iwCLL 2017| Anti-CD19 CAR-T cell therapy with defined T-cell subsets for ibrutinib-refractory CLL

During iwCLL, on 15^th 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⁺ T_CM 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⁺ T_CM 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).

Study objectives:

• Feasibility of manufacturing a defined composition CAR-T cell product
• Safety of CD19 CAR-T cells
• CAR-T cell persistence and migration
• Anti-tumor efficacy in advanced B-cell malignancies

Patient eligibility:

• R/R CD19+ B-cell malignancies (ALL, NHL, CLL)
• ≥18 years of age
• No inclusion/exclusion based on: ALC, circulating tumor, prior transplant, test expansion

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

Lymphodepletion and JCAR014 immunotherapy in high-risk CLL patients:

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

• CR by iwCLL criteria requires all lymph nodes to be ≤15mm in longest axis
• After JCAR014, 7/16 (44%) ibrutinib-refractory patients achieved PR by iwCLL
  • 4/5 (80%) with PET scans pre- and post-CAR-T cells had no FDG-avid disease
  • 4/6 (67%) were negative by IGH sequencing of the bone marrow

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, 0.34–0.93; 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:

• Bone marrow: clearance by flow cytometry in 15/17 (88%) and by IGHseq in 7/14 (50%)
• iwCLL (at 4 weeks): ORR 14/19 (74%), CR 4/19 (21%)
• PET-avid disease at baseline: CR (PET-negative): 7/11 (64%)

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: