Objective To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.

Objective To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.

Objective. To provide guidance to rheumatology providers on the use of coronavirus disease 2019 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).Methods. A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings.Results. Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination.Conclusion. These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.Due to the rapidly expanding information and evolving evidence related to COVID-19, which may lead to modification of some guidance statements over time, it is anticipated that updated versions of this article will be published, with the version number included in the title. Readers should ensure that they are consulting the most current version. A summary of revisions over time and their location is included in the Supplementary Tables.Guidance developed and/or endorsed by the American College of Rheumatology (ACR) is intended to inform particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to this guidance to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. Guidance statements are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidance developed or endorsed by the ACR is subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

Introduction: CD137L is a member of the tumor necrosis factor superfamily that provides a costimulatory signal to T cells. In this study, two novel CD137L fusion proteins were produced and compared with the CD137 agonist antibody 2A. Materials and Methods: Murine CD137L was linked to the COOH terminus of either the Fc fragment of immunoglobulin (untargeted version) or TNT-3 (targeted version), an antibody that binds to necrotic regions of tumors. Groups of mice bearing established Colon 26 tumors were then treated daily Â5 with each fusion protein or 2A to determine their immunotherapeutic potential. Results: Both fusion proteins retained CD137L activity in vitro and TNT-3/CD137L showed tumor-binding activity by biodistribution analysis in tumor-bearing mice. The fusion proteins also produced similar responses in vivo at the 1 nmol per dose range and showed a 60% (TNT-3/ CD137L) or 40% (Fc/CD137L) survival of treated mice at 150 days after tumor implantation, similar to the effects of 2A. Morphologic and immunohistochemical analyses showed massive central necrosis and infiltration of granzyme B^positive cells in necrotic areas and viable peripheral regions of treated tumors. Finally, cell depletion studies showed that CD137L-mediated tumor regression was CD8 + Tcell dependent. Conclusions: From these studies, it was determined that both targeted and untargeted CD137L fusion proteins showed effective antitumor activity, but that the targeted version was more potent. Therefore, the use of the natural CD137 ligand is a promising approach to the treatment of solid tumors by virtue of its ability to produce physiologic costimulation within the tumor, limiting side effects often seen with agonist antibody therapies.T-cell anergy is one of the major impediments to the ability of the immune system to eradicate established tumors (1 -4). To elicit an effective T-cell response, the engagement of the T-cell receptor by MHC-peptide complex needs to occur in the setting of a second signal provided by costimulation (5). The B7/CD28 interaction has been widely studied as the primary pathway for costimulatory activation of resting T cells (6, 7). Recently, however, signaling relayed through CD137 and other members of the CD28 and tumor necrosis factor receptor (TNFR) families have received broad attention as additional mechanisms for the induction of potent T-cell effector functions (8, 9). CD137 (4-1BB) and its natural ligand CD137L (4-1BBL) are members of the TNFR/TNF superfamily (10 -12). CD137 is transiently expressed primarily on activated T cells (13,14), whereas CD137L has been found on activated antigenpresenting cells (10, 15 -17). Although the engagement of CD137 by CD137L provides costimulation to both CD4 + and CD8 + T cells (18 -20), evidence indicates that costimulation has a more profound effect on CD8 + T cells (21). In experiments using a CD137 agonist antibody or cells constitutively expressing CD137L (18, 21 -31), CD137 engagement was shown to regulate T-cell number and functions, including the secre...

