Targeting CD20+ Relapsed Refractory B Cell Lymphoma with ACTR087, Antibody-Coupled T-Cell Receptor (ACTR) Engineered Autologous T Cells, in Combination with Rituximab

The Antibody-Coupled T-cell Receptor (ACTR) platform is a universal engineered T cell therapy developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct is composed of the extracellular domain of CD16 (FCGR3A; high-affinity V158 variant) linked to CD3ζ signaling and 41BB co-stimulatory domains. ACTR-expressing T cells recognize antibodies bound to antigen on the surface of target cells, and this receptor engagement results in T cell activation, proliferation, and cytotoxic attack of target cells. Previous preclinical research has demonstrated that ACTR T cells elicit tumor cell cytotoxicity in combination with rituximab, trastuzumab, and hu14.18K322A against CD20, HER2, and GD2 expressing tumor cell lines, respectively (Kudo et al., Cancer Res 2014; 74:93-103). The safety of ACTR T cells in combination with rituximab for subjects with B-cell malignancies is currently being explored in a pilot phase 1 clinical study (ATTCK-20) sponsored by National University Hospital, Singapore. Electroporation of mRNA is being used to deliver the ACTR transgene to study subjects' T-cells, creating a transiently active form of the therapy.

In this study, we present non-clinical data supporting the first-in-human clinical trial of ACTR087, the ACTR transgene (CD16V-41BB-CD3ζ) delivered by γ-retrovirus to human T cells, in combination with rituximab in relapsed refractory B cell lymphoma (NCT02776813). In vitro data demonstrate that in the absence of rituximab or in the presence of non-targeting antibodies, no increase in cytotoxicity is observed, demonstrating that ACTR signaling is target- and antibody-specific. ACTR T cells proliferate in response to rituximab-bound lymphoma cells, but this proliferation is antibody-dependent and self-limiting in the absence of antibody. In vivo efficacy and pharmacokinetic studies further support the dependence on adequate rituximab exposure for ACTR T cell response, suggesting that ACTR T cell activity can be modulated by antibody dose and schedule, which is a potential advantage over other chimeric antigen receptor (CAR) T cell therapies.

Additional in vitro studies were conducted to explore the effects of potential interventional antibody therapies used to mitigate adverse events reported for CAR-T therapies in similar patient populations. These include tocilizumab, used to treat cytokine release syndrome (CRS), and intravenous immunoglobulin (IVIG), used to treat hypogammaglobulinemia complicated by recurrent sinopulmonary infections. At therapeutically relevant doses, rituximab was able to compete with substantial excess IVIG to induce a CD20-specific ACTR T cell response. Importantly, IVIG did not induce greater cytokine release from ACTR T cells. Likewise, tocilizumab did not mediate ACTR T cell activation or cytotoxicity of IL-6R+ target cells, consistent with reports that tocilizumab is ADCC-deficient. These data illustrate an important principal of Fc receptor biology: not all IgG1 antibodies mediate ADCC despite binding to CD16, and support the considered use in the presence of ACTR T cells under certain circumstances. Taken together, these non-clinical data demonstrate the specificity and versatility of the ACTR T cell therapeutic approach to target diverse cancer antigens.

The Phase 1 study (ATTCK20-2, ClinicalTrial.gov No. NCT02776813) of ACTR087 plus rituximab in subjects with relapsed or refractory CD20-positive B cell lymphoma is a multi-center, single-arm, open-label study evaluating the safety and efficacy of an autologous T-cells, culture expanded and transduced ex vivo with a γ-retrovirus containing an ACTR expression construct (CD16V-41BB-CD3ζ). Subjects who meet eligibility requirements with histologically-confirmed relapsed or refractory CD20+ B-cell lymphoma of one of the following types are eligible for the study: DLBCL, MCL, PMBCL, Gr3b-FL, TH-FL. Following a conditioning regimen with fludarabine and cyclophosphamide, and prior to ACTR087 infusion, subjects will receive rituximab at the standard IV clinical dose, 375 mg/m². Subjects may receive up to 7 additional cycles of rituximab 375 mg/m² at 3-week intervals and continuing as long as they show evidence of response.