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).
| Patient | Age/Gender | Malignancy | Number of prior therapies | Total cyclo- phosphamide dose (mg/kg) | Number of CAR+ T cells infused (X106/kg) | Response (time after cell infusion in months) |
|---|---|---|---|---|---|---|
| 1 | 56/M | SMZL | 4 | 120 | 5 | PR (20+) |
| 2 | 43/F | PMBCL | 4 | 60 | 5 | CR (19+) |
| 3 | 61/M | CLL | 2 | 60 | 4 | CR (16+) |
| 4 | 30/F | PMBCL | 3 | 120 | 2.5 | NE |
| 5 | 63/M | CLL | 4 | 120 | 2.5 | CR (10+) |
| 6 | 48/M | CLL | 1 | 60 | 2.5 | CR (7+) |
| 7 | 42/M | DLBCL | 5 | 60 | 2.5 | CR (4+) |
| 8 | 44/F | PMBCL | 10 | 60 | 2.5 | PR (6+) |
| 9 | 38/M | PMBCL | 3 | 120 | 2.5 | SD (1) |
| 10 | 57/F | Low-grade NHL | 4 | 60 | 1 | PR (4+) |
| 11 | 58/F | DLBCL from CLL | 13 | 60 | 1 | PR (2) |
| 12 | 60/F | DLBCL | 3 | 60 | 1 | SD (1+) |
| 13 | 68/M | CLL | 4 | 60 | 1 | PR (2+) |
| 14 | 43/M | DLBCL | 2 | 60 | 1 | PR (1+) |
| Patient | Age/Gender | Malignancy | Number of prior therapies | Total cyclo- phosphamide dose (mg/kg) | Number of CAR+ T cells infused (X106/kg) | Response (time after cell infusion in months) |
|---|---|---|---|---|---|---|
| 1 | 56/M | SMZL | 4 | 120 | 5 | PR (20+) |
| 2 | 43/F | PMBCL | 4 | 60 | 5 | CR (19+) |
| 3 | 61/M | CLL | 2 | 60 | 4 | CR (16+) |
| 4 | 30/F | PMBCL | 3 | 120 | 2.5 | NE |
| 5 | 63/M | CLL | 4 | 120 | 2.5 | CR (10+) |
| 6 | 48/M | CLL | 1 | 60 | 2.5 | CR (7+) |
| 7 | 42/M | DLBCL | 5 | 60 | 2.5 | CR (4+) |
| 8 | 44/F | PMBCL | 10 | 60 | 2.5 | PR (6+) |
| 9 | 38/M | PMBCL | 3 | 120 | 2.5 | SD (1) |
| 10 | 57/F | Low-grade NHL | 4 | 60 | 1 | PR (4+) |
| 11 | 58/F | DLBCL from CLL | 13 | 60 | 1 | PR (2) |
| 12 | 60/F | DLBCL | 3 | 60 | 1 | SD (1+) |
| 13 | 68/M | CLL | 4 | 60 | 1 | PR (2+) |
| 14 | 43/M | DLBCL | 2 | 60 | 1 | 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.
Rosenberg:Kite Pharma: Research Funding.
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