Catch me if you can: Leukemia Escape after CD19-Directed T Cell Immunotherapies

Abstract

Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells. The anti-CD19/CD3 bispecific antibody blinatumomab and anti-CD19 chimeric antigen receptor T cells (CART19) have produced deep responses in patients with relapsed and refractory B-cell acute leukemias. However, although the majority of these patients responds to anti-CD19 immunotherapy, a subset of them still relapses. Interestingly, a novel family of leukemia escape mechanisms has been described, all characterized by the apparent loss of CD19 on the surface of leukemic blasts. This extraordinary finding demonstrates the potent selective pressure of CART19/blinatumomab that drives extreme and specific escape strategies by leukemic blasts. Patients with CD19-negative relapsed leukemia have very poor prognosis and novel approaches to treat and ideally prevent antigen-loss are direly needed. In this review we discuss the incidence, mechanisms and therapeutic approaches for CD19-negative leukemia relapses occuring after CD19-directed T cell immunotherapies and present our future perspective.

Keywords: Adoptive cell therapy; Bispecific antibodies; Blinatumomab; CART19; CTL019; Chimeric antigen receptor T cells; Leukemia; biCAR; dualCART; tanCAR.

Fig. 1

Different strategies to target 2 antigens on the surface of leukemic cells to avoid antigen-loss relapses. A. Chimeric antigen receptor T cells. Pooled CART are a 1:1 mixture of single–specificity CART: each cell remains able to recognize only one target (e.g. CD19 or CD123). Dual (or bi-) CART: every T cell bears 2 distinct CAR structures able to recognize 2 different targets (e.g. CD19 and CD123). Tandem CART: every T cell bears 1 CAR structure where 2 scFvs are built in series and are able to recognize 2 different targets (e.g. HER2 and IL13Rα2). B. Trispecific antibodies. Trispecific antibodies carry 3 scFvs, two recognize tumor targets (e.g. CD123 and CD33) and one engages the immune system (e.g. CD16). Trispecific antibody conjugates include 3 scFvs plus the respective Fabs; two recognize tumor targets (e.g. EGFR and HER2) and one engages the immune system (e.g.CD64). C. Bispecific antibody-toxin conjugates. Bispecific antibody-toxin conjugates carry 2 scFvs that recognize tumor targets (e.g. CD19 and CD22) linked to a toxin (e.g. Diphtheria toxin).