Resistance to CAR T Cell Therapy

Acquired resistance mechanistic insights

Two Brief Communication papers published on 1 October 2018 in the Nature Medicine underline that acquired resistance to CD19-targeted CAR T cell therapy can occur through mutations in the CD19 gene or after insertion of a chimeric antigen receptor (CAR) into leukaemia cells, resulting in the adjacent receptor being masked by the CAR. 

Elena J. Orlando of the Novartis Institutes for BioMedical Research, Cambridge, MA, USA and collaborators reported that they identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19 relapse to CAR therapy of acute lymphoblastic leukaemia. The mutations are present in the vast majority of resistant tumour cells and are predicted to lead to a truncated protein with a non-functional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach. 

In second report Carl H. June and J. Joseph Melenhorst of the Perelman School of Medicine at the University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA, USA and colleagues described a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19 leukaemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019. 

Great advances occurred in the field of cancer immunotherapy. Bringing clinical benefit to the majority of patients requires a complete understanding of the mechanisms that would lead to an effective antitumour response and different factors that result in resistance to treatment. Elucidation of these mechanisms is important to reveal the next steps to be taken to potentially overcome resistance to immunotherapy. 

References 

Orlando EJ, Han X, Tribouley C, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia.
 Nature Medicine 2018; 24(10):1504–1506.   

Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nature Medicine 2018; 24(10):1499–1503.