Abstract IA10: CARs for leukemia and beyond?

Abstract

Abstract Relapsed hematologic malignancies pose a substantial unmet therapeutic challenge despite aggressive therapies. Engineered T cells have shown promise for a variety of malignancies and chronic infections. In this session we will review the current status of trials testing chimeric antigen receptor (CAR)-modified T cells for acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML) and for myeloma. As of April 2014, twenty-five children and 5 adults with relapsed or refractory ALL were treated with anti-CD19:4-1BB:CD3zeta CAR T cells (CTL019). Complete remissions (CR) were achieved in 27/30 patients (90%). CTL019 cells proliferated up to 1000-fold and were detectable in blood, bone marrow, and cerebrospinal fluid of responding patients. Sustained remissions were achieved in 15/22 evaluable patients with median follow-up of 7 months (2-24 months), with event-free survival of 67% (95% confidence interval [CI], 51% to 88%) and overall survival of 78% (95% CI, 65% to 95%) measured at 6 months. CTL019-mediated B cell aplasia persisted for up to 2 years and is ongoing. Cytokine release syndrome (CRS) was observed in all patients. Severe CRS, seen in 27% of patients, was associated with high disease burden and was effectively treated with the IL-6 receptor antibody tocilizumab. More than 50 patients with advanced refractory chronic lymphocytic leukemia have been treated with CTL019. Two of the first three patients treated remain in complete remission nearly 4 years after infusion. An ongoing randomized phase II trial testing a high and a low dose of CTL019 has not shown a difference in the response rate. The lack of an obvious dose response rate is consistent with the high level proliferation of CAR T cells in vivo and suggests that once a threshold dose is reached, further dose escalation does not increase efficacy. Persistent B cell aplasia is observed in responding patients (more than 3 years in CLL patients and more than 2 years in pediatric ALL patients). No patient with persistent B cell aplasia has relapsed with CD19+ tumor. A major issue in the field is whether it is necessary to have ongoing immunosurveillance by CAR T cells or whether they induce “sterile remissions” where every last tumor cell is eradicated. CAR T cells can target very low levels of targets expressed at the cell surface. Because some myeloma cells express low levels of CD19, and because B cells may be a precursor of malignant myeloma cells, an ongoing pilot trial is testing whether CTL019 cells might recognize and eliminate malignant cells in patients with advanced plasma cell myeloma. In preclinical studies we have found that CD33 and CD123 CAR T cells have potent therapeutic effects in mice bearing xenografts with AML. At issue is whether off tumor toxicity on normal cells will be tolerable with CD33 and CD123 specific CARs. In summary, CAR-modified T cell therapy directed against CD19 is highly effective as salvage therapy for children and adults with relapsed/refractory ALL and CLL. Moreover, long-term remissions may be possible in some patients. Our findings support the advancement of CAR-modified T cell therapy into multicenter phase 2 clinical trials. 1. M. Kalos, C. H. June, Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49 (2013). 2. S. A. Grupp et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. New England Journal of Medicine 368, 1509 (2013). 3. D. L. Porter, B. L. Levine, M. Kalos, A. Bagg, C. H. June, Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia New England Journal of Medicine 365, 725 (2011). 4. M. Kalos et al., T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia. Science Translational Medicine 3, 95ra73 (2011). 5. S. Maude et al., Sustained Remissions with Chimeric Antigen Receptor T Cells for Leukemia. New England Journal of Medicine, in press (2014). Citation Format: Carl H. June, David Porter, Stephan Grupp, Bruce L. Levine. CARs for leukemia and beyond? [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA10.