ACIR Journal Articles

Personalized, autologous neoantigen-specific T cell therapy in metastatic melanoma: a phase 1 trial

(1) Borgers JSW (2) Lenkala D (3) Kohler V (4) Jackson EK (5) Linssen MD (6) Hymson S (7) McCarthy B (8) O'Reilly Cosgrove E (9) Balogh KN (10) Esaulova E (11) Starr K (12) Ware Y (13) Klobuch S (14) Sciuto T (15) Chen X (16) Mahimkar G (17) Sheen JHF (18) Ramesh S (19) Wilgenhof S (20) van Thienen JV (21) Scheiner KC (22) Jedema I (23) Rooney M (24) Dong JZ (25) Srouji JR (26) Juneja VR (27) Arieta CM (28) Nuijen B (29) Gottstein C (30) Finney OC (31) Manson K (32) Nijenhuis CM (33) Gaynor RB (34) DeMario M (35) Haanen JB (36) van Buuren MM

Nature medicine - Open Access

New treatment approaches are warranted for patients with advanced melanoma refractory to immune checkpoint blockade (ICB) or BRAF-targeted therapy. We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3_+_3 dose-finding study with two dose levels (DLs) in patients with locally advanced or metastatic melanoma, disease progression after ICB, measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1) and, where appropriate, BRAF-targeted therapy. Primary and secondary objectives were evaluation of safety, highest tolerated dose and anti-tumor activity. We report here the non-pre-specified, final results of the completed monotherapy arm consisting of nine patients: three at DL1 (1___10(8)-1___10(9) cells) and six at DL2 (2___10(9)-1___10(10) cells). Drug products (DPs) were generated for all enrolled patients. BNT221 was well tolerated across both DLs, with no dose-limiting toxicities of grade 3 or higher attributed to the T cell product observed. Specifically, no cytokine release, immune effector cell-associated neurotoxicity or macrophage activation syndromes were reported. A dose of 5.0___10(8)-1.0___10(10) cells was identified for further study conduct. Six patients showed stable disease as best overall response, and tumor reductions (²20%) were reported for four of these patients. In exploratory analyses, multiple mutant-specific CD4(+) and CD8(+) T cell responses were generated in each DP. These were cytotoxic, polyfunctional and expressed T cell receptors with broad functional avidities. Neoantigen-specific clonotypes were detected after treatment in blood and tumor. Our results provide key insights into this neoantigen-specific adoptive T cell therapy and demonstrate proof of concept for this new therapeutic approach. ClinicalTrials.gov registration: NCT04625205 .

Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (2) BioNTech US, Cambridge, MA, USA. (3) BioNTech US, Cambridge, MA, USA. (4) Bi

Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (2) BioNTech US, Cambridge, MA, USA. (3) BioNTech US, Cambridge, MA, USA. (4) BioNTech US, Cambridge, MA, USA. (5) BioTherapeutics Unit, Division of Pharmacy and Pharmacology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (6) BioNTech US, Cambridge, MA, USA. (7) BioNTech US, Cambridge, MA, USA. (8) BioNTech US, Cambridge, MA, USA. (9) BioNTech US, Cambridge, MA, USA. (10) BioNTech US, Cambridge, MA, USA. (11) BioNTech SE, Mainz, Germany. (12) BioNTech US, Cambridge, MA, USA. (13) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (14) BioNTech US, Cambridge, MA, USA. (15) BioNTech US, Cambridge, MA, USA. (16) BioNTech US, Cambridge, MA, USA. (17) BioNTech US, Cambridge, MA, USA. (18) BioNTech US, Cambridge, MA, USA. (19) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (20) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (21) BioTherapeutics Unit, Division of Pharmacy and Pharmacology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (22) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (23) BioNTech US, Cambridge, MA, USA. (24) BioNTech US, Cambridge, MA, USA. (25) BioNTech US, Cambridge, MA, USA. (26) BioNTech US, Cambridge, MA, USA. (27) BioNTech US, Cambridge, MA, USA. (28) BioTherapeutics Unit, Division of Pharmacy and Pharmacology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (29) BioNTech SE, Mainz, Germany. (30) BioNTech US, Cambridge, MA, USA. (31) BioNTech US, Cambridge, MA, USA. (32) BioTherapeutics Unit, Division of Pharmacy and Pharmacology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (33) BioNTech US, Cambridge, MA, USA. (34) BioNTech US, Cambridge, MA, USA. (35) Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. j.haanen@nki.nl. (36) BioNTech US, Cambridge, MA, USA. marit.vanbuuren@biontech.us.

