NO ABSTRACT
Author Info: -1
Author Info: -1
CD28-costimulated CD19 CAR-T cells for pediatric mature non-Hodgkin B-cell lymphoma
Children with relapsed or refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL) have a poor prognosis with approved therapies. Chimeric antigen receptor (CAR)-T cells are approved for adults with R/R B-NHL, but pediatric data is lacking. We report on 13 children with R/R mature B-NHL enrolled on a clinical trial for CD19 CAR-T cells harboring CD28 costimulation. Twelve patients were infused with CAR-T cells, and one had progressed and died prior to infusion. Toxicities included cytokine release syndrome in 8 patients and neurotoxicity in 6, including two patients with grade 4 neurotoxicity. All patients responded to CAR-T cells, including a complete response in 6, complete metabolic response in 2 and partial response in four. The median event-free survival was 15.2 months and median overall survival was not reached. Outcome differed by disease type, as most patients with primary mediastinal B-cell lymphoma had long term remissions, while only two of seven patients with Burkitt lymphoma were long term survivors. Thus, initial response may suffice for certain patients, but further consolidative strategies should be studied in patients with R/R Burkitt lymphoma.
Author Info: (1) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences,
Author Info: (1) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (2) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (3) Department of Pediatric Hematology-Oncology, Rambam Medical Center, and The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. (4) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. (5) Ella Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer, Israel. (6) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (7) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (8) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. elad.jacoby@sheba.health.gov.il. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. elad.jacoby@sheba.health.gov.il.
Exosome-based cancer vaccine: a cell-free approach
Despite advancements in medical research, cancer remains a significant and persistent cause of death globally. Cancer vaccine, a novel approach, holds immense promise in development of potentially effective cancer treatment. While the concept of developing cancer vaccines has been explored for decades, significant challenges have hindered their clinical translation. Recent researchers have introduced exosomes as the key element for novel cell-free approach of cancer vaccines. Exosomes are a type of extracellular vesicle (EVs) secreted by various cells. These tiny structures can transport and deliver important biomolecules, such as DNA, RNA, proteins, lipids, and immune-stimulatory molecules, to stimulate the body's anti-tumor immune response. Their biocompatibility, targeting ability, immunogenicity, and a notable capacity to cross biological barriers nominate them as promising candidates for cancer vaccine development by addressing current challenges in cancer therapy. This review explores the current state of knowledge on the efficacy of exosomes from various sources for personalized cancer vaccine development, preclinical and clinical evaluations, along with the strategies to optimize immunogenicity and antigen presentation. We also discuss the challenges and potential solutions for overcoming tumor microenvironment-related hurdles, highlighting the promise of exosome-based approaches for cancer immunotherapy by developing a novel cell-free cancer vaccine in future.
Author Info: (1) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (2) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharash
Author Info: (1) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (2) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (3) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (4) Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Subang Jaya, Selangor, 47500, Malaysia. vetris@sunway.edu.my.
Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein
Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.
Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US
Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (3) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (4) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (5) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (6) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. (7) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. Max Planck Institute for the Science of Light, Erlangen, Germany. (8) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (9) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (10) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (11) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (12) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (13) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (14) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (15) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (16) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (17) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (18) Max Planck Institute for the Science of Light, Erlangen, Germany. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (21) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (22) Department of Haematology, University of Cambridge, Cambridge, UK. (23) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (24) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. (25) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (26) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (27) Max Planck Institute for the Science of Light, Erlangen, Germany. Faculty of Medicine 1, Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Faculty of Sciences, Department of Physics, Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (28) Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (29) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. ryan.flynn@childrens.harvard.edu. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. (30) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Department of Haematology, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Wellcome Trust Sanger Institute, Hinxton, UK. kt404@cam.ac.uk.
Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity
Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA. (3) Stanford Institute for Immunity, Trans
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA. (3) Stanford Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. (4) Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA. (6) ImmunEdge Inc., Mountain View, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA. (8) Department of Pathology, Stanford University, Stanford, CA, USA. (9) Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA. (10) Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA. (11) Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, CA, USA. (12) Department of Radiation Oncology, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA.
