Research Articles
Background
Cancers produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. We studied cytokine production by helper T cells responding to vaccination with 6 melanoma helper peptides (6MHP) in blood and lymph nodes.
Methods
Twenty-three patients with stage IIIB-IV melanoma received a 6MHP vaccine. Antigenreactive T cells from blood and draining lymph nodes were cultured, exposed to antigen, and then supernatants (days 2 and 5) were assayed for Th1 and Th2 cytokines. Results from 4 time points were compared to pre-vaccine levels.
Results
Cytokine responses to vaccinating peptides were observed in 83% of patients. Th1 favoring responses were most common (17 of 19 responders). The most abundant cytokines produced were IFN-γ and IL-5 in the PBMC’s. IL-2 responses predominated in cells obtained from draining lymph nodes in 2-day culture but not in 5-day cultures. Patients with clinically measurable disease produced similar levels of total cytokine and similar degree of Th1 polarization as patients with no evidence of disease (NED).
Conclusions
The MHC class II-associated peptides used in this study induced helper T cells with a Th1-biased cytokine response in both PBMC and sentinel immunized nodes. Most patients can mount a Th1 dominant response to these peptides. Future studies are needed to test newer vaccine adjuvants in combination with these peptides.
Trial registration
CDR0000378171, Clinicaltrials: NCT00089219.
From the Authors
"This evaluation of helper peptides from a melanoma vaccine clinical trial offers a timely look at cytokine polarization in blood and vaccinated lymph nodes," said Dr. Patrick Dillon.
To access the full article, please click here.
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The Indoleamine 2,3-Dioxygenase Pathway Controls Complement-Dependent Enhancement of Chemo-Radiation Therapy Against Murine Glioblastoma
Minghui Li, Aaron R Bolduc, Md Nasrul Hoda, Denise N Gamble, Sarah-Bianca Dolisca, Anna K Bolduc, Kelly Hoang, Claire Ashley, David McCall, Amyn M Rojiani, Bernard L Maria, Olivier Rixe, Tobey J MacDonald, Peter S Heeger, Andrew L Mellor, David H Munn and Theodore S Johnson
Journal for ImmunoTherapy of Cancer 2014, 2:21 (7 July 2014) |
Background
Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction.
Methods
To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy.
Results
Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival.
Conclusions
Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation 3 and protects itself from immune-mediated tumor destruction.
From the Authors
“Our work addresses the long-standing question concerning the role of complement within the tumor microenvironment," said Dr. Theodore S. Johnson. "To our knowledge, this is the first report demonstrating a previously unsuspected mechanistic link between indoleamine 2,3-dioxygenase (IDO) and complement in tumor microenvironments, and implicating complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade. This may represent a fundamental pathway for regulating tumor vasculature and immune-mediated tumor destruction.”
To access the full article, please click here.
Review Articles
Abstract
The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are “oncogene addicted.” Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4+ helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits “oncogene withdrawal.” Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.
From the Authors
"We describe how therapeutic oncogene inactivation may contribute to sustained tumor regression through the activation of an immune response," said Dr. Stephanie C. Casey. "This mechanism could have implications for the development of therapies that combine oncogene inactivation with immune therapy for the treatment of cancer."
To access the full article, please click here.
Review Commentary
May 8, 2014
Dear Dr. Romero,
We read with interest the work by Olin and collaborators published in the Journal for ImmunoTherapy of Cancer under the title “Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4 + IL17+ response” [1]. Immune therapy trials for malignant brain tumors are challenging to undertake and there are many factors, including the high expense per patient which limits the number of patients enrolled, hence curtailing the ability to demonstrate that the intervention improves clinical outcomes. Furthermore, the baseline immune competence of patients with gliomas is heterogeneous and is an important variable in determining who will benefit from this therapeutic modality. Assessment of immune markers before treatment with immunotherapy which could reliably predict response is highly desirable, since patients unlikely to benefit could be considered for alternate clinical trials.
Profiling the immune cell populations in peripheral blood by flow cytometry is a potentially useful tool, and hierarchical clustering analysis of the multiple cell populations measured may provide a distinct and comprehensive overview of the immune status [2]. Olin et al. use this methodology to separate patients with brain tumors who had stable or progressive disease after being treated with dendritic cells loaded with allogeneic tumor. We would like to bring to the attention of the authors and readership that in our 2011 publication, we applied hierarchical clustering to functional immune assay measures of antigen specific response to treatment with autologous tumor lysate loaded DC vaccination in a cohort of glioblastoma patients [3]. The shift of immune response measures discerned 2 groups of patients that correlated with survival.
