Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia
Paul Maciocia, Patrycja Wawrzyniecka, Nicola Maciocia, Amy Burley, Thaneswari Karpanasamy, Sam Devereaux, Malika Hoekx, David O’Connor, Theresa E. León, Tanya Rapoz-D’Silva, Rachael Pocock, Sunniyat Rahman, Giuseppe Gritti, Diana C. Yánez, Susan R. Ross, Tessa Crompton, Owen Williams, Lydia Lee, Martin Pulé, Marc R. Mansour
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.