Optimizing cell therapy against tumors is a balancing ACT
Adoptive cell transfer (ACT) therapy is used to treat patients with metastatic solid tumors. ACT involves the removal of some of the patient's cancer cells, and some of their immune T cells. When the cells are mixed together, specific parts of the cancer cells that stimulate the T cells to cause an immune attack can be identified. The T cells get expanded and re-infused into the patient to mount an immunological, anti-cancer response against the tumors. One of the challenges faced is selecting the appropriate T cells with proper antigen specificity.
In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Nicholas Restifo and colleagues identified which cells are optimal for treating large, vascularized, established tumors. The authors use a mouse model that mimics the human clinical situation. They find that phenotypic and functional qualities of T cells are associated with the ability of ACT to cause regression of large, established melanomas. Seemingly paradoxical, naïve and early effector T cells are more effective for tumor treatment than more differentiated T cells.
In an accompanying commentary, Daniel Speiser and Pedro Romero write, "optimal therapeutic efficacy may depend on different T cell selection and preparation strategies" and these findings indicate that a pragmatic strategy for ACT is to keep the in vitro T cell expansion phase as short as possible to keep them naïve. These findings are important for development of improved adoptive immunotherapy approaches for treating tumors and established infectious diseases.
TITLE: Acquisition of full effector function in vitro paradoxically impairs the in vivo anti-tumor efficacy of adoptively transferred CD8+ T cells
AUTHOR CONTACT:
Nicholas P. Restifo
NIH - National Cancer Institute, Bethesda, MD USA
Phone: 301-496-4904; Fax: 301-496-0011; E-mail: restifo@nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=24480
ACCOMPANYING COMMENTARY:
TITLE: Towards improved immunocompetence of adoptively transferred CD8+ T cells
AUTHOR CONTACT:
Pedro Romero
Ludwig Institute for Cancer Research, Lausanne, Switzerland
Phone: 4121 314 0198; Fax: +41 21 314 74 77; E-mail: pedro.romero@isrec.unil.ch
View the PDF of this article at: https://www.the-jci.org/article.php?id=25427
EDITORS' PICK
Eleven gene signature that predicts cancer prognosis
The rather new concept of "tumor stem cells" maintains that a rare, stem cell-like population of cancer cells exists among the mix of other cells found in a tumor and that these tumor stem cells are responsible for tumor progression and metastasis. In a revolutionary study appearing in the June 1 print issue of The Journal of Clinical Investigation, Gennadi Glinsky and colleagues from the Sidney Kimmel Cancer Center evaluated 1122 cancer patients diagnosed with 10 different types of cancer.
The researchers used genetic approaches to identify an 11-gene BMI-1-pathway signature, which determines normal stem cell proliferation and which also consistently displays a stem cell-like expression profile in metastatic tumors in a mouse cancer model as well as metastatic tumors from prostate cancer patients. The results show that a stem cell-like expression profile of the 11-gene signature in primary tumors is a consistent and powerful predictor of a short interval to disease recurrence, metastasis, and death after therapy in cancer patients diagnosed with ten distinct types of cancer.
This work indicates that the presence of the conserved BMI-1-associated gene expression pathway that exists in a very malignant subset of human cancers predicts a marked predisposition toward metastasis and a high probability of poor therapy outcome. In an accompanying commentary, Gordon Mills and others write, "such a "magic marker" [will] have a major impact on patient care."
TITLE: Microarray analysis identifies a death from cancer signature predicting therapy failure in patients with multiple types of cancer
AUTHOR CONTACT:
Gennadi Glinsky
Sidney Kimmel Cancer Center, San Diego, CA USA
Phone: 858-4505990; Fax: 858-623-2740; E-mail: gglinsky@skcc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=23412
ACCOMPANYING COMMENTARY:
TITLE: Stem cell–ness: a "magic marker" for cancer
AUTHOR CONTACT:
Gordon Mills
U.T.M.D. Anderson Cancer Center, Houston, TX USA
Phone: 713-563-4200; Fax: 713-745-1184; E-mail: gmills@mdanderson.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25455
ONCOLOGY
Leukemia prognosis predicted with HS1
Chronic lymphocytic leukemia (CLL) is an adult malignancy that occurs when B cells expand uncontrollably. In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Federico Caligaris-Cappio and colleagues identified molecules involved in CLL pathogenesis. Using a proteomic approach, the authors compared CLL patients based on their clinical course and prognosis. They found that the two groups of patients (poor prognosis or good prognosis) had differential expression of a protein called HS1. HS1 in the patients with poor prognosis was phosphorylated, whereas only a small portion of the patients with good prognosis had phosphorylated HS1. Thus, HS1 protein and its functional status may discriminate between good and bad prognosis in patients. Given that HS1 is involved in B cell receptor signaling, its differential phosphorylation in the two patients groups provides new insights in the pathogenesis of CLL.
