In a Nature study, researchers at the University of Pennsylvania identified a patient with an enhanced response to CAR T therapy Kymriah tisagenlecleucel, and suggested targeting the epigenome by inhibiting Tet2 could improve the efficacy of CAR T therapies.
The paper's authors include CAR T pioneer Carl June, whose research led to the development of Kymriah, which Novartis AG (NYSE:NVS; SIX:NOVN) licensed from UPenn.
Tet methylcytosine dioxygenase 2 (Tet2) mediates DNA demethylation, and is a tumor suppressor gene and epigenetic master regulator of blood cell formation.
The authors described a single patient with advanced relapsed or refractory chronic lymphocytic leukemia (CLL) from a Phase I trial who had a progressive leukemia six weeks after the first dose of Kymriah. However, peak expansion of Kymriah CAR T cells were evident at two months following the second infusion. The patient achieved complete remission, and remains in complete remission for more than five years.
At the peak response, the researchers found that 94% of the CAR T cells came from a single clone in which the CAR was inserted into one allele of the Tet2 gene in the patient's T cells. The patient also had a hypomorphic mutation in the second Tet2 allele, leading to loss of function of Tet2.
Characterization of the patient's CAR T cells showed altered T cell differentiation and increased levels of cytotoxic enzymes granzyme B (GrB; GZMB) and perforin. In the patient, 65% of CAR T cells had a central memory phenotype, which was higher than two patients with long-term durable remissions without Tet2 integrations. This suggests Tet2 dysfunction led to development of persistent memory T cells with increased tumor-killing capacity.
In T cells from healthy volunteers, shRNA knockdown of Tet2 increased the percentage of central memory cells and increased proliferation upon antigen stimulation while decreasing the percentage of effector cells.
Kymriah comprises autologous T cells loaded with a lentiviral vector expressing CART-19, which consists of a cancer antigen-binding domain targeting CD19 linked to CD3zeta/CD137 immunostimulatory domains. The therapy is approved in the U.S. to treat pediatric relapsed, refractory acute lymphoblastic leukemia (ALL) and adults with relapsed or refractory diffuse large B cell lymphoma (DLBCL).