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68 Anti-CD19 Chimeric Antigen Receptor (CAR) T Cells Produce Complete Responses With Acceptable Toxicity But Without Chronic B-Cell Aplasia In Children With Relapsed Or Refractory Acute Lymphoblastic Leukemia (ALL) Even After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Novel Immune-Based Therapies and Novel Targets
Sunday, December 8, 2013: 5:15 PM
La Nouvelle Ballroom C (Ernest N. Morial Convention Center)

Daniel W. Lee III, MD1, Nirali N Shah, MD2, Maryalice Stetler-Stevenson, MD, PhD3*, Marianna Sabatino4*, Cindy Delbrook, RN2*, Kelly Richards, RN2*, James N Kochenderfer, M.D.5, Steven A. Rosenberg, M.D., Ph.D.6*, David Stroncek, MD4, Alan S. Wayne, MD2 and Crystal L Mackall, MD2

1Pediatric Oncology Branch/NCI, National Cancer Institute, Bethesda, MD
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
3Laboratory of Pathology/CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD
4Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD
5Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
6Surgery Branch, NCI, Bethesda, MD

Survival after relapsed and refractory pediatric pre-B ALL and non-Hodgkin lymphoma (NHL) is poor despite intensive chemotherapy and HSCT.  CAR T cells combine the specificity and MHC independence of antibodies with the cytotoxic capacity of T cells.  By genetically engineering them with a CAR that links an scFv for CD19, present on most NHL and ALL blasts, with the CD3zeta activation domain of the T cell receptor and the CD28 co-stimulatory domain, cytotoxicity can be specifically and fully activated with a single interaction. We undertook a Phase I clinical trial (NCT01593696) of anti-CD19-CD28-zeta CAR T cells in children with relapsed and refractory ALL and NHL with the aim of assessing 1) feasibility of generating adequate numbers of CAR T cells from a high risk population including post-HSCT patients 2) response rate 3) CAR T cell persistence and trafficking to extramedullary sites and 4) toxicities including acute toxicity related to cytokine release syndrome (CRS) and chronic B-cell aplasia related to long-term persistence of CAR T cells.

Patients were enrolled on study, then PBMCs were collected by apheresis then immediately enriched for T cells using activating anti-CD3/CD28 beads before retroviral transduction of the CAR gene.  After an 11-day manufacturing process, CAR T cells were infused fresh to patients who have received fludarabine (25 mg/m2/day Days -4, -3, -2) and cyclophosphamide (900 mg/m2/day Day -2). 

We have enrolled and treated 8 patients (7 ALL, 1 NHL; 4 pre-HSCT, 4 post-HSCT) aged 10-23 years.  Regarding feasibility, 6 of 8 patients had successful expansion of CAR T cells that met the assigned dose level, with transduction efficiencies of 18-87%. Expansion was insufficient to meet the target dose for 2 patients, but each still received products that were 3% and 14% of the target dose.

Response rate: The overall complete response (CR) rate is 5 of 8 (62.5%; 95% CI 29-96%) or 5 of 7 ALL patients (71.4%; 95% CI 38-105%) with 3 of these being MRD-negative, including 1 patient who was primarily refractory to chemotherapy, and who proceeded to HSCT following CD19 CAR therapy.  Both patients who received cells below the target dose experienced anti-leukemic effects, one with a transient CR and the other with an MRD-negative CR.

CAR T cell expansion, persistence and trafficking: CAR T cells have been identified in blood (0.1-38%) and marrow (0.1-5%) in all responding patients.  They have also been found in the CSF of 3 patients (0.3-17%), in the pleural fluid (13%) of an NHL patient with pre-existing malignant pleural effusions, and are suspected to have caused Gr 1 scrotal edema in a patient with a remote history of testicular disease.  One patient with CNS2 disease at the time of enrollment cleared all CSF blasts as detected by flow cytometry without additional intrathecal chemotherapy after CAR T cells were administered (max 17% CAR T cells in CSF).  The mean time to undetectable CAR T cells in any tissue in responding patients was 55 days (± 22.6; 95% CI 35-72).

Toxicity:  Treatment was well tolerated.  Two patients had Gr 2 CRS (Gr 3 fever, Gr 2 hypotension) that resolved with IV fluids and correlated with high IL6, GM-CSF, IFNg, TNFa, and C-reactive protein.  One DLT (Gr 4 CRS) occurred (3 x 10^6 CAR+ T cells/kg) and required vasopressors for hypotension.  After identifying high plasma IL6, the anti-IL6 receptor antibody, tocilizumab, was administered, and quickly reversed most toxicity from CRS. At the time of Day 28 restaging, CD19+ hematogones were detected by flow cytometry in four of five responding patients (mean 81.4% of all CD19+ cells; 95% CI 51-112%), indicating that significant antileukemic effects can be induced by CD19 CAR T cells without chronic depletion of B cell precursors. None of the patients with prior HSCT developed graft versus host (GVH) disease despite administering donor-derived activated T cells harvested from the recipient.

 Conclusions:  Anti-CD19-CD28-zeta CAR T cells that mediate potent antileukemic effects can be reliably generated, even from very advanced patients with or without a history of allogeneic HSCT. Using intent-to-treat reporting, CR rates are high (62.5%) in this refractory population.  CD19 CAR T cells traffic to extramedullary sites and can mediate anti-tumor effects in CSF.  Acute toxicity is manageable and because the anti-CD19-CD28-zeta CAR T cells do not persist at high levels for prolonged periods of time, rapid resumption of B cell lymphopoiesis occurs following therapy.

Disclosures: Off Label Use: Anti-CD19 CAR T cells for the treatment of ALL and NHL..

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