Anti-CD19 CAR-T cell therapy with defined T-cell subsets for ibrutinib-refractory CLL presentation at iwCLL 2017 – Lymphoma Hub

During iwCLL, on 15th May 2017, the Additional Therapies for the Relapsed/Refractory CLL Patient session took place and was co-chaired by Michael Keating (MD Anderson Cancer Center) and Jacqueline Barrientos (The Feinstein Institute for Medical Research).

Anti-CD19 CAR-T Cell Therapy With Defined T-Cell Subsets for Ibrutinib-Refractory CLL was a presentation given during this session by David G. Maloney, MD, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Maloney began by explaining that CAR-T cells produced from distinct T-cell subsets differ in potency. NSG mice bearing Raji tumors (0.5x106 tumor cell inoculation; day 0) were treated with human CAR-T cells manufactured from distinct T-cell subsets (on day 7). CAR-T cells produced from CD8+ TCM cells were highly potent (Sommermeyer et al. 2015).

Engineering selected T-cell subsets could enhance potency and allow delivery of the same cell product in all patients, potentially providing more uniform data on dose response and toxicity.

Pre-clinical studies have established that a defined composition of CD8+ TCM derived and CD4+ derived CAR T-cells provides optimal potency.

The talk then focused on the outline of the phase I/II study of JCAR014 in adult B-cell ALL, NHL, and CLL patients (NCT01865617).

As of 9/1/16, 136 patients had been treated: ALL = 48, NHL = 64, and CLL = 24.

Dose Level

Cells/kg

1

2x105 EGFRt+

2

2x106 EGFRt+

3

2x107 EGFRt+

Lymphodepletion and JCAR014 immunotherapy in high-risk CLL patients:

Treatment

N=24

Lymphodepleting chemotherapy

Cyclophosphamide/fludarabine (Cy/Flu)

21 (87%)

Non-Cy/Flu

3 (13%)

CAR-T cell manufacturing

CD8+ central memory and CD4+

7 (29%)

CD8+ all subsets and CD4+

17 (71%)

CD19 CAR-T cell dose level

DL1 (2x105 EGFRt+ cells/kg)

4 (17%)

DL2 (2x106 EGFRt+ cells/kg)

19 (79%)

DL3 (2x107 EGFRt+ cells/kg)

1 (4%)

Cycles

Single cycle

18 (75%)

Outpatient lymphodepletion and CAR-T cells

18 (75%)

Second cycle for residual disease or relapse

6 (25%)

Maloney then asked can IGH sequencing of the marrow at 4 weeks after JCAR014 identify patients with better outcomes?

Additionally, higher JCAR014 counts in the blood after infusion were associated with better bone marrow response in high-risk CLL. Patients with a higher peak CD3+/EGFRt+ CAR-T cell count in the blood had a reduced hazard of progression or death (HR, 0.56; 95% CI, 0.340.93; P = 0.025).

Maloney concluded that in high-risk CLL patients CD19 CAR-T cells of defined composition (JCAR014) can be administered with an acceptable early toxicity profile. JCAR014 and Cy/Flu lymphodepletion shows a high-level or anti-tumor activity as measured by:

Deep marrow clearance by IGHseq after JCAR014 provides early signs of durable responses with 100% PFS and OS.

Lastly, Maloney presented evidence that ROR1 presents as a novel target for CAR-T cell therapy for CLL, MCL, and solid tumors as it is highly expressed on the surface of malignant B-cells:

Go here to see the original:
Anti-CD19 CAR-T cell therapy with defined T-cell subsets for ibrutinib-refractory CLL presentation at iwCLL 2017 - Lymphoma Hub