) Department of Immunology, School of Medicine,

Author Info: (1) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. nh.he21@yahoo.com. (2) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. hajar.abbasi64@yahoo.com. (3) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. bahare.niknam@yahoo.com. (4) Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. ali.asadirad@gmail.com. (5) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Amanid@sbmu.ac.ir. (6) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. sz.mirsanei@gmail.com. (7) Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran AND Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. smmhashemi@sbmu.ac.ir.

Particle-Based Artificial Antigen-Presenting Cell Systems for T Cell Activation in Adoptive T Cell Therapy

T cell-based adoptive cell therapy (ACT) has emerged as a promising treatment for various diseases, particularly cancers. Unlike other immunotherapy modalities, ACT involves directly transferring engineered T cells into patients to eradicate diseased cells; hence, it necessitates methods for effectively activating and expanding T cells in vitro. Artificial antigen-presenting cells (aAPCs) have been widely developed based on biomaterials, particularly micro- and nanoparticles, and functionalized with T cell stimulatory antibodies to closely mimic the natural T cell-APC interactions. Due to their vast clinical utility, aAPCs have been employed as an off-the-shelf technology for T cell activation in FDA-approved ACTs, and the development of aAPCs is constantly advancing with the emergence of aAPCs with more sophisticated designs and additional functionalities. Here, we review the recent advancements in particle-based aAPCs for T cell activation in ACTs. Following a brief introduction, we first describe the manufacturing processes of ACT products. Next, the design and synthetic strategies for micro- and nanoparticle-based aAPCs are discussed separately to emphasize their features, advantages, and limitations. Then, the impact of design parameters of aAPCs, such as size, shape, ligand density/mobility, and stiffness, on their functionality and biomedical performance is explored to provide deeper insights into the design concepts and principles for more efficient and safer aAPCs. The review concludes by discussing current challenges and proposing future perspectives for the development of more advanced aAPCs.

Author Info: (1) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia. (2) School of Chemical E

Author Info: (1) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia. (2) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia. (3) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia. (4) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia. (5) School of Chemical Engineering, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T(reg) cells

Tiragolumab, an anti-TIGIT antibody with an active IgG1_ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone(1). However, there remains little consensus on the mechanism(s) of response with this combination(2). Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fc_ receptors (Fc_R), in turn driving anti-tumour CD8(+) T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that Fc_R engagement is an important consideration in anti-TIGIT antibody development.

Author Info: (1) Genentech Inc., South San Francisco, CA, USA. (2) Genentech Inc., South San Francisco, CA, USA. (3) Genentech Inc., South San Francisco, CA, USA. (4) Genentech Inc., South San

Author Info: (1) Genentech Inc., South San Francisco, CA, USA. (2) Genentech Inc., South San Francisco, CA, USA. (3) Genentech Inc., South San Francisco, CA, USA. (4) Genentech Inc., South San Francisco, CA, USA. (5) Genentech Inc., South San Francisco, CA, USA. (6) Genentech Inc., South San Francisco, CA, USA. (7) Genentech Inc., South San Francisco, CA, USA. (8) Genentech Inc., South San Francisco, CA, USA. (9) Genentech Inc., South San Francisco, CA, USA. (10) Genentech Inc., South San Francisco, CA, USA. (11) Genentech Inc., South San Francisco, CA, USA. (12) Genentech Inc., South San Francisco, CA, USA. (13) Genentech Inc., South San Francisco, CA, USA. (14) Genentech Inc., South San Francisco, CA, USA. (15) Genentech Inc., South San Francisco, CA, USA. (16) Genentech Inc., South San Francisco, CA, USA. (17) Genentech Inc., South San Francisco, CA, USA. (18) Genentech Inc., South San Francisco, CA, USA. (19) Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA. (20) Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain. (21) Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea. (22) Institut Bergonie CLCC Bordeaux, Bordeaux, France. Faculty of Medicine, University of Bordeaux, Bordeaux, France. (23) Cl’nica Universidad de Navarra, CIMA Universidad de Navarra Pamplona, Pamplona, Spain. (24) Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (25) Genentech Inc., South San Francisco, CA, USA. (26) Genentech Inc., South San Francisco, CA, USA. (27) Genentech Inc., South San Francisco, CA, USA. (28) Genentech Inc., South San Francisco, CA, USA. (29) Genentech Inc., South San Francisco, CA, USA. (30) Genentech Inc., South San Francisco, CA, USA. johnston.robert@gene.com. (31) Genentech Inc., South San Francisco, CA, USA. patil.namrata@gene.com.

Regulatory Effects of Long Non-coding RNAs on Th17/Treg Differentiation and Imbalance

Scientific research over the past decades has proven the pivotal role of long non-coding RNAs (LncRNAs) in regulating gene expression. The immune responses are controlled through the interaction of pro-inflammatory (predominance of T helper 17 cells (Th17)) and anti-inflammatory cytokines excretion (predominance of Regulatory T cells (Treg)). Recent studies have marked the impact of many diverse LncRNAs on Treg/Th17 imbalances. Moreover, some of the roots and causes of human diseases can be associated with the alterations in the Th17/Treg ratio. In this review study, we overviewed the association between LncRNAs and Th17/Treg, with the potential of providing novel prognostic and diagnostic biomarkers and promising therapeutic targets in various diseases, particularly cancer.

Author Info: (1) Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran AND Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. dabaghi

Author Info: (1) Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran AND Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. dabaghipourreza@gmail.com. (2) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ahmadi4bio@gmail.com. (3) Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran. entezam@sums.ac.ir. (4) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. omid.rahbar.farzam@gmail.com. (5) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. amirbaghbanzadeh@gmail.com. (6) Department of Biology, Texas A&M University, College Station, TX, USA. alisaber.as1996@gmail.com. (7) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. jalilzadehnazila@gmail.com. (8) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Mehdijafarlou@gmail.com. (9) Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran AND Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. behzad_im@yahoo.com.

Biodistribution of Drug/ADA Complexes: The Impact of Immune Complex Formation on Antibody Distribution

The clinical use of therapeutic monoclonal antibodies (mAbs) for the treatment of cancer, inflammation, and other indications has been successfully established. A critical aspect of drug-antibody pharmacokinetics is immunogenicity, which triggers an immune response via an anti-drug antibody (ADA) and forms drug/ADA immune complexes (ICs). As a consequence, there may be a reduced efficacy upon neutralization by ADA or an accelerated drug clearance. It is therefore important to understand immunogenicity in biological therapies. A drug-like immunoglobulin G (IgG) was radiolabeled with tritium, and ICs were formed using polyclonal ADA, directed against the complementary-determining region of the drug-IgG, to investigate in vivo biodistribution in rodents. It was demonstrated that 65% of the radioactive IC dose was excreted within the first 24 h, compared with only 6% in the control group who received non-complexed (3)H-drug. Autoradiographic imaging at the early time point indicated a deposition of immune complexes in the liver, lung, and spleen indicated by an increased radioactivity signal. A biodistribution study confirmed the results and revealed further insights regarding excretion and plasma profiles. It is assumed that the immune complexes are readily taken up by the reticuloendothelial system. The ICs are degraded proteolytically, and the released radioactively labeled amino acids are redistributed throughout the body. These are mainly renally excreted as indicated by urine measurements or incorporated into protein synthesis. These biodistribution studies using tritium-labeled immune complexes described in this article underline the importance of understanding the immunogenicity induced by therapeutic proteins and the resulting influence on biological behavior.

Author Info: (1) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, DE-82377, Penzberg, Germany. Eugenia

Author Info: (1) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, DE-82377, Penzberg, Germany. Eugenia.opolka-hoffmann@roche.com. (2) Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Therapeutic Modalities, CH-4070, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland. (4) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland. (5) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, DE-82377, Penzberg, Germany. (6) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, DE-82377, Penzberg, Germany. (8) Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians University, DE-80539, Munich, Germany. (9) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, DE-82377, Penzberg, Germany.

Lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy

Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.

Author Info: (1) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of

Author Info: (1) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (2) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (3) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (4) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (5) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (6) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. (7) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.

Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors

Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L_+__CD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

Author Info: (1) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (2) Cellular Immunology, International Centre for Genetic Engineerin

Author Info: (1) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (2) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (3) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. (4) UniversitŽ Paris CitŽ, Institut Cochin, INSERM 1016, Paris, France. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, KU Leuven, Leuven, Belgium. (5) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. (6) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (7) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (8) G. Armenise-Harvard Immune Regulation Unit, IIGM, Candiolo, TO, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy. (9) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. Cellular and Molecular Oncoimmunology, IRCCS Humanitas Research Hospital, Rozzano, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. (10) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (11) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (12) Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy. Vita-Salute San Raffaele University, Milan, Italy. (13) Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy. Vita-Salute San Raffaele University, Milan, Italy. (14) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy. (15) Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria. (16) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy. (17) Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France. (18) G. Armenise-Harvard Immune Regulation Unit, IIGM, Candiolo, TO, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy. (19) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. (20) Institut Pasteur, CNRS 3738, University de Paris CitŽ, Paris, France. (21) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. benvenut@icgeb.org.

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E7(84-98) specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4(+) and CD8(+) T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.

Author Info: (1) Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (2) HRYZ Biotech Co., Guangzhou, PR China. (3) Department of

Author Info: (1) Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (2) HRYZ Biotech Co., Guangzhou, PR China. (3) Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (4) HRYZ Biotech Co., Guangzhou, PR China. (5) Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (6) HRYZ Biotech Co., Guangzhou, PR China. (7) HRYZ Biotech Co., Guangzhou, PR China. (8) Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (9) Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. (10) HRYZ Biotech Co., Guangzhou, PR China. (11) HRYZ Biotech Co., Guangzhou, PR China. chujunjun@shhryz.com. (12) HRYZ Biotech Co., Guangzhou, PR China. hanyanyan@shhryz.com.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.