Citation: Nat Med 2025 Jan 3 Epub01/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39753970

A phase I clinical trial adding OX40 agonism to in situ therapeutic cancer vaccination in patients with low-grade B cell lymphoma highlights challenges in translation from mouse to human studies

(1) Shree T (2) Czerwinski D (3) Haebe S (4) Sathe A (5) Grimes S (6) Martin B (7) Ozawa M (8) Hoppe R (9) Ji H (10) Levy R

Clinical Cancer Research

(1) Shree T (2) Czerwinski D (3) Haebe S (4) Sathe A (5) Grimes S (6) Martin B (7) Ozawa M (8) Hoppe R (9) Ji H (10) Levy R

Clinical Cancer Research

PURPOSE: Activating T cell costimulatory receptors is a promising approach for cancer immunotherapy. In preclinical work, adding an OX40 agonist to in situ vaccination (ISV) with SD101, a TLR9 agonist, was curative in a mouse model of lymphoma. We sought to test this combination in a Phase I clinical trial for patients with low-grade B cell lymphoma. PATIENTS AND METHODS: We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody. The primary outcome was safety. Secondary outcomes included overall response rate and progression-free survival. RESULTS: Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and 9 patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment. However, high baseline OX40 expression on T follicular helper and T regulatory type 1 cells, as well as high post-treatment soluble OX40, shed from these T cells upon activation, associated with progression-free survival of less than 6 months. CONCLUSIONS: Clinical results of T cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogenous T cell subpopulations, some of which may antagonize immunotherapy.

Author Info: (1) Oregon Health & Science University, Portland, Oregon, United States. (2) Stanford School of Medicine, Stanford, CA, United States. (3) Stanford School of Medicine, Stanford, CA

Author Info: (1) Oregon Health & Science University, Portland, Oregon, United States. (2) Stanford School of Medicine, Stanford, CA, United States. (3) Stanford School of Medicine, Stanford, CA, United States. (4) Stanford University, Stanford, CA, United States. (5) Stanford University, Stanford, CA, United States. (6) Stanford University, United States. (7) Stanford Medicine, United States. (8) Stanford University, Stanford, CA, United States. (9) Stanford University, Stanford, CA, United States. (10) Stanford University, Stanford, CA, United States.

Citation: Clin Cancer Res 2025 Jan 2 Epub01/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39745391

A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors

(1) Bei Y (2) Huang Y (3) Wu N (4) Li Y (5) Xu R (6) Liu B (7) Li R

EMBO molecular medicine - Open Access

(1) Bei Y (2) Huang Y (3) Wu N (4) Li Y (5) Xu R (6) Liu B (7) Li R

EMBO molecular medicine - Open Access

The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.

Author Info: (1) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. (2) Department of Oncology,

Author Info: (1) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. (2) Department of Oncology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, 223022, Huai'an, China. (3) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. (4) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. Clinical Cancer Institute of Nanjing University, 210008, Nanjing, China. (5) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. (6) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. baoruiliu@nju.edu.cn. (7) The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210008, Nanjing, China. rutianli@nju.edu.cn. Clinical Cancer Institute of Nanjing University, 210008, Nanjing, China. rutianli@nju.edu.cn.

Citation: EMBO Mol Med 2025 Jan 2 Epub01/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39748060

Cancer immune evasion, immunoediting and intratumour heterogeneity

(1) Roerden M (2) Spranger S

Nature reviews. Immunology

(1) Roerden M (2) Spranger S

Nature reviews. Immunology

Cancers can avoid immune-mediated elimination by acquiring traits that disrupt antitumour immunity. These mechanisms of immune evasion are selected and reinforced during tumour evolution under immune pressure. Some immunogenic subclones are effectively eliminated by antitumour T cell responses (a process known as immunoediting), which results in a clonally selected tumour. Other cancer cells arise to resist immunoediting, which leads to a tumour that includes several distinct cancer cell populations (referred to as intratumour heterogeneity (ITH)). Tumours with high ITH are associated with poor patient outcomes and a lack of responsiveness to immune checkpoint blockade therapy. In this Review, we discuss the different ways that cancer cells evade the immune system and how these mechanisms impact immunoediting and tumour evolution. We also describe how subclonal antigen presentation in tumours with high ITH can result in immune evasion.

Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, MA, USA. (2) Koch Institute for Integrative Cancer Research, Massachusetts In

Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, MA, USA. (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, MA, USA. spranger@mit.edu. Department of Biology, Massachusetts Institute for Technology, Cambridge, MA, USA. spranger@mit.edu. Ragon Institute of Mass General Hospital, Massachusetts Institute for Technology and Harvard, Cambridge, MA, USA. spranger@mit.edu.

Citation: Nat Rev Immunol 2025 Jan 2 Epub01/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39748116

ATLAS-seq: a microfluidic single-cell TCR screen for antigen-reactive TCRs

(1) Luo S (2) Notaro A (3) Lin L

Nature communications - Open Access

(1) Luo S (2) Notaro A (3) Lin L

Nature communications - Open Access

Discovering antigen-reactive T cell receptors (TCRs) is central to developing effective engineered T cell immunotherapies. However, the conventional technologies for isolating antigen-reactive TCRs (i.e., major histocompatibility complex (MHC) multimer staining) focus on high-affinity interactions between the TCR and MHC-antigen complex, and may fail to identify TCRs with high efficacy for activating T cells. Here, we develop a microfluidic single-cell screening method for antigen-reactive T cells named ATLAS-seq (Aptamer-based T Lymphocyte Activity Screening and SEQuencing). This technology isolates and characterizes activated T cells via an aptamer-based fluorescent molecular sensor, which monitors the cytotoxic cytokine IFN_ secretion from single T cells upon antigen stimulation, followed by single-cell RNA and single-cell TCR sequencing. We use ATLAS-seq to screen TCRs reactive to cytomegalovirus (CMV) or prostate specific antigen (PSA) from peripheral blood mononuclear cells (PBMCs). ATLAS-seq identifies distinct TCR clonotype populations with higher T cell activation levels compared to TCRs recovered by MHC multimer staining. Select TCR clonotypes from ATLAS-seq are more efficient in target cell killing than those from MHC multimer staining. Collectively, ATLAS-seq provides an efficient and broadly applicable technology to screen antigen-reactive TCRs for engineered T cell immunotherapy.

Author Info: (1) Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Center for Computational and Genomic Medicine, C

Author Info: (1) Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (2) Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (3) Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. linlan@chop.edu. Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. linlan@chop.edu. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. linlan@chop.edu.

Citation: Nat Commun 2025 Jan 2 16:216 Epub01/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39746936

Targeting macrophage circadian rhythms with microcurrent stimulation to activate cancer immunity through phagocytic defense

(1) Yoshida Y (2) Tanihara T (3) Hamasaki K (4) Tsurusaki F (5) Fukuda T (6) Adachi S (7) Terada Y (8) Otsuki K (9) Nishikawa N (10) Fukuoka K (11) Tsukamoto R (12) Hamamura K (13) Oyama K (14) Tsuruta A (15) Mayanagi K (16) Koyanagi S (17) Ohdo S (18) Matsunaga N