Glioblastoma Cell Lysate and Adjuvant Nanovaccines via Strategic Vaccination Completely Regress Established Murine Tumors
Tumor vaccines have shown great promise for treating various malignancies; however, glioblastoma (GBM), characterized by its immunosuppressive tumor microenvironment, high heterogeneity, and limited accessibility, has achieved only modest clinical benefits. Here, it is reported that GBM cell lysate nanovaccines boosted with TLR9 agonist CpG ODN (GlioVac) via a strategic vaccination regimen achieve complete regression of malignant murine GBM tumors. Subcutaneous administration of GlioVac promotes uptake by cervical lymph nodes and antigen presentation cells, bolstering antigen cross-presentation and infiltration of GBM-specific CD8(+) T cells into the tumor. Notably, a regimen involving two subcutaneous and three intravenous vaccinations not only activates systemic anti-GBM immunity but also further enhances the tumor infiltration of cytotoxic T lymphocytes, effectively reshaping the "cold" GBM tumor into a "hot" tumor. This approach led to a state of tumor-free survival in 5 out of 7 mice bearing the established GL261 GBM model with complete protection from tumor rechallenge. In an orthotopic hRas-GBM model induced by a lentiviral plasmid, GlioVac resulted in Å100% complete tumor regression. These findings suggest that GlioVac provides a personalized therapeutic vaccine strategy for glioblastoma.
Author Info: (1) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow Univers
Author Info: (1) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (2) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (3) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (4) College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (5) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (6) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (7) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (8) College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (9) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (10) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China.
A dissolvable microneedle platform for the delivery of tumor-derived total RNA nanovaccines for enhanced tumor immunotherapy
Tumor-derived total RNA (TdRNA) vaccines induce broad immune responses by either synthesizing tumor-specific antigens or activating pattern recognition receptors, making them a promising tool in cancer immunotherapy for the activation of cytotoxic T lymphocytes (CTLs). However, TdRNA vaccines face issues such as low stability and inadequate immune activation. To overcome these challenges, we have developed a dissolvable microneedle delivery platform, PTC NVs@MNs, designed for the simultaneous delivery of TdRNA and CpG oligodeoxynucleotides (CpG ODN). This platform stabilizes TdRNA, maintaining its activity for up to 30 days at room temperature and promotes dendritic cell maturation and then activates T lymphocyte-mediated antitumor immunity through the targeted delivery of TdRNA and CpG. PTC NVs@MNs not only enhance dendritic cell maturation and increase CD8(+) T cell infiltration into tumors, eliciting robust antitumor immune responses that inhibit tumor growth in mice, but also induce antitumor immune memory to prevent tumor development. This innovative approach offers therapeutic and preventive benefits in tumor management. STATEMENT OF SIGNIFICANCE: Tumor-derived total RNA (TdRNA) holds potential for eliciting a broad immune response; however, its therapeutic efficacy against triple-negative breast cancer (TNBC) is constrained by low stability and inadequate immune activation. To overcome these limitations, we engineered a dissolving microneedle patch for transdermal co-delivery of TdRNA and CpG oligodeoxynucleotides (CpG ODN). This system not only stabilizes TdRNA-maintaining its bioactivity for 30 days at room temperature-but also promotes dendritic cell maturation and activates T lymphocyte-mediated antitumor immunity via targeted delivery of both components. This study demonstrated that the well-designed microneedle patch effectively prevents RNA degradation without requiring stringent storage conditions, offering both therapeutic and preventive benefits in tumor management.
Author Info: (1) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (2) PCFM Lab of Ministry of Education, Sc
Author Info: (1) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (2) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (3) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (4) Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. (5) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (6) Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. Electronic address: xiaozc5@mail.sysu.edu.cn. (7) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China; Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. Electronic address: shuaixt@mail.sysu.edu.cn.
Immunogenicity and Safety Profile of Two Adjuvanted-PD-L1-Based Vaccine Candidates in Mice, Rats, Rabbits, and Cynomolgus Monkeys
BACKGROUND: The therapeutic blockade of the PD1/PD-L1 axis with monoclonal antibodies has led to a breakthrough in cancer treatment, as it plays a key role in the immune evasion of tumors. Nevertheless, treating patients with cancer with vaccines that stimulate a targeted immune response is another attractive approach for which few side effects have been observed in combination immunotherapy clinical trials. In this sense, our group has recently developed a therapeutic cancer vaccine candidate called PKPD-L1(Vac) which contains as an antigen the extracellular domain of human PD-L1 fused to a 47 amino-terminal, part of the LpdA gene of N. meningitides, which is produced in E. coli. The investigation of potential toxicities associated with PD-L1 blockade by a new therapy in preclinical studies is critical to optimizing the efficacy and safety of that new therapy. METHODS: Here, we describe immunogenicity and preliminary safety studies in mice, rats, rabbits, and non-human primates that make use of a 200 _g dose of PKPD-L1 in combination with VSSPs or alum phosphate to contribute to the assessment of potential adverse events that are relevant to the future clinical development program of this novel candidate. RESULTS: The administration of PKPD-L1(Vac) to the four species at the doses studied was immunogenic and did not result in behavioral, clinical, hematological, or serum biochemical changes. CONCLUSIONS: Therefore, PKPD-L1(Vac) could be considered suitable for further complex toxicological studies and the way for its clinical evaluation in humans has been opened.
