Quantitative imaging of the T cell antitumor response by positron-emission tomography

Abstract

We describe a noninvasive, quantitative, and tomographic method to visualize lymphocytes within the whole animal. We used positron-emission tomography (PET) to follow the localization of adoptively transferred immune T lymphocytes. Splenic T cells from animals that had rejected a Moloney murine sarcoma virus͞ Moloney murine leukemia virus (M-MSV͞M-MuLV)-induced tumor were marked with a PET reporter gene, injected into tumor-bearing mice, and imaged in a microPET by using a substrate specific for the reporter. Specific localization of immune T cells to the antigenpositive tumor was detected over time, by sequential imaging of the same animals. Naive T cells did not localize to the tumor site, indicating that preimmunization was required. Autoradiography and immunohistochemistry analysis corroborated the microPET data. The method we have developed can be used to assess the effects of immunomodulatory agents intended to potentiate the immune response to cancer, and can also be useful for the study of other cell-mediated immune responses, including autoimmunity.

Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive In vivo Positron Emission Tomography Imaging

“…We use the term ''tracer cells'' in context of the potential future clinical scenario, in which the HSV1-TK-expressing hMSCs will be used to ''trace'' the coadministered therapeutic hMSCs genetically modified to express various anticancer cytokines (12,13). Similar PET imaging approach was applied in several recent studies for noninvasively visualization of HSV1-TK-expressing stem cells after direct intramyocardial injection (30,31) and for visualization of tumor targeting by the adoptively transferred tumor antigen-specific T cells (32,33). Another potential clinical therapeutic protocol, which would be greatly facilitated by noninvasive imaging, would include repetitive (e.g., biweekly or monthly) administration of HSV1-TK-expressing autologous stem cells to patients following resection of a primary tumor, which has high likelihood of metastases that are radiologically not detectable at the time of resection.…”

Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment

“…Other investigators have reported that the localization of tumorspecific T cells at the tumor site is often a requirement for regression of systemic tumors (42) and even CNS tumors (43). In this clinical trial, we also observed dramatic intratumoral infiltration of CD8 + and CD4 + CTL in some patients following dendritic cell vaccination.…”

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

“…The study of the in vivo dynamics of the infused cells and how they specifically target tumors would provide information about potential problems, such as lack of specific tumor homing following ex vivo expansion, inappropriate sequestration in nonantigen positive sites, or rapid cell death and inability for the adoptively transferred TCR transgenic cells to persist in vivo. The study of these possibilities can be achieved with modern molecular imaging techniques with reporter gene labeling of cells to allow noninvasive detection of adoptively transferred TCR transgenic cell populations in recipients (8). In the current work we have taken the molecular imaging gene marking approach of antigen-specific T cells one step closer to the clinic by simultaneously redirecting the TCR specificity of T cells and providing genetic labeling for molecular imaging demonstrating robust antitumor activity correlated with specific tumor targeting.…”