Editors' ChoiceImmunology

Hybrid CARs for Cancer?

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Science Translational Medicine  13 Aug 2014:
Vol. 6, Issue 249, pp. