Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer

Adoptive cellular therapy (ACT) has revolutionized the treatment of certain malignancies and responses
in refractory B cell tumors treated with chimeric antibody receptor (CAR)-expressing T cells have
been remarkable. However, ACT is not consistently curative even in these particularly responsive cancers,
highlighting the critical need for innovative approaches to improve this powerful therapeutic approach. Type I
interferon (IFN) signaling through the type I interferon receptor (IFNAR) plays a key role in the activation,
differentiation and function of T cells. Importantly, degradation of the type I interferon receptor chain subunit
1 (IFNAR1) in anti-tumor T cells favors tumor progression whereas its genetic or pharmacologic (by p38
inhibition) stabilization improves anti-tumor T cell activity in mouse models. While rodent studies have yielded
much preclinical insight into CAR T cells, they fail to accurately predict clinical safety and efficacy. However,
genetically outbred and immunologically intact canine cancer patients that develop tumors spontaneously are
rapidly gaining traction as an invaluable preclinical model. In exciting new preliminary data, we infused CAR T
cells treated with the IFNAR1 stabilizing p38 inhibitor ralimetinib into a canine B cell lymphoma patient.
Following treatment, we observed signs associated with CAR T cell mediated anti-tumor activity that have not
been previously observed in canine patients treated with CAR T cells. Furthermore, in human chronic
lymphocytic leukemia patients, an active type I IFN gene signature was associated with improved outcomes
following CAR T cell therapy. Together, these data support the hypothesis that stabilization of IFNAR1 on the
surface of CAR T cells will improve their therapeutic efficacy for the treatment of B cell malignancies. We will
perform the following studies to test this:
1. Canine cancer patients with spontaneous diffuse large B cell lymphoma currently being enrolled in a pilot
trial will be used to determine the safety and efficacy of IFNAR1-stabilized CART cells.
2. CART cells derived from multiple species will be evaluated in vitro and in vivo to ascertain the mechanism
by which genetic and pharmacologic IFNAR1 stabilization enhances the anti-tumor activity of CART cells.
3. The prognostic significance of IFNAR1 and downstream signaling in T cell apheresis products used to
manufacture CAR T cells and CAR T cells themselves will be evaluated in patients with B cell malignancies.
We anticipate that IFNAR1 stabilization will safely enhance the activity of CAR T cells. As a veterinary
oncologist with doctoral training in immunology I have a solid foundation of the knowledge and skillsets required
to undertake these studies. The proposed research on the application of CART cell therapy for the treatment of
B cell neoplasia will be performed under the expert guidance of Ors. Fuchs and Mason and represents a field for
which the University of Pennsylvania is globally renowned.

Grant Number: 5K08CA252619-05
NIH Institute/Center: NIH
Principal Investigator: Matthew Atherton