Effective Treatment Of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma With Autologous T Cells Genetically-Engineered To Express An Anti-CD19 Chimeric Antigen Receptor
Authors: Kochenderfer James N. , Dudley Mark E. , Kassim Sadik H. , Carpenter Robert O. , Yang James C. , Phan Giao Q. , Hughes Marybeth S. , Sherry Richard M. , Feldman Steven , Spaner David , Nathan Debbie-Ann N. , Morton Kathleen E. , Toomey Mary Ann , Rosenberg Steven A. 
Published: October 2019

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).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.