Abstract A041: CD19-targeting third generation CAR T cells for relapsed and refractory lymphoma and leukemia – report from the Swedish phase I/IIa trial

Abstract

Chimeric antigen receptor (CAR) T cells have shown promising results in patients with B cell malignancy. In preclinical studies we showed that CD19-targeting third generation (3G) CAR T cells containing signaling domains from both CD28 and 4-1BB as co-stimulatory molecules have a higher activation status and greater proliferation in response to antigens. Herein we report initial results from a phase I/IIa study (NCT:02132624) using these 3G CAR T cells. Patients with relapsed or refractory CD19+ B-cell malignancy were eligible, provided there was no other curative treatment available. Of the first eleven patients reported, nine had lymphoma and two patients had acute lymphoblastic leukemia (ALL). Autologous CAR T cells were manufactured using a gamma retrovirus encoding the CAR and expanded by αCD3/αCD28/IL2. During CAR T cell production, all lymphoma patients received treatment to control tumor burden (-90 to -3 days before T cell infusion). Type of treatment depended on the type of lymphoma and previous treatments. In addition, prior to T cell infusion (day -2 to -1) patients #6-11 received cyclophosphamide (500mg/m2) and fludarabine (25mg/m2) as preconditioning to decrease immunosuppressive cells. The patients received one infusion of CAR T cells starting at a dose of 2x107 cells/m2 (patients 1 and 2), 1x108 (patients 4, 5, 7, 8, 9) and 2x108 (patients 6, 10, 11, 12). Patient #1 (DLBCL) had a mild cytokine release syndrome (CRS) after four weeks (never requiring treatment), followed by a complete response of his lymphoma. A relapse and a second CRS occurred after six weeks and he was treated with prednisone with good symptomatic effect and reduction of tumor size. The patient progressed after three months. Patients #2, 4, 5 (CLL, MCL, MCL) all progressed after 2, 1, and 3 months, respectively. Patient #6 (DLBCL) responded to treatment (CR) prior to T cell infusion and remained in complete remission for 6 months post T cell infusion. Patient #7 (CLL) and #9 (DLBCL) also responded to treatment prior to T cell infusion and remains in complete remission (>3 months). The CLL patient has a tumor negative bone marrow. Patient #8 (FL-DLBCL) progressed after 1 month but had a mild CRS. Patient #10 (ALL) experienced transient CNS toxicity followed by a complete response. However, at 3 months the patient relapsed with a CD19 negative ALL, accompanied by increased levels of immunosuppressive cells. Patient #11 (ALL) is in complete remission after a CRS (>1 month) and patient #12 (FL/Burkitt) had a major CRS requiring intensive care but is too early to evaluate. The CAR transgene could be detected in blood at the time of patient response. In summary, eleven patients have been treated with increasing doses of CAR T cells in Sweden. All treatments were given as out-patients. The conditioning has been relatively mild as compared to previous published studies. Six patients had complete remission, or complete clinical responses, at the time of evaluation of which two relapsed later. Four patients did not respond to treatment and progressed early; and 1 is still too early to evaluate. Correlations between the levels of immunosuppressive cells and patient response are currently under investigation. Citation Format: Gunilla Enblad, Hannah Karlsson, Kristina I. Wikstrom, Magnus Essand, Barbara Savoldo, Malcolm K. Brenner, Gianpietro Dotti, Martin Hoglund, Hans Hagberg, Angelica Loskog. CD19-targeting third generation CAR T cells for relapsed and refractory lymphoma and leukemia – report from the Swedish phase I/IIa trial. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A041.

Acute lymphoblastic leukemia relapse after CD19-targeted chimeric antigen receptor T cell therapy

“…To further amplify the activation signal, efforts to combine 2 costimulatory domains into 1 CAR molecule, which denotes the 3rd-generation CAR T cells (Fig. 3C), has been reported; however, a pilot clinical trial that assessed CD28-4-1BB double costimulatory domain CAR T cells (ClinicalTrials.gov: NCT02132624) achieved only a 54.5% CR rate in 11 patients with B cell malignancy, as reported in the 2015 American Society of Hematology meeting [71]. As excessive signaling can lead to CAR T cell exhaustion, it is still unclear whether the boosted signaling with 2 costimulatory domains would generate more favorable results.…”

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

“…14,15 In addition to CD28 and 4-1BB, other co-stimulatory molecules, such as ICOS, OX-40, CD40, and CD27, have been tested in multiple pre-clinical model. 16–19 Previously, we determined that co-stimulation of toll-like receptor 2 can potentiate the anti-tumor efficacy of CAR-T cell.…”