Successful use of hierarchical clustering analysis of multiple immune measures as a prognostic and predictive marker in patients with gliomas first reported by us and confirmed by Olin et al., serves as a proof of principle. A substantially larger study using supervised classification techniques to identify the key prognostic factors, will allow validation of a prediction system. Integrated biomarkers that are able to more accurately and reliably quantify immune competence are needed to be able to do clinical trials enriched for individuals likely to benefit from immune therapy.
Sincerely,
Camilo E. Fadul, MD
Jan L. Fisher, MS
Thomas H. Hampton, MS
Marc S. Ernstoff, MD
To access the full article with references, please click here.
Last Month for JITC Best Paper Award Eligibility
The JITC Best Clinical Application Paper and the JITC Best Basic Science Paper Award will celebrate excellence in scientific research and be awarded to researchers demonstrating leadership in the field as well as innovation and high-quality execution and discussion in their manuscripts. All articles published in JITC from the journal's inception through August 19, 2014 will be eligible to win a JITC Best Paper Award.
Award winners will be announced and highlighted at the SITC 2014 Annual Meeting & Associated Programs in National Harbor, MD from November 6-9, 2014. Along with their $1,000 prize, recipients will also be featured in multiple Society outlets and networks.
Eligible articles must be original research authored by a SITC member. SITC members, don’t forget to contact the SITC office for your membership code to receive waived article processing charges when you submit your research.
For more information regarding the SITC Best Paper Awards please visit http://www.sitcancer.org/journal or contact info@sitcancer.org.
Highly Accessed Article Update
Below are the highly accessed research articles published in the month of June:
 Optimizing Immune-Related Tumor Response Assessment: Does Reducing the Number of Lesions Impact Response Assessment in Melanoma Patients Treated with Ipilimumab?
Nishino M, Gargano M, Suda M, Ramaiya NH and Hodi FS Journal for ImmunoTherapy of Cancer 2014, 2:17 (18 June 2014)
A Phase 2, Single-Arm Study of an Autologous Dendritic Cell Treatment Against Mucin 1 in Patients with Advanced Epithelial Ovarian Cancer
Mitchell PLR, Quinn MA, Grant PT, Allen DG, Jobling TW, White SC, Zhao A, Karanikas V et al. Journal for ImmunoTherapy of Cancer 2014, 2:16 (18 June 2014)
Waived Article Processing Charges for SITC Members
SITC members – Don’t forget to take advantage of waived article processing charges when you submit your research to JITC through 2014 (a $2,400 USD savings). For your membership code, please contact the SITC office at +1(414) 271-2456.
Need to renew your membership dues for 2014 or become a SITC Member to take advantage of this benefit? Simply click here.
Submit your Research to JITC!
SITC Members and non-members alike are invited to submit their manuscript in the following categories:
- Basic Tumor Immunology
Section Editor: Cornelis J.M. Melief, MD, PhD - ISA Therapeutics BV
Topics Include: tumor antigens, innate and adaptive anti-tumor immune mechanisms, immune regulation, immune response, cancer and inflammation, preclinical models, chemotherapy and radiotherapy interactions with the anti-tumor immune response, oncolytic viruses
- Case Reports
Section Editor: F. Stephen Hodi, Jr., MD - Dana-Farber Cancer Institute
Topics Include: unusual or unexpected clinical cases that expand the field of general medical knowledge
- Clinical/Translational Cancer Immunotherapy
Section Editor: Walter J. Urba, MD, PhD - Earle A. Chiles Research Institute
Topics Include: first in man clinical trials, phase II/III clinical studies, immune monitoring investigations, tumor microenvironment, host genetics and clinical outcome, updates on clinical trials
- Immunotherapy Biomarkers:
Section Editor: Lisa H. Butterfield, PhD - University of Pittsburgh Cancer Institute
Topics Include: predictive/prognostic biomarker studies, gene expression studies in cancer immunotherapy, serological immune biomarkers, multiparameter flow cytometry-defined immune biomarkers, high content immunohistological studies
- Reviews/Editorials:
Section Editors: Bernard A. Fox, PhD - Earle A. Chiles Research Institute and Thomas F. Gajewski, MD, PhD - University of Chicago
Topics include: discussion on hot topics and innovative concepts
JITC Editor-in-Chief
Pedro J. Romero, MD - Ludwig Center for Cancer Research
To submit your research visit: www.sitcancer.org/journal.
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