A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor

Abstract

Adoptive immunotherapies composed of T cells engineered to express a chimeric antigen receptor (CAR) offer an attractive strategy for treatment of human cancer. However, CARs have a fixed antigen specificity such that only one tumor-associated antigen (TAA) can be targeted, limiting the efficacy that can be achieved due to heterogeneous TAA expression. For this reason, a more generalized and effective application of CAR therapy would benefit from the capability to produce large panels of CARs against many known TAAs. In this study, we demonstrate a novel strategy to extend the recognition specificity potential of a bioengineered lymphocyte population, allowing flexible approaches to redirect T cells against various TAAs. Our strategy employs a biotin-binding immune receptor (BBIR) composed of an extracellular-modified avidin linked to an intracellular T cell signaling domain. BBIR T cells recognized and bound exclusively to cancer cells pre-targeted with specific biotinylated molecules. The versatility afforded by BBIRs permitted sequential or simultaneous targeting of a combination of distinct antigens. Together, our findings demonstrate that a platform of universal T cell specificity can significantly extend conventional CAR approaches, permitting the tailored generation of T cells of unlimited antigen specificity for improving the effectiveness of adoptive T cell immunotherapies for cancer.

Redirecting Gene-Modified T Cells toward Various Cancer Types Using Tagged Antibodies

“…It is worth highlighting that the tag used in such platform is not limited to FITC but can be applied to any types of reagents mediating proteinprotein interaction and being conjugated with antitumor Abs. Indeed, during preparation of the manuscript, Urbanska and colleagues reported a method using biotinconjugated Ab together with CAR expressing dimeric form of avidin (29). Our studies show complete tumor regression using both human tumor models in immunocompromised NSG mice and syngeneic mouse tumor models in immunocompetent hosts, emphasizing the antitumor effects mediated by this type of approach.…”

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

“…Moreover, we show this methodology allows one to systematically optimize the activity of the sCAR by varying the geometry and valency of the switch molecule. Similar approaches have been described using antibodies that are nonspecifically or enzymatically labeled with small-molecule haptens to redirect the activity antihapten CARs (16,17). However, these systems do not easily allow for optimization of the immunological synapse between the CAR-T cell, antibody, and target cell.…”

“…Alternatively, strategies that use antibodybased switches to mediate the interaction between the CAR-T cell and target cell enable full control over both activity and specificity (SI Appendix, Fig. S1A) (16)(17)(18). By combining the titratability of antibody-based therapies with the efficacy of genetically modified CAR-T cells, this approach has the potential to prevent CRS and TLS through improved control of the CAR-T-cell…”

Versatile strategy for controlling the specificity and activity of engineered T cells

“…In addition, unlike the intracellular switch approach described by Wu et al, an intercellular switch approach enables the targeting of multiple TAAs with a "universal" CAR-T cell. Examples of switches used in this approach include TAA-specific monoclonal antibodies that elicit antitumor activity from Fc-specific CAR-T cells (17), and chemically or enzymatically modified antibody-hapten conjugates that redirect antihapten CAR-T cells (18,19). Recently, we have demonstrated the redirection of anti-FITC CAR-T cells with a heterobifunctional small-molecule switch, folate-FITC, which selectively targets folate receptor-overexpressing cancers (20).…”