TITLE: HS1 protein, a target of B-cell-receptor signaling, is differentially expressed in chronic lymphocytic leukemia subsets
AUTHOR CONTACT:
Federico Caligaris-Cappio
Università Vita-Salute San Raffaele, Milan, Italy
Phone: 39-02-2643-2390; Fax: 39-02-2641-0154; E-mail: caligaris.federico@hsr.it
View the PDF of this article at: https://www.the-jci.org/article.php?id=24276
PHYSIOLOGY
Taming tuberculosis
In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Julio Aliberti and colleagues from Duke University document a novel pathway involved in modulation of resistance to infection with Mycobacterium Tuberculosis. The authors found that lipoxins regulate the development of an immune response and resistance to experimental infection with M. tuberculosis in mice.
In an accompanying commentary, Christopher Karp and Andrea Cooper write, "the study raises the possibility that pharmacological inhibition of lipoxin synthesis may provide a method of augmenting inefficient immune responses in TB and other important chronic infectious diseases."
TITLE: Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production
AUTHOR CONTACT:
Julio Aliberti
Duke University Medical Center, Durham, NC USA
Phone: 919-613-7833; Fax: 919-684-8982; E-mail: julio.aliberti@duke.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23949
ACCOMPANYING COMMENTARY:
TITLE: An oily, sustained counter-regulatory response to TB
AUTHOR CONTACT:
Christopher L. Karp
Children's Hospital Research Foundation, Cincinnati, OH USA
Phone: 513-636-7608; Fax: 513-636-5355; E-mail: chris.karp@chmcc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25353
PHYSIOLOGY
New mouse to monitor plasma volume and blood pressure
The heart maintains arterial blood pressure by secreting a hormone called ANP. In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Michaela Kuhn and colleagues from University of Muenster generated mice with a selective deletion of the ANP receptor, called GC-A, in endothelial cells in order to dissociate the endothelial functions of the ANP/GC-A system from other endocrine cardiovascular functions of the ANP/GC-A system. The endothelial functions of ANP were unknown.
The authors show that the vascular endothelium is critically involved in the actions of ANP and blood volume. In an accompanying commentary, Fitz-Roy Curry writes, "the elegant study…points the way to important new experiments and approaches for investigating in what way defects in ANP-dependent mechanisms regulating endothelial permeability may contribute to development of cardiovascular disease, including hypertension."
TITLE: Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide.
AUTHOR CONTACT:
Michaela Kuhn
University of Muenster, Muenster, Germany
Phone: 011 49 251 83 52597; Fax: 011 49 251 83 55501; E-mail: mkuhn@uni-muenster.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=23360
ACCOMPANYING COMMENTARY:
TITLE: Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume
AUTHOR CONTACT:
Fitz-Roy Curry
University of California Davis, Davis, CA USA
Phone: 530-752-7081; Fax: 530-752-5423; E-mail: fecurry@ucdavis.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25417
PHYSIOLOGY
Survivin' pulmonary arterial hypertension
Pulmonary Arterial Hypertension (PAH) is a pulmonary vascular disease characterized by proliferation of the blood vessels in the lung, leading to heart failure and death within a few years from diagnosis. The few available treatments are associated with significant toxicity and are not especially effective.
In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Evangelos Michelakis and colleagues from University of Alberta have identified a protein called survivin as a potential therapeutic target in PAH. The authors show that increased survivin may contribute to PAH by inhibiting mitochondria-dependent apoptosis. The authors show that patients with PAH express survivin in arteries in the lung. Gene therapy using an inhaled adenovirus that blocks survivin prolongs survival of rats with PAH by 25%.