Author Info: (1) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (2) Center for Genetic Engineering and Biotechnology (CIGB), P.O. B
Author Info: (1) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (2) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (3) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (4) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (5) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (6) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (7) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (8) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (9) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba. (10) CONAHCYT-Innovation and Development Promotion Direction, Centro de Investigacin Cientfica y Educacin Superior de Ensenada (CICESE), Ensenada 22860, Mexico. (11) Biomedical Innovation Department, Centro de Investigacin Cientfica y Educacin Superior de Ensenada (CICESE), Ensenada 22860, Mexico. (12) Biomedical Innovation Department, Centro de Investigacin Cientfica y Educacin Superior de Ensenada (CICESE), Ensenada 22860, Mexico. (13) Center for Genetic Engineering and Biotechnology (CIGB), P.O. Box 6162, Playa Cubanacn, Havana 10600, Cuba.
CLN-619, a MICA/B monoclonal antibody that promotes innate immune cell-mediated antitumor activity
BACKGROUND: Major histocompatibility complex class I-related protein A and B (MICA/B) are ligands for the natural killer group 2 member D (NKG2D) receptor and are broadly expressed on tumor cells but minimally on normal tissues. When cytotoxic NKG2D-expressing immune cells engage MICA/B, the ligand-expressing cells are targeted for lysis. Cancer cells can evade NKG2D-mediated destruction by shedding MICA/B from their cell surface via proteases present in the tumor microenvironment. CLN-619 is a humanized IgG1 monoclonal antibody (mAb) which binds MICA/B and inhibits shedding resulting in accumulation of MICA/B on the tumor cell surface. CLN-619 may thereby have therapeutic effects in a broad range of malignancies by re-establishing the MICA/B-NKG2D axis to enable NKG2D-mediated, as well as Fc-gamma receptor-mediated, tumor cell lysis. METHODS: CLN-619 was characterized for binding epitope and affinity, effects on surface and soluble levels of MICA/B, and in vitro tumor cell killing. In mouse models, the mAb was tested for tumor growth inhibition. The contribution of the Fc-gamma (Fc_) 1 domain to CLN-619 activity was also assessed. RESULTS: CLN-619 bound with high affinity to the alpha-3 domain of MICA/B without encumbering the interaction with NKG2D on natural killer cells. CLN-619 increased the level of cell surface expression of MICA/B and concomitantly decreased the levels of soluble MICA/B in cell culture assays. Treatment of cancer cell lines with CLN-619 induced antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. CLN-619 resulted in potent inhibition of tumor growth in multiple xenograft models and increased survival of mice in a disseminated cancer model. CONCLUSIONS: CLN-619 inhibited the shedding of MICA/B to effectively restore cytotoxic signaling pathways in immune cells. Potent antitumor activity of CLN-619 as a monotherapy was observed in several preclinical models. Activity of CLN-619 required a functional Fc_1 domain, suggesting the requirement of simultaneous engagement of NKG2D and cluster of differentiation 16A (CD16A) on immune cells for optimal cytotoxicity. The preclinical data reported here support the assessment of CLN-619 in patients with cancer.
Author Info: (1) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA kwhalen@cullinantx.com. (2) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (3) Cullinan Therapeutics Inc, Ca
Author Info: (1) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA kwhalen@cullinantx.com. (2) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (3) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (4) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (5) PDI Therapeutics, San Diego, California, USA. (6) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (7) PDI Therapeutics, San Diego, California, USA. (8) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA. (9) Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA.
Plasticity of tumor cell immunogenicity: is it druggable
This short perspective presents, at a high level, some observations and speculations about cancer immunotherapy that derive from experiences at the Dana-Farber Cancer Institute and the Novartis Institutes of Biomedical Research.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA glenn_dranoff@dfci.harvard.edu.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA glenn_dranoff@dfci.harvard.edu.