Purpose: Despite lymphocyte infiltration of tumors and the activation of tumor-draining lymph nodes, malignant tumors are able to ''escape'' from both innate and adaptive immune responses. For immunotherapy to be successful, it must reverse these escape mechanisms, which necessitates explicit and tumor-specific elucidation of tumor escape strategies. Research Design: To identify relevant escape mechanisms in murine tumors and in two corresponding human cancers, real-time reverse transcription-PCR was used to measure a panel of genes associated with T-cell activation and inhibition pathways. Results: Comparative analysis of the expression levels of these immunomodulatory genes showed astonishing similarities in expression patterns between murine and human breast cancers but profound variability in the expression of immunomodulatory genes in colorectal cancers. For human ductal adenocarcinoma of the breast, down-regulation of dendritic cell maturation marker CD83 and T-cell activation gene CD28 was observed as well as a notable increase in the expression of the immunoinhibitory gene B7-H4. By contrast, colorectal adenocarcinoma cases showed high variability in tumor escape mechanisms, indicating a need to produce immune signatures for individual patients to identify appropriate immunotherapeutic targets. Conclusions: These results show that certain tumors, such as ductal carcinoma of the breast, show consistent immunologic abnormalities that can be used as targets for immunotherapy. These findings also show the importance and feasibility of determining the immune signatures of patients' tumors to select appropriate immunotherapeutic strategies. Ultimately, these results advocate for the determination of immune signatures as part of the customary repertoire of clinical diagnostics for cancer.Immunotherapy defines the process by which immune mediators are able to recognize and attack tumors (1, 2). The ability of the immune system to recognize and destroy tumor cells is supported by observations of spontaneous T-cell responses in human malignancies (3), spontaneous CTLinduced tumor regression (4), and the involvement of innate immune effectors in the identification and elimination of tumor cells (5). Nevertheless, although the immune system may on occasion succeed in eliminating nascent tumor, immunoediting places a strong selection pressure on tumor cells. Because tumors are often genetically unstable (6), immunoediting confers a survival advantage on tumor cells, enabling them to develop strategies for evading the immune system. Consistent with the multihit model of oncogenesis (7), the acquisition of tumor escape mechanisms may be a necessary ''hit'' for a malignancy and is hence considered by many to be ''the seventh hallmark of cancer'' (8). Tumor escape strategies include mechanisms as varied as clonal deletion (9), induction of peripheral anergy (10), and epigenetic modification (11). In each instance, the tumor exploits immunologic signaling pathways to create a microenvironment favorable to tumor g...

To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).Methods. This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to the recommendations within this guideline to be voluntary, with the ultimate determination regarding their application to be made by the clinician in light of each patient's individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions, and drug formularies or other third-party analyses that cite ACR guidelines should state this. These recommendations cannot adequately convey all uncertainties and nuances of patient care.

OX40L is a member of the tumor necrosis factor superfamily that provides a costimulatory signal to CD4+ and CD8+ T cells while inhibiting the effects of suppressive CD4+ CD25+ regulatory T cells. Because of this dual activity, OX40L may provide significant antitumor immunity in tumor-bearing mice. To study its clinical potential, a fusion protein consisting of mOX40L linked to the C-terminus of the Fc fragment of immunoglobulin was genetically engineered. After demonstrating its potency in vitro, several assays were performed to evaluate its antitumor effect in comparison to the OX40 agonist antibody OX86. Dosing studies in Colon 26-bearing and renal cell carcinoma (RENCA)-bearing mice showed that although OX86 produced modest tumor regression, Fc-mOX40L produced complete remission in both tumor models. Survival studies confirmed these results and showed that Fc-mOX40L treatment produced lasting responses throughout the 5-month observation period. Flow cytometric analysis of treated and untreated tumors and tumor-draining lymph nodes identified a qualitative difference in the activity of Fc-mOX40L compared with OX86 treatment as evidenced by differences in lymphoid and macrophage populations. These studies reflect the profound therapeutic potential of Fc-mOX40L, which substantially exceeds the agonist antibody OX86 in ability to produce complete tumor remissions and promote long-term survival in solid tumor models.

Purpose:To provide proper costimulation required for effective cancerT-cell immunity, Fc-GITRL fusion proteins were generated for use in immunotherapy protocols. Experimental Design: Soluble fusion proteins consisting of the Fc fragment of immunoglobulin and the murine glucocorticoid-induced tumor necrosis factor^related receptor ligand (mGITRL) connected with different linkers were genetically engineered and tested for their potency in two BALB/c solid tumor models. Results: In vivo, construct #178-14 (-5aa, -linker) showed the best activity (>90% tumor reduction) at doses ranging from 5 to 25 Ag and was found to be intact by gel electrophoresis. Similar doses used with construct #175-2 (-linker) produced good but not as high tumor regression. Construct #5-1 (+linker), which was found to be relatively unstable by SDS gel electrophoresis, produced <60% tumor regression and required a higher dose (100 Ag) to produce optimal results.Survival curves showed that Fc-mGITRL treatment extended the life of 80% of tumor-bearing mice to >3 months compared with controls that died by day 40. T-cell depletion studies showed that CD8 + T cells play a major role in Fc-mGITRL immunotherapy, and tumors removed from Fc-mGITRL^and DTA-1^treated mice showed a significant influx of granzyme B + lymphocytes compared with controls. Finally,Tregulatory (Treg) cell assays showed that, unlike other Fc fusion proteins, all three Fc-mGITRL constructs profoundly suppressed Treg activity. Conclusions: These studies suggest that a stable, intact Fc-mGITRL fusion protein can provide missing costimulation for the immunotherapy of solid tumors. In addition, Fc-mGITRL may alter Treg activity to enhance its effectiveness for tumor immunotherapy.