In an accompanying commentary, Serge Adnot writes, "Until now, alterations in apoptotic processes have not been considered to play a role in [PAH]…These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies."
TITLE: Gene therapy targeting survivin induces pulmonary vascular apoptosis and reverses established pulmonary arterial hypertension
AUTHOR CONTACT:
Evangelos D. Michelakis
University of Alberta, Edmonton, Canada
Phone: 780-407-1576; Fax: 780-407-6032; E-mail: emichela@cha.ab.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=23203
ACCOMPANYING COMMENTARY:
TITLE: Lessons learned from cancer may help treat pulmonary hypertension
AUTHOR CONTACT:
Serge Adnot
INSERM, Creteil, France
Phone: +33 1 48 98 4603; Fax: +33 1 48 98 1777; E-mail: serge.adnot@hmn.ap-hop-paris.fr
View the PDF of this article at: https://www.the-jci.org/article.php?id=25399
PHYSIOLOGY
Chronic disease body wasting due to loss of appetite
Cachexia, the loss of body weight and muscle mass, is common in patients with chronic illnesses and contributes to mortality in patients with chronic kidney disease. These patients develop uremia, abnormally high levels of waste products in the blood, and often suffer from cachexia, but it was not clear why. In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Robert Mak and colleagues from Oregon Health and Science University investigate the role of hypothalamic melanocortin system, an essential regulator of food intake and energy balance, in the pathogenesis of uremia-associated cachexia.
The authors show that mice lacking melanocortin-4-receptor and mice treated with melanocortin blockers resist the cachexic effects of uremia on weight gain, body composition and metabolic rate. Therefore, kidney disease cachexia is caused by defective brain regulation of appetite. These observations may lead to novel therapies for the cachexia syndrome in patients with chronic kidney disease.
In an associated commentary, William Mitch writes that "the development of molecules capable of preventing these regulatory abnormalities holds the promise of eliminating the contribution of anorexia to the development of cachexia."
TITLE: Role of leptin and melanocortin signaling in uremia-associated cachexia
AUTHOR CONTACT:
Robert Mak
Oregon Health & Science University, Portland, OR USA
Phone: 503-494-7564; Fax: 503-494-0428; E-mail: makr@ohsu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=22521
ACCOMPANYING COMMENTARY:
TITLE: Cachexia in chronic kidney disease: a link to defective central nervous system control of appetite
AUTHOR CONTACT:
William E. Mitch
University of Texas, Galveston, TX USA
Phone: 409-772-9891; Fax: 409-772-8762; E-mail: wmitch@utmb.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25255
PHYSIOLOGY
Drawing blood from red cell disorders
Erythropoietic protoporphyria (EPP) and beta-thalassemia are two types of inherited red blood cell disorders. In a new study appearing in the June 1 print issue of The Journal of Clinical Investigation, Jane-Jane Chen and colleagues from MIT demonstrate a protective role of a protein called HRI, which had never previously been shown to play a role in any known human disease, in these red cell disorders. In both diseases, HRI deficiency worsens EPP and beta-thalassemia, while HRI itself decreases disease severity in mice, by reducing the amount of a protein called alpha globin, which has toxic effects.
In an accompanying commentary, Arthur Banks writes, "New insights into the mechanisms of globin regulation, such as those [here] may eventually lead to new, more rational treatments for patients with beta-thalassemia."
TITLE: Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia
AUTHOR CONTACT:
Jane-Jane Chen
Massachusetts Institute of Technology, Cambridge, MA USA
Phone: 617-253-9674; Fax: 617-253-3459; E-mail: j-jchen@mit.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24141
ACCOMPANYING COMMENTARY:
TITLE: Understanding globin regulation in beta thalassemia: it's as simple as alpha, beta, gamma, delta
AUTHOR CONTACT:
Arthur Bank
Columbia University, New York, NY USA
Phone: 212-305-4186; Fax: 212-923-2090; E-mail: ab13@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25398
Journal
Journal of Clinical Investigation