Allogeneic T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor Cause Remissions of B-Cell Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation without Causing Graft-Versus-Host Disease

Introduction

Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem cell transplantation (alloHSCT).  After alloHSCT, B-cell malignancies are often treated with infusions of unmanipulated donor lymphocytes (DLIs) from the transplant donor.  DLIs are frequently not effective at eradicating malignancy, and DLIs often cause graft-versus-host disease (GVHD), which is a potentially lethal allogeneic immune response against normal recipient tissues.

Methods

We conducted a clinical trial of allogeneic T cells that were genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19.  The CAR was encoded by a gamma-retroviral vector and included a CD28 costimulatory domain.  Patients with B-cell malignancies after alloHSCT received a single infusion of CAR T cells.  No chemotherapy or other therapies were administered.  The T cells were obtained from each recipient’s alloHSCT donor. 

Findings

Eight of 20 treated patients obtained remissions, including 6 complete remissions (CR) and 2 partial remissions.  The response rate was highest for acute lymphoblastic leukemia with 4/5 patients obtaining minimal-residual-disease-negative CRs, but responses also occurred in chronic lymphocytic leukemia (CLL) and lymphoma.  The longest ongoing CR is 30+ months in a patient with CLL.  No patient developed new-onset acute GVHD after CAR T-cells were infused.  Toxicities included fever, tachycardia, and hypotension.  

     Median peak blood CAR T-cell levels were higher in patients who obtained remissions (39 CAR+ cells/mL) than in patients who did not obtain remissions (2 CAR+ cells/mL, P=0.001).  Presence of endogenous normal or malignant blood B lymphocytes before CAR T-cell infusion was associated with higher post-infusion median blood CAR T-cell levels (P=0.04).   Compared to patients who did not obtain a remission of their malignancies, patients obtaining remissions had a higher CD8:CD4 ratio of blood CAR+ T cells at the time of peak CAR T-cell levels (P=0.007).  The mean percentage of CAR+CD8+ T cells expressing the programmed cell death-1 (PD-1) protein increased from 12% at the time of infusion to 82% at the time of peak blood CAR T-cell levels (P<0.0001).  The mean percentage of CAR+CD4+ T cells expressing PD-1 increased from 32% at the time of infusion to 91% at the time of peak blood CAR T-cell levels (P<0.0001).

Interpretation

Infusion of allogeneic anti-CD19 CAR T cells is a promising approach for treating B-cell malignancies after alloHSCT.  Our findings point toward a future in which antigen-specific T-cell therapies will be an important part of the field of allogeneic hematopoietic stem cell transplantation.

Patient Number	Malignancy	Transplant type	Total T cells infused/kg	Anti-CD19 CAR-expressing T cells infused/kg	Malignancy response at last follow-up (interval from infusion to last follow-up in months)
1	CLL	URD 10/10 HLA match	1x106	0.4x106	SD (3)
2	DLBCL	Sibling	2x106	0.7x106	SD (1)
3	CLL	Sibling	4x106	2.4x106	PD
4	DLBCL	Sibling	4x106	2.2x106	SD (31+)
5	CLL	URD 10/10 HLA match	1.5x106	1.0x106	CR (30+)
6	MCL	Sibling	7x106	4.6x106	SD (3)
7	CLL	URD 10/10 HLA match	1x106	0.7x106	PD
8	MCL	Sibling	7x106	3.9x106	SD (24+)
9	MCL	URD 10/10 HLA match	4x106	2.2x106	PR (3)
10	MCL	Sibling	10x106	7.8x106	SD (2)
11	CLL	URD 9/10 HLA match	5x106	3.1x106	PR (12+)
12	ALL Ph+	Sibling	7x106	5.2x106	MRD-negative CR (15+)
13	MCL	Sibling	10x106	7.1x106	SD (9)
14	ALL Ph-neg	Sibling	10x106	7.0x106	MRD-negative CR (5)
15	ALL Ph-neg	Sibling	10x106	6.9x106	MRD-negative CR (3)
16	ALL Ph-neg	Sibling	7x106	5.6x106	PD
17	DLBCL	Sibling	10x106	8.2x106	CR (6+)
18	DLBCL	Sibling	10x106	3.1x106	SD (2)
19	FL transformed to DLBCL	URD 10/10 HLA match	5x106	4.3x106	PD
20	ALL Ph-neg	URD 9/10 HLA match	5x106	4.2x106	MRD-negative CR (3+)^

CLL, chronic lymphocytic leukemia; ALL Ph+, Philadelphia chromosome positive acute lymphoblastic leukemia; ALL Ph-neg, Philadelphia chromosome negative acute lymphoblastic leukemia; MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; Sibling, human leukocyte antigen-matched sibling donor; URD, unrelated donor; HLA, human leukocyte antigen; PD, progressive disease; SD, stable disease; PR, partial remission; CR, complete remission; MRD-negative, minimal residual disease negative.  ^Patient 20 underwent a second alloHSCT 3.5 months after anti-CD19 CAR T-cell infusion while in MRD-negative CR.

Disclosures: Goy: Celgene: Consultancy , Research Funding , Speakers Bureau ; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau . Rosenberg: Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma . Kochenderfer: bluebird bio Inc.: Research Funding .

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