CLL/SLL|DLBCL|FL|MCL|MZL

AACR 2017 – Understanding success and failure of CAR T-cell therapy for Non-Hodgkin Lymphoma

This year’s American Association for Cancer Research (AACR) annual meeting took place on 1–5 April in Washington, DC, USA. The program committee Chair was Kornelia Polyak, MD, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts.

On Sunday 2nd April, during the “RAOS02 - Immunotherapy of Lymphoid Malignancies” session, Stanley R. Riddell of the Fred Hutchinson Cancer Research Center, Seattle, WA, gave a talk titled: “Understanding success and failure of T-cell therapy for B-cell malignancies.”

Stanley Riddell began his talk by outlining the advantages and disadvantages of Chimeric Antigen Receptors (CARs) as well as the potential targets for CAR directed therapy in a range of B-cell malignancies:

For CAR therapy, the patient needs to undergo leukapheresis to obtain T-cells, however an issue arises due to “cell composition”, a mixture of T-cell types can be collected and different T-cell subsets have different attributes for cell therapy.

Moreover, patients suffering with B-cell malignancies are often lymphopenic, and harbor a variable distribution of phenotypic subsets. Ideally, effective T-cell subsets need to be identified and consistent products need to be produced for all patients. However, currently a method for accurate and quick selection of T-cell subsets with clinical grade selection agents is not available.

The talk then focused on data published by Turtle et al. in Science Translational Medicine in 2016, who treated NHL patients with CAR T-cells prepared from a strictly defined ratio of CD4 to CD8 T-cells.

It has been found that different subtypes of NHL respond differently to CAR T-cell therapy. Stanley Riddell then asked what mediates resistance to CAR T-cells in some patients, providing three potential mechanisms:

  • Local resistance to CAR T-cells infiltrating in tumor microenvironment
  • Immune checkpoint molecules on tumor (e.g. PD-L1) and CAR T-cells (PD-1, Lag-3, Tim3)
  • Local metabolic impediments to CAR T-cell function

The talk then focused on CAR T-cell therapy for CLL patients, prior to ibrutinib, and has resulted in high response rates. In 24 patients (n = 19 ibrutinib refractory; n = 3 ibrutinib intolerant), ORR was 74% (14/19), CR by iwCLL criteria was 21% (4/19) but CR by PET was 64% (7/11).

Stanley Riddell also presented incidence data of cytokine release syndrome and neurotoxicity that occurs as a result of CAR T-cell therapy:

It has also been found that high levels of IL-15 and IL-6, as well as low levels of TGF-β, on day 1 are associated with grade 3 or higher neurotoxicity.

To counteract B-cell aplasia caused by persistence of CAR T-cells, it has been suggested that antibody targeting of EGFRt can eliminate CD19 CAR T-cells allowing B-cells to recover.

Stanley Riddell concluded the talk with a succinct summary slide:

Reference:
  1. Riddell S.R. Understanding success and failure of T-cell therapy for B-cell malignancies [Presentation]. In: Proceedings of the107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; 2017. Session nr [RAOS02].