Structural and diffusion weighted MRI demonstrates responses to ibrutinib in a mouse model of follicular helper (Tfh) T-cell lymphoma

Abstract

Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquin san/+ ) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquin san/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.

The new biology of PTCL‐NOS and AITL: current status and future clinical impact

“…The tyrosine kinase inhibitor dasatinib has been shown to block VAV1 phosphorylation and increased TCR signalling due to RHOA (p.Gly17Val) in a T‐cell line (Fujisawa et al , ). ITK is expressed in AITL and we have demonstrated in cell lines (Mamand et al , ) and also in a mouse model of Tfh lymphoma (Allchin et al , ) that ibrutinib, a dual ITK and Bruton's tyrosine kinase (BTK) inhibitor, can repress growth and reduce tumour size. A clinical trial that enrolled patients with a mixture of T‐cell lymphoma diagnoses did not support the use of ibrutinib (Kumar et al , ) but the effects of this drug on specific AITL populations is unknown.…”

Targeting ITK signaling for T cell-mediated diseases

“…A topical retinoid was shown to inhibit ITK and reduce tumor growth in a murine model of cutaneous T cell lymphoma (Li et al, 2020). Another study showed that ITK inhibition worked synergistically with chemotherapy in a T cell lymphoma xenograft model (Liu et al, 2019), and ibrutinib was shown to shrink tumor burden using a novel T cell lymphoma murine model (Allchin et al, 2019). However, despite these findings, a recent pilot study found that 14 patients with refractory T cell lymphoma failed to respond to ibrutinib (Kumar et al, 2018).…”

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

“…A large proportion of PTCL cases are derived from follicular helper T cells (Tfh), which express high levels of ITK proteins (66). In a mouse model of Tfh-derived lymphoma, ibrutinib effectively induces lymphoma regression (67). However, the preliminary results of the Phase I trial NCT02309580 suggest that ibrutinib has limited clinical benefits in 13 patients with R/R TCL (49) (Table 2).…”