Purpose T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR cell level of 98/μL and those who did not achieve a remission had a median peak blood CAR cell level of 15/μL ( P = .027). High serum IL-15 levels were associated with high peak blood CAR cell levels ( P = .001) and remissions of lymphoma ( P < .001). Conclusion CAR-19 T cells preceded by low-dose chemotherapy induced remission of advanced-stage lymphoma, and high serum IL-15 levels were associated with the effectiveness of this treatment regimen. CAR-19 T cells will likely become an important treatment for patients with relapsed lymphoma.
in the CD13+ myeloid compartment (88.3 ± 4.5%) compared to other lineages, including CD20+ lymphoid (9.1 ± 3.9%), CD235a+ erythroid (0.2 ± 0.1%) and CD41+ megakaryocytic (0.6 ± 0.2%) lineages. Interestingly, human myeloid engraftment was superior in recipient mice engrafted with human CD18+ cells (81.5 ± 4.3%) compared to animals transplanted with non-transduced (CD18-) LAD-1 cells (65.3 ± 11.3%). Integration site analysis of engrafted human cells is ongoing. Thus, FVV-mediated transduction of human LAD-1 CD34 + cells leads to clinically significant levels of CD18 expression, supporting the use of this CD18-expressing FVV in a human clinical trial.
LBA3010 Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with low-dose conditioning chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T cells 2 days after completion of chemotherapy. Blood CAR T cells and serum cytokines were analyzed in all patients. Results: Nineteen patients with various subtypes of diffuse large B-cell lymphoma (DLBCL) had the following responses: 8 CR, 5 PR, 2 SD, and 4 PD. One patient with mantle cell lymphoma obtained a CR. Two patients with follicular lymphoma both obtained CRs. Durations of response currently range from 1 to 20 months; 10 remissions are ongoing. All but 4 patients had either chemotherapy-refractory lymphoma or lymphoma that had relapsed after autologous stem cell transplant. The most prominent toxicities were various neurological toxicities. Other toxicities included fever and hypotension. The median peak blood CAR+ cell level was 47/μL (range 4-1217/μL). Patients obtaining CRs or PRs had higher peak blood CAR+ cell levels than patients experiencing SD or PD. The mean serum IL-15 level was 4 pg/mL before the conditioning chemotherapy and 32 pg/mL after chemotherapy (P < 0.0001). Conclusions: Anti-CD19 CAR T cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemotherapy. In the near future, CAR T cells will likely be a standard therapy for lymphoma. Clinical trial information: NCT00924326.
Introduction: KTE-C19 is an autologous anti-CD19 CAR T cell product that is being studied in a phase 2 multicenter trial (ZUMA-1, NCT02348216). We developed a robust and efficient manufacturing process to support this trial, and compared the characteristics of the starting lymphocytes to resultant CAR T cells. Methods: After apheresis and PBMC enrichment, cells were activated with anti-CD3 antibody and cultured in serum free medium. T cells were transduced with a retroviral vector encoding the CAR gene, expanded to achieve a target dose and cryopreserved. The product CAR T cells and the starting PBMCs were evaluated by flow cytometry. Results: 7 subjects were dosed in the phase 1 portion of the trial. KTE-C19 was successfully manufactured at a dose of 2 × 106/kg (minimum 1 × 106/kg) for all subjects. All lots contained mainly CD3+ T cells (median 97%; 94-99%). While there was inter-subject variability in PBMC and CAR T cell product characteristics, the CD8/CD4 T cell ratios in PBMC and corresponding CAR product were similar (Table 1). T cells in PBMC from patients with NHL contained a majority of effector memory (36%) and effector T cells (27%), however, T cells in KTE-C19 contained a majority of central memory (37%) and effector memory (42%) CAR+ T cells. These CAR T cells were active and objective responses occurred in 5/7 patients. Conclusions: A KTE-C19 dose was successfully produced for all subjects. The optimized manufacturing process generated clinically active CAR T cells with a less differentiated phenotype than T cells in the starting PBMC population. Less differentiated cells likely confer preferred product characteristics based on preclinical studies. This manufacturing process is robust and well suited for multicenter clinical trials. Table 1.Comparative analysis of T cells from KTE-C19 and PBMC from patients with refractory aggressive NHL.IDSampleNaïve (%)Central Memory (%)Effector Memory (%)Effector (%)CD8/CD4 ratioSubject 1KTE-C1911583014.6PBMC161246272.3Subject 2KTE-C1914473540.37PBMC26303490.27Subject 3KTE-C196345642.3PBMC4536552.9Subject 4KTE-C19111552222.0PBMC1224721.8Subject 5KTE-C1915403871.0PBMC91550261.1Subject 6KTE-C1919344252.3PBMC101359192.0Subject 7KTE-C19152645140.5PBMC121336390.5Median (Range)KTE-C1913 (6-15)37 (15-58)42 (30-56)5 (1-22)1.9 (0.4-4.6)PBMC10 (1-26)13 (2-30)36 (24-59)27 (9-72)1.9 (0.3-2.9) Citation Format: Marc Better, Vijay Chiruvolu, James Oliver, Maryam Sorkhabi, Jeff S. Aycock, Emily Lowe, Edmund Chang, Arianne Perez, Lynn Navale, John M. Rossi, Adrian Bot. Manufacturing and characterization of KTE-C19 in a multicenter trial of subjects with refractory aggressive non-Hodgkin's lymphoma (NHL) (ZUMA-1). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2308.
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