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We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a low-dose chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose chemotherapy, toxicity was reduced when CAR T cells were infused after low-dose chemotherapy. None of the 9 patients treated with low-dose chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils

We have treated 20 patients and administered 23 total T-cell infusions on a clinical trial of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. This is the largest reported clinical trial of anti-CD19-CAR T cells. The first 9 CAR-T-cell treatments have been reported (Kochenderfer et al. Blood 2010 and Blood 2012). This abstract communicates unreported results from 14 patients who received anti-CD19-CAR T cells produced with a new 10-day culture process. These patients did not receive exogenous interleukin-2. Of these 14 patients, 5 obtained complete remissions (CR), and 6 obtained partial remissions (PR), (see table).TablePatientAge/GenderMalignancyNumberof priortherapiesTotal cyclo-phosphamidedose(mg/kg)Number ofCAR+ T cellsinfused(X106/kg)Response(timeafter cellinfusion inmonths)156/MSMZL41205PR (20+)243/FPMBCL4605CR (19+)361/MCLL2604CR (16+)430/FPMBCL31202.5NE563/MCLL41202.5CR (10+)648/MCLL1602.5CR (7+)742/MDLBCL5602.5CR (4+)844/FPMBCL10602.5PR (6+)938/MPMBCL31202.5SD (1)1057/FLow-grade NHL4601PR (4+)1158/FDLBCL from CLL13601PR (2)1260/FDLBCL3601SD (1+)1368/MCLL4601PR (2+)1443/MDLBCL2601PR (1+) The CAR used in this work is encoded by a gammaretrovirus and incorporates the variable regions of an anti-CD19 antibody, part of CD28, and part of CD3-zeta. A mean of 70.5% of the infused T cells expressed the CAR, and the infused cells produced cytokines and degranulated in a CD19-specific manner. Because prior chemotherapy has been shown to enhance the activity of adoptively-transferred T cells, patients received cyclophosphamide (total doses shown in table) plus fludarabine (25 mg/m2 daily for 5 days) before a single infusion of anti-CD19-CAR-transduced T cells. This is the first report of successful treatment of chemotherapy-refractory primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma not otherwise specified (DLBCL) with anti-CD19-CAR T cells. All of the 8 treated patients with either PMBCL or DLBCL were chemotherapy-refractory, and 5 of these 8 patients obtained either a CR or PR on this trial. We defined chemotherapy-refractory as progression or no response 1 month after the end of the most recent chemotherapy. For example, Patient 2 had PMBCL that was refractory to 3 different chemotherapy regimens and that relapsed after radiation therapy. Patient 2 obtained a CR after infusion of anti-CD19 CAR T cells and remains in CR 19 months post-infusion. Blood B-cell depletion lasting more than 3 months occurred in 3 of 3 evaluable patients. Most patients were not evaluable for B-cell depletion due to B-cell depletion by prior treatments. One patient died suddenly of unknown etiology 16 days after infusion of CAR T cells. Acute toxicities including fever, hypotension, and delirium occurred after infusion of anti-CD19-CAR T cells. The toxicities resolved in less than 3 weeks after the cell infusion and were temporally associated with elevated serum interleukin-6 and interferon gamma levels in most patients. Peak blood levels of cells containing the CAR gene ranged from 2.3% to 66.5% of blood mononuclear cells. These results demonstrate the feasibility of treating patients with chemotherapy-refractory B-cell malignancies by using autologous anti-CD19 CAR T cells. The numerous remissions obtained should encourage further development of this approach. SMZL, splenic marginal zone lymphoma; PMBCL, primary mediastinal B-cell lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma not otherwise specified. CR, complete remission; NE, not evaluable; PR, partial remission; SD, stable disease. (+) indicates an ongoing response. Disclosures: Rosenberg: Kite Pharma: Research Funding.