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.
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.
Dendritic Cell Cancer Vaccines: Clinical Production for Cancer Immunotherapy
Dendritic cell (DC) cancer vaccines are used to circumvent the problem that DCs in patients with cancer usually do not mature properly in the cancer environment. Peripheral DCs are fewer in number and hard to isolate cleanly. Instead, autologous DCs can be matured from monocyte precursors obtained by apheresis and elutriation from peripheral blood. Here, we describe procedures for harvesting cells, growing them into DCs, inducing antigen expression by pulsing them with antigenic peptides or inducing antigen expression by transducing them with antigens expressed by a recombinant adenovirus (or other viral vector), maturing them in vitro, and then administering them to patients.
Author Info: (1) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hoyoung.maeng@nih.gov. (2) Vaccine Branch, Center for C
Author Info: (1) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hoyoung.maeng@nih.gov. (2) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (4) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (5) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (6) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies
Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROS(low) B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROS(low) cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.
Author Info: (1) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. domizi@stanford.edu. (2) Department of P
Author Info: (1) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. domizi@stanford.edu. (2) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. School of Medicine and Surgery, University of Milano-Bicocca, 20126, Milan, Italy. (3) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. (4) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. (5) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (6) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. (9) Department of Pathology, Stanford University, Stanford, CA, USA. (10) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (11) Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (12) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA. (14) Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. (15) Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (16) Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (17) Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (18) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (21) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (23) Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Kite Pharma, Santa Monica, CA, USA. (25) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (26) Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. kardavis@stanford.edu. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. kardavis@stanford.edu.
Intrinsic properties of the lymph node render it immunologically susceptible to metastasis
Lymph nodes (LNs) are the staging grounds for anti-tumor immunity, therefore their high susceptibility to metastatic colonization is a paradox. Previous studies have suggested that extrinsic tumor-derived factors precondition the draining LN to enable tumor cell survival by promoting a state of immune suppression. Here, we investigate whether properties of the LN itself may impede its ability to clear metastasizing tumor cells. Using multiple immunocompetent transplant models, we show that LNs possess intrinsic features, independent of preconditioning, which make them an advantageous site for tumor cells to evade T cell control. Tumor growth in the LN is facilitated by regulatory T cells, which locally suppress the cytolytic capacity of tumor-specific CD8 T cells by restricting IL-2. These findings identify an intrinsic mechanism that contributes to the high rate of LN metastasis in solid tumors.
Author Info: (1) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (2) Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States. (3) University
Author Info: (1) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (2) Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States. (3) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (4) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (5) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (6) Qilu Hospital of Shandong University, Jinan, China. (7) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (8) Huazhong University of Science and Technology, Wuhan, China. (9) Memorial Sloan Kettering Cancer Center, New York, NY, United States. (10) University of Pennsylvania, Philadelphia, Pennsylvania, United States.
CTLA-4-two pathways to anti-tumour immunity
Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1, and LAG-3. Despite their success, efficacy, and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by the identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICIs affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to the complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is a direct enhancement of effector T-cell responses through simple blockade of CTLA-4-'releasing the brakes', while the second requires prior elimination of regulatory T cells (T(REG)) to allow emergence of T-cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.
Author Info: (1) Medical Sciences and Nutrition, Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom. (2) Department of Pharmacology and Therapeu
Author Info: (1) Medical Sciences and Nutrition, Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom. (2) Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom. (3) Medical Sciences and Nutrition, Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom. (4) Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom. (5) Medical Sciences and Nutrition, Institute of Dentistry, School of Medicine, Sciences & Nutrition, University of Aberdeen, Aberdeen, United Kingdom. School of Dentistry, College of Medicine and Health, The University of Birmingham, Birmingham, United Kingdom.
Dendritic Cell Cancer Vaccines: A Focused Review
Dendritic cells (DCs) are the most potent professional antigen-presenting cells to activate both CD4+ and CD8+ T lymphocytes. When immature, they take up and process antigens efficiently. When mature, they express high levels of MHC class I and II molecules and costimulatory molecules on their surface and secrete both IL-12 and IL-15 that can activate and steer T cells. However, in patients with cancer or tumor-bearing animals, cancers secrete cytokines that suppress DC development or maturation. To circumvent this barrier to immunization against cancer, strategies have been developed to grow and mature DCs ex vivo from precursors, such as peripheral blood monocytes or bone marrow precursors, induce expression of tumor antigens ex vivo, and then administer the autologous DCs to the patient as a vaccine. The DCs may be coated with synthetic antigenic peptides or transduced with a virus expressing the tumor antigen (see Note 1). Both of these have been used in early clinical trials with promising immunogenicity. Such cancer vaccines may be especially critical for "cold" tumors that do not induce a sufficient immune response by themselves to be amenable to checkpoint inhibitor therapy or blockade of other negative regulators of immunity but with a cancer vaccine to induce the immune response, may become responsive to such immunotherapies. Conversely, cancer vaccines should become more effective if immunosuppressive mechanisms are blocked. Thus, the two approaches should synergize to optimize anticancer immune responses and reject the cancer like an allogeneic organ transplant.
Author Info: (1) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hoyoung.maeng@nih.gov. (2) Vaccine Branch, Center for C
Author Info: (1) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hoyoung.maeng@nih.gov. (2) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (4) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (5) Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD, USA. (6) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
