A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant

Ronald, John A.; Kim, Byung Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S.; D’Souza, Aloma L.; Nishikii, Hidekazu; Chuang, Hui Yen; Ilovich, Ohad; Lin, Chih Feng; Reeves, Robert E.; Shuhendler, Adam J.; Hoehne, Aileen; Chan, Carmel T.; Baker, Jeanette; Yaghoubi, Shahriar; VanBrocklin, Henry F.; Hawkins, Randall A.; Franc, Benjamin L.; Jivan, Salma; Slater, James B.; Verdin, Emily F.; Gao, Kenneth T.; Benjamin, Jonathan; Negrin, Robert S.; Gambhir, Sanjiv S.

doi:10.1158/0008-5472.can-16-2953

Cited by 104 publications

(124 citation statements)

References 33 publications

(62 reference statements)

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…Small-molecule tracers, as previously mentioned, have focused on metabolic pathways that are not immune cell specific. Nucleoside analogs like 18 F-FLT, 18 F-AraC, and 18 F-AraG have all been explored for immune cell imaging (11,12,32). The latter, for instance, has increased specificity for activated T cells (33) and recently showed utility in the detection of these cells in murine models of acute graft versus host disease (GVHD) and arthritis (34).…”

Section: Discussionmentioning

confidence: 99%

“…For example, 18 F-fluorodeoxyglucose ( 18 F-FDG), the most widely used clinical PET tracer, has principally been used to assess the efficacy of traditional nontargeted chemotherapies, but has also been used extensively to evaluate inflammation in the clinic (8,9). A major challenge in delineating immunotherapy response, however, is that 18 F-FDG suffers from relatively high uptake in both tumor-infiltrating T cells and cancer cells (10), as do other small-molecule metabolic tracers including 3′-deoxy-3′[ 18 F]-fluorothymidine ( 18 F-FLT), 1-(2′deoxy-2′-[ 18 F]fluoro-β-d arabinofuranosyl)cytosine ( 18 F-AraC) (11), and 2′-deoxy-2′-[ 18 F]fluoro-9-β-D-arabinofuranosyl guanine ( 18 F-AraG) (11,12). Reporter gene strategies, such as the use of herpes simplex virus type 1 thymidine kinase (HSV1-tk) in conjunction with the PET tracer 9-[4-[ 18 F]-fluoro-3-(hydroxymethyl)butyl] guanine ( 18 F-FHBG), represent a powerful way to monitor the traf-…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Imaging activated T cells predicts response to cancer vaccines

Alam¹,

Mayer²,

Sagiv-Barfi

et al. 2018

Journal of Clinical Investigation

Self Cite

112

View full text Add to dashboard Cite

In situ cancer vaccines are under active clinical investigation, given their reported ability to eradicate both local and disseminated malignancies. Intratumoral vaccine administration is thought to activate a T cell-mediated immune response, which begins in the treated tumor and cascades systemically. In this study, we describe a PET tracer (64Cu-DOTA-AbOX40) that enabled noninvasive and longitudinal imaging of OX40, a cell-surface marker of T cell activation. We report the spatiotemporal dynamics of T cell activation following in situ vaccination with CpG oligodeoxynucleotide in a dual tumor-bearing mouse model. We demonstrate that OX40 imaging was able to predict tumor responses on day 9 after treatment on the basis of tumor tracer uptake on day 2, with greater accuracy than both anatomical and blood-based measurements. These studies provide key insights into global T cell activation following local CpG treatment and indicate that 64Cu-DOTA-AbOX40 is a promising candidate for monitoring clinical cancer immunotherapy strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Imaging activated T cells predicts response to cancer vaccines

Alam¹,

Mayer²,

Sagiv-Barfi

et al. 2018

Journal of Clinical Investigation

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…Several other groups have sought to image aGVHD using dedicated immunological PET imaging tracers. Ronald et al [20], using an activated T cell imaging compound, imaged recipient mice on transplant days +3 and +10 in a completely MHC-mismatched B6 into BALB/c model system. Similar to our findings, the authors observed a consistently increased PET signal within the peripheral lymph nodes of aGVHD mice given BM plus alloreactive T cells compared with control mice receiving BM alone.…”

Section: Discussionmentioning

confidence: 99%

18F-3′-Deoxy-3′-Fluorothymidine Positron Emission Tomography Imaging for the Prediction of Acute Graft-Versus-Host Disease in Mouse Hematopoietic Stem Cell Transplant Models

Lee

Akinnagbe-Zusterzeel

Fowler

et al. 2018

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation. In mice, studies have demonstrated that donor conventional T cells traffic into host secondary lymphoid tissues early after transplant, and that this process is critical for the development of disease. As a result, the measurement of cellular proliferation within lymphoid sites early after transplant might be a useful approach for predicting aGVHD in humans. 18F-3'-deoxy-3'-fluorothymidine (FLT) positron emission tomography (PET) imaging has recently emerged as a functional imaging modality in oncology patients. FLT, a thymidine analog, is incorporated into replicating DNA and is thus an indirect marker of cellular proliferation. Here we report that FLT PET imaging can differentiate mice receiving alloreactive T cells and destined to develop lethal aGVHD from control mice. Mice receiving allogeneic T cells demonstrated a stronger FLT signal within the peripheral lymph nodes compared with control mice at all time points after transplant. In addition, allogeneic T cell recipients transiently demonstrated stronger FLT uptake within the spleen. Importantly, these differences were apparent before the development of clinical disease. In contrast, the FLT signal within the host bowel, an important aGVHD target organ, was more variable after transplant and was not consistently different between aGVHD mice and control mice. Collectively, these findings suggest that the imaging of patient lymphoid sites using existing FLT PET technology might be useful for predicting aGVHD in the clinical setting.

show abstract

“…Other T-cell imaging strategies take advantage of specific T-cell surface markers, such as CD8 (NCT03107663) (24). Another strategy is based on imaging T-cell activation with 29-deoxy-29- 18 F-fluoro-9-b-D-arabinofuranosylguanine, a radiolabeled analog of the DNA nucleoside guanine (NCT03142204) (25). The utility of these methods for CAR T-cell tracking has yet to be evaluated.…”

Section: Real-time Applicationmentioning

confidence: 99%

Imaging of CAR T-Cells in Cancer Patients: Paving the Way to Treatment Monitoring and Outcome Prediction

et al. 2019

View full text Add to dashboard Cite

In 2013, the journal Science named cancer immunotherapy as the ''breakthrough of the year'' based on targeted approaches using chimeric antigen receptor (CAR) T-cells. CD19-specific CAR T-cell therapy has revolutionized the treatment landscape for patients with relapsed B-cell acute lymphocytic leukemia (1,2). Similar successes have not been seen in patients with solid tumors, in part because of inconsistent expression of specific tumor antigens and physical impediments to T-cell trafficking, for example, for passing the blood-brain barrier or reaching metastatic disease in bone marrow. Other factors interfering with prolonged response to CAR T-cell therapy include loss of target antigen and T-cell exhaustion. These resistance mechanisms may be alleviated by CARs targeting 2 or more tumor antigens (NCT03019055), more sophisticated T-cell engineering techniques, or combination therapies of CARs with various immune checkpoint inhibitors. So far, it has remained unclear why certain cell therapies succeed and even provide durable clinical responses (1,2) whereas others fail (3). Ideal monitoring of CAR T-cell therapies should include the ability to track T-cell migration, engagement with the antigenbearing tumor cells, as well as T-cell expansion and persistence at the tumor site-all essential steps for therapeutic efficacy. Imaging studies might perhaps also enable timely intervention to avoid potentially lethal systemic toxicity. Current clinical methods to monitor the infused cells include serum profiling of cytokines associated with T-cell activation, direct enumeration of tumorspecific T-cells in peripheral blood, and (repeated) tumor biopsies. Overall, the in vivo activation dynamics of engineered immune cells remain incompletely understood, as no means of real-time monitoring of the intratumoral milieu currently exists. PRINCIPLES OF CELL TRACKING Cell tracking by imaging requires the direct or indirect labeling of cells. Direct labeling is relatively simple and has been used clinically for several decades, for instance, with 99m Tc or 111 Inlabeled leukocytes. More recently, 89 Zr-oxine has been used for cell labeling and PET imaging (4). As a major disadvantage, the

show abstract

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant

Cited by 104 publications

References 33 publications

Imaging activated T cells predicts response to cancer vaccines

Imaging activated T cells predicts response to cancer vaccines

18F-3′-Deoxy-3′-Fluorothymidine Positron Emission Tomography Imaging for the Prediction of Acute Graft-Versus-Host Disease in Mouse Hematopoietic Stem Cell Transplant Models

Imaging of CAR T-Cells in Cancer Patients: Paving the Way to Treatment Monitoring and Outcome Prediction

Contact Info

Product

Resources

About