Theranostics - Open Access | Free PMC Article

Rationale: Macrophage phagocytosis plays a role in cancer immunotherapy. The phagocytic activity of macrophages, regulated by circadian clock genes, shows time-dependent variation. Intervening in the circadian clock machinery of macrophages is a potentially novel approach to cancer immunotherapy; however, data on this approach are scarce. Microcurrent stimulation (MCS) promotes inflammation, proliferation, and remodeling, suggesting its potential to modulate macrophage function; however, its application has been limited. In this study, we investigated the impact of MCS on macrophage phagocytosis of cancer cells using mouse/human macrophage cell lines and various mouse/human cancer cell lines. Methods: Cells and mice received 300 µA, 400 Hz bidirectional pulsed MCS. Gene expression, protein expression, and phagocytosis activity were assessed in intraperitoneal macrophages collected from mice, as well as in RAW264.7, and THP-1 cells. Flow cytometry, population, phagocytosis activity, RNA-seq, and immunohistochemistry analyses were performed. Results: Noninvasive MCS prevented time-dependent reduction in macrophage phagocytosis of cancer cells by modulating the circadian clock genes. MCS also enhanced phagocytosis in mouse RAW264.7 and human THP-1 cells across various cancer types by promoting actin polymerization; similar in vivo effects were observed in mice. This enhancement occurred in abdominal macrophages of both sexes and was mediated by changes in clock gene expression. Specifically, suppressing the clock gene Per1 nullified the effects of MCS. Moreover, although macrophage phagocytosis typically declined during the dark period, MCS during the light period prevented this reduction. MCS also increased phagocytosis of peritoneally implanted cancer cells (4T1, ID8, and Hepa1-6) in mice, significantly reducing tumor engraftment and growth, and ultimately improving prognosis. Conclusions: The findings of this study suggest that targeting macrophage circadian mechanisms via MCS could enhance cancer immunity, offering new avenues for cancer immunotherapy.

Author Info: (1) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (2) Department of Clinical P

Author Info: (1) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (2) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (3) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (4) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (5) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (6) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (7) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (8) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (9) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (10) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (11) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (12) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (13) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. (14) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (15) Department of Drug Discovery Structural Biology, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (16) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (17) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. (18) Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.

Citation: Theranostics 2025 15:340-361 Epub01/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39744689

Delivery of IL-12 by neoantigen-reactive T cells promotes antitumor immunity in murine osteosarcoma mode

(1) Tian C (2) Sun X (3) Zhu H (4) Zhou M (5) Chen Q (6) Min D (7) Huang Y (8) Han K

Immunotherapy advances - Open Access | Free PMC Article

(1) Tian C (2) Sun X (3) Zhu H (4) Zhou M (5) Chen Q (6) Min D (7) Huang Y (8) Han K

Immunotherapy advances - Open Access | Free PMC Article

PURPOSE: Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma. MATERIALS AND METHODS: We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells' antitumor activity and the production of IL-12 and IFN-_ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival. RESULTS: In vitro assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-_. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment. CONCLUSION: Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.

Author Info: (1) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (2) Department of Oncology, Shanghai Jiao Tong UniversityAffil

Author Info: (1) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (2) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (3) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (4) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (5) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (6) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China. (7) Department of Radiation Oncology, Tenth People's Hospital of Tongji University, Shanghai 200072, China. (8) Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China.

Citation: Immunother Adv 2025 5:ltae010 Epub11/28/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39742319

The efficacy of an embryonic stem cell-based vaccine for lung cancer prevention depends on the undifferentiated state of the stem cells

(1) Meng S (2) Whitt AG (3) Eaton JW (4) Yaddanapudi K (5) Li C

Scientific reports - Open Access | Free PMC Article

(1) Meng S (2) Whitt AG (3) Eaton JW (4) Yaddanapudi K (5) Li C

Scientific reports - Open Access | Free PMC Article

Based on the antigenic similarity between tumor cells and embryonic stem cells (ESCs), several recent studies report the use of intact murine ESCs or exosomes from murine ESCs as cancer vaccines. Since the capacity for self-renewal is one of the most specialized properties shared between ESCs and a subset of tumor cells, cancer stem cells (CSCs), we investigated whether the undifferentiated state of murine ESCs is essential for the prophylactic effectiveness of an ESC-based vaccine. The undifferentiated state of ES-D3, a murine ESC line, was essential for their anchorage-independent growth potential. Importantly, differentiation of ES-D3 cells decreased their efficacy in preventing the outgrowth of implanted lung tumors. Furthermore, the long-term cancer-preventive potential of this vaccine was also inhibited by the differentiation of these cells. To examine the antigenicity of the ESC-derived vaccine, we performed combined affinity chromatography shotgun immunoproteomic experiments to identify antigens specific to the whole-cell ES vaccine as well as to the ESC-derived exosome vaccine. Our data demonstrate that antibodies against several lung cancer-associated keratin members were enriched in the serum of vaccinated mice. In summary, these data suggest that the tumor-preventing efficacy of ESC-based vaccine is reliant on the differentiation properties of these stem cells.

Author Info: (1) Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, Universi

Author Info: (1) Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, USA. (2) Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, USA. (3) Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, USA. (4) Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA. kavitha.yaddanapudi@louisville.edu. Immuno-Oncology Program, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, USA. kavitha.yaddanapudi@louisville.edu. Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY, USA. kavitha.yaddanapudi@louisville.edu. (5) Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. chi.li@louisville.edu. Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, USA. chi.li@louisville.edu.

Citation: Sci Rep 2024 Dec 30 14:32127 Epub12/30/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39739089

Trogocytosis-mediated immune evasion in the tumor microenvironment

(1) Kim J (2) Park S (3) Kim J (4) Kim Y (5) Yoon HM (6) Rayhan BR (7) Jeong J (8) Bothwell ALM (9) Shin JH

Experimental & molecular medicine - Open Access

(1) Kim J (2) Park S (3) Kim J (4) Kim Y (5) Yoon HM (6) Rayhan BR (7) Jeong J (8) Bothwell ALM (9) Shin JH

Experimental & molecular medicine - Open Access

Trogocytosis is a dynamic cellular process characterized by the exchange of the plasma membrane and associated cytosol during cell-to-cell interactions. Unlike phagocytosis, this transfer maintains the surface localization of transferred membrane molecules. For example, CD4 T cells engaging with antigen-presenting cells undergo trogocytosis, which facilitates the transfer of antigen-loaded major histocompatibility complex (MHC) class II molecules from antigen-presenting cells to CD4 T cells. This transfer results in the formation of antigen-loaded MHC class II molecule-dressed CD4 T cells. These "dressed" CD4 T cells subsequently participate in antigen presentation to other CD4 T cells. Additionally, trogocytosis enables the acquisition of immune-regulatory molecules, such as CTLA-4 and Tim3, in recipient cells, thereby modulating their anti-tumor immunity. Concurrently, donor cells undergo plasma membrane loss, and substantial loss can trigger trogocytosis-mediated cell death, termed trogoptosis. This review aims to explore the trogocytosis-mediated transfer of immune regulatory molecules and their implications within the tumor microenvironment to elucidate the underlying mechanisms of immune evasion in cancers.

Author Info: (1) Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea. (2) Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea. (3) Integr

Author Info: (1) Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea. (2) Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea. (3) Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea. (4) Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea. (5) Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea. (6) Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea. (7) Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. (8) Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, 505 S. 45th Street, Omaha, NE, 68198, USA. albothwell@unmc.edu. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA. albothwell@unmc.edu. (9) Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea. jaehun.shin@yonsei.ac.kr. Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea. jaehun.shin@yonsei.ac.kr.

Citation: Exp Mol Med 2025 Jan 1 Epub01/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39741180

Vaccines targeting p53 mutants elicit anti-tumor immunity

(1) Chai D (2) Wang X (3) Fan C (4) Wang J (5) Lim JM (6) Yu X (7) Young KH (8) Li Y

Cancer letters

(1) Chai D (2) Wang X (3) Fan C (4) Wang J (5) Lim JM (6) Yu X (7) Young KH (8) Li Y

Cancer letters

The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8(+) T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c(+), CD103(+)CD11c(+), and CD8(+)CD11c(+) cells, which in turn promoted tumor-specific antibody production, as well as Th1 and CD8(+) T cell-mediated immune responses. Several antigenic epitopes of p53-S237G effectively stimulated multifunctional CD8(+) T cells to secrete IFN-_ and TNF-_. The vaccine showed long-term anti-tumor effects that were dependent on memory CD8(+) T cells. Furthermore, the anti-p53-S237G vaccine exhibited significant protective efficacy in the A20 liver metastasis models. When combined with PD-1 inhibition, the vaccine showed superior inhibition of tumor growth and liver metastasis. Targeting p53 mutants by vaccination represents a potential precision medicine strategy against cancers harboring p53 mutations.

Author Info: (1) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electroni

Author Info: (1) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: Dafei.Chai@bcm.edu. (2) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (3) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (4) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (5) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (6) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (7) Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC 27710, USA. (8) Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: Yong.Li@bcm.edu.

Citation: Cancer Lett 2024 Dec 29 217421 Epub12/29/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39740750

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