Editors' ChoiceCancer

Hiding from the enemy

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Science Translational Medicine  11 Nov 2015:
Vol. 7, Issue 313, pp. 313ec193
DOI: 10.1126/scitranslmed.aad5509

In recent years, we have learned a number of tricks for training the immune system to launch attacks on cancer. One such approach is to equip immune cells with man-made receptors, so-called chimeric antigen receptors (CARs), to enable them to recognize specific targets on cancer cells. Among diseases that have been targeted with CARs loaded onto T cells (CART) is B cell acute lymphoblastic leukemia (B-ALL) of childhood. Although mostly a curable disease, B-ALL can be resistant to conventional treatment. In such cases, experimental treatment using the CAR technology has had promising successes by aiming CART at the B cell receptor, CD19. Nevertheless, about one-fifth of children who initially respond to CART therapy will relapse with cancer, often accompanied by loss of CD19 from cancerous B cells. The precise mechanism underlying these relapses and the loss of CD19 remains elusive.

Now, Sotillo et al. have dissected the biology underlying failure of CART therapy in four children suffering from B-ALL, using massively parallel sequencing of tumors in conjunction with functional experiments. In some of the cases they studied, loss of CD19 was caused by the emergence of truncating DNA mutations. In others, CD19 loss was generated through alternative splicing of the CD19 transcripts, mediated by a specific splicing factor (SRSF3), which generated a CD19 protein invisible to CART. Together, these findings begin to paint a picture of the sophisticated evolution the tumor genome undergoes as it evades the immune system.

The larger importance of this study is that it provides a specific explanation as to why CART may fail, thus revealing possible strategies of how to combat CART resistance. Furthermore, it shows how human cancers are capable of evading even the most precise, elaborate of therapies at our disposal. Yet, the experiment of Sotillo et al. should encourage researchers to continue to study the manifold mechanisms underlying treatment resistance.

E. Sotillo et al., Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 10.1158/2159-8290.CD-15-1020 (2015).[Abstract]

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