Natural killer (NK) cells and T cells are two critical effectors of the adaptive immune system and represent approximately 30% of circulating lymphocytes. Both NK and T cells infiltrate virtually all tissues and were originally characterized by their ability to kill tumor cells effectively without the need for prior sensitization. NK and T cells respond to signals through a variety of activating and inhibitory receptors on their surfaces. For example, when NK cells encounter healthy cells, their activities are inhibited through recognition and signaling of their surface killer-cell immunoglobulin-like receptors. Alternatively, when NK cells encounter foreign or cancerous cells, their responses are mediated via activating signals through a variety of receptors (e.g. NKG2D, NCRs, DNAM1). The overall sensitivity of these immune cells to activation depends on the combination of stimulatory and inhibitory signals. Recent studies on the developments of immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC), bispecific T-cell receptor (TCR) engagers, and chimeric antigen receptor (CAR) cell-based therapies, have highlighted their potential to treat Multiple Myeloma (MM). These treatments, however, are expensive. The manufacturing processes that are employed for their generation are lengthy, and their commercial scale production is reliant on a multitude of equipment and operators that cannot easily be incorporated in the footprint of most local hospitals. Moreover, patient responses to these treatments remain heterogenous.
Here, we propose an innovative multidisciplinary approach that aims to develop a novel theranostic immune-cell based compound. This approach is based on the functionalization of the immune cells with theranostic ultrasmall macromolecules (USM); USM having a diameter size below 10 nm to allow renal clearance and minimize toxicity. The clinically-relevant imaging properties of the USM will allow to unveil various challenges remaining in the field of immunotherapy, such as to better elucidate the priming sites of immune cells, to track their migration in the body, as well as to localize their niche upon the establishment of minimal residual disease. By labelling the immune cells ex vivo, the diagnostic imaging properties enabled by the presence of the USM on the immune cell surface will allow to generate better ex vivo immune cell therapeutics (such as simili-CAR NK cells) with a rationalized target selection, will improve the cell dosing, and will help to better stratify the patient population in order to offer an improved personalized treatment plan.
Through this project, we plan: i) understand the impact of USM on immune cells; ii) determine the sensitivity for in vivo imaging and the threshold for quantitative tissue detection of autologous/allogeneic immune cells after ex vivo labeling with USMs; and iii) validate in vivo the targeted theranostic CAR-like NK cells for Multiple Myeloma early diagnostic and therapeutic properties.
