Actr Platform As an Adaptable, Universal T Cell Therapy That Can Target Multiple Tumor Antigens to Overcome Antigen Escape

Adoptive T-cell therapy with single-chain variable fragment (scFv)-derived chimeric antigen receptors (CARs) has transformed cancer therapy. Nevertheless, treatment failure can occur and is often associated with loss of the targeted antigen-an outcome affecting nearly 65% of patients that have failed CD19-targeted CAR T cell therapy (1). Targeting more than one tumor antigen expressed on the surface of tumor cells to mitigate antigen loss is a strategy that has been tested preclinically with CAR-T therapy. This approach is challenging due to the complexities of validating numerous CAR constructs or generating functional CARs which contain several tandem scFvs. The Antibody-Coupled T-cell Receptor (ACTR) platform is a universal, engineered T-cell therapy technology developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct, derived from human CD16 and coupled to T-cell signaling domains, is designed to engage the Fc domain of therapeutic antibodies, resulting in a novel platform for T-cell targeted cancer therapy. In contrast to CAR T-cell constructs that are restricted to a single antigen, the ACTR platform is highly adaptable, which can be targeted against a diverse set of tumor antigens-thus circumventing the need to generate and characterize multiple CAR-T therapeutics.

We first determined whether ACTR expressing T cells could be combined with a diverse array of tumor-targeting antibodies directed against B cell malignancies. Using cell lines derived from B cell lymphomas or multiple myeloma, we found that ACTR-expressing T cells could be activated with antibodies against multiple B-cell targets including CD19, CD20, CD22, CD38, and CS1. One approach to address CD19 antigen loss in patients relapsing following CD19 CAR-T therapy is to treat with a CD22 CAR-T therapy (2). Given that ACTR can be paired with single antibodies as described above, a flexible sequential administration of targeted antibodies could be utilized. However, we also sought to determine whether combinations of antibodies against CD19 and CD22, when used concurrently, could improve ACTR-activity. We found that dual antigen targeting with anti-CD19 and anti-CD22 antibodies could enhance both ACTR-mediated cytotoxicity and cytokine production in an antibody dose-dependent manner. Taken together, our results provide preclinical evidence for ACTR as a universal, chimeric receptor that could engage multiple tumor antigens with potential to improve patient outcomes by eliminating antigen negative relapse.

References

1. Grupp SA, et al. 681 Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019). ASH. Dec 2015 2. Xinqiao Hospital of Chongqin. Anti-CD22 CAR-T Therapy for CD19-refractory or Resistant Lymphoma Patients.https://www.clinicaltrials.gov/ct2/show/NCT02721407