CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia

Abstract

Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…The clinical benefits of this approach have been validated using CAR-CD19 T cells to treat a range of CD19 + hematological malignancies including B cell chronic lymphocytic leukemia (B-CLL) and acute lymphoblastic leukemia (ALL). [29][30][31][32] For example, Grupp and colleagues 30 recently reported a complete remission rate of 92% in pediatric patients with relapsed/refractory CD19 + ALL, while Davila et al 3 achieved an overall complete remission rate of 88% in adults with B-ALL. In many cases, clinical benefit correlated with the ability of infused cells to expand and persist in vivo.…”

“…In many cases, clinical benefit correlated with the ability of infused cells to expand and persist in vivo. 2,3,29 However, it is possible that this remarkable T cell expansion is, at least in part, due to the result of the potent antigen-presenting qualities of normal and malignant B cells, which are easily accessible and express co-stimulatory molecules, making them highly stimulatory.…”

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…The effect on circulating serum cytokines may have value for other T-cell immunotherapies, such as adoptive transfer of CAR-T cells in which CRS is more prevalent and severe. [42][43][44][45] For personal use only. on April 3, 2019. by guest www.bloodjournal.org From Our data also show that AP1903 may control iC9-T cells in the CNS.…”

Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity

“…CARs activate T cells through intracellular signaling domains such as CD3z, which is improved by costimulation including CD28 or 4-1BB (6). Recently, transfer of such second generation CAR T cells targeting CD19 + B cell lymphoid leukemia has shown encouraging clinical results in treating patients with bulky tumors (7)(8)(9)(10). Although these results are galvanizing the field of adoptive cell therapy, clinical trials focusing on solid tumors have seen less success (11)(12)(13).…”