Abstract

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).

Table
PatientAge/GenderMalignancyNumber
of prior
therapies
Total cyclo-
phosphamide
dose
(mg/kg)
Number of
CAR+ T cells
infused
(X106/kg)
Response
(time
after cell
infusion in
months)
56/M SMZL 120 PR (20+) 
43/F PMBCL 60 CR (19+) 
61/M CLL 60 CR (16+) 
30/F PMBCL 120 2.5 NE 
63/M CLL 120 2.5 CR (10+) 
48/M CLL 60 2.5 CR (7+) 
42/M DLBCL 60 2.5 CR (4+) 
44/F PMBCL 10 60 2.5 PR (6+) 
38/M PMBCL 120 2.5 SD (1) 
10 57/F Low-grade NHL 60 PR (4+) 
11 58/F DLBCL from CLL 13 60 PR (2) 
12 60/F DLBCL 60 SD (1+) 
13 68/M CLL 60 PR (2+) 
14 43/M DLBCL 60 PR (1+) 
PatientAge/GenderMalignancyNumber
of prior
therapies
Total cyclo-
phosphamide
dose
(mg/kg)
Number of
CAR+ T cells
infused
(X106/kg)
Response
(time
after cell
infusion in
months)
56/M SMZL 120 PR (20+) 
43/F PMBCL 60 CR (19+) 
61/M CLL 60 CR (16+) 
30/F PMBCL 120 2.5 NE 
63/M CLL 120 2.5 CR (10+) 
48/M CLL 60 2.5 CR (7+) 
42/M DLBCL 60 2.5 CR (4+) 
44/F PMBCL 10 60 2.5 PR (6+) 
38/M PMBCL 120 2.5 SD (1) 
10 57/F Low-grade NHL 60 PR (4+) 
11 58/F DLBCL from CLL 13 60 PR (2) 
12 60/F DLBCL 60 SD (1+) 
13 68/M CLL 60 PR (2+) 
14 43/M DLBCL 60 PR (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.

Author notes

*

Asterisk with author names denotes non-ASH members.

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