T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target

Abstract

Cancer immunotherapy has proven high efficacy in treating diverse cancer entities by immune checkpoint modulation and adoptive T-cell transfer. However, patterns of treatment response differ substantially from conventional therapies, and reliable surrogate markers are missing for early detection of responders versus non-responders. Current imaging techniques using 18F-fluorodeoxyglucose-positron-emmission-tomograpy (18F-FDG-PET) cannot discriminate, at early treatment times, between tumor progression and inflammation. Therefore, direct imaging of T cells at the tumor site represents a highly attractive tool to evaluate effective tumor rejection or evasion. Moreover, such markers may be suitable for theranostic imaging.Methods: We mainly investigated the potential of two novel pan T-cell markers, CD2 and CD7, for T-cell tracking by immuno-PET imaging. Respective antibody- and F(ab´)2 fragment-based tracers were produced and characterized, focusing on functional in vitro and in vivo T-cell analyses to exclude any impact of T-cell targeting on cell survival and antitumor efficacy.Results: T cells incubated with anti-CD2 and anti-CD7 F(ab´)2 showed no major modulation of functionality in vitro, and PET imaging provided a distinct and strong signal at the tumor site using the respective zirconium-89-labeled radiotracers. However, while T-cell tracking by anti-CD7 F(ab´)2 had no long-term impact on T-cell functionality in vivo, anti-CD2 F(ab´)2 caused severe T-cell depletion and failure of tumor rejection.Conclusion: This study stresses the importance of extended functional T-cell assays for T-cell tracer development in cancer immunotherapy imaging and proposes CD7 as a highly suitable target for T-cell immuno-PET imaging.

Cancer immunotherapy is accompanied by distinct metabolic patterns in primary and secondary lymphoid organs observed by non-invasive in vivo 18F-FDG-PET

“…Novel and more sophisticated noninvasive in vivo molecular imaging methods using radiolabeled antibodies or immune cells are in preclinical development, and these methods inherently have a higher specificity than 18 F-FDG-PET for the characterization of immune responses 34-37. Nevertheless, these approaches lack the possibility of immediate clinical translation due to regulatory, organizational, or economic issues, unlike 18 F-FDG-PET, which is already part of the staging routine in many cancer types.…”

CD4+ and CD8a+ PET imaging predicts response to novel PD-1 checkpoint inhibitor: studies of Sym021 in syngeneic mouse cancer models

“…Imaging markers directly reflecting the functional status, i.e. activation or exhaustion state of specific cells, have the potential to be more predictive 74 and PET imaging of activated T cells has successfully been pursued 75,76 in addition to the secreted activation markers Granzyme B 77 and IFNγ 78. Indeed, it can be debated whether a specific cellular subtype and/or activation state or the simple presence of immune cells in the tumor microenvironment is the paramount biomarker of immunotherapeutic response.…”

Cell Tracking in Cancer Immunotherapy

“…Ideally, this antigen should be exclusively expressed on target cells, but most of the time other tissue also express it. For T lymphocytes, many targets have been tested, e.g., CD3, CD8, CD2, and CD7 (56)(57)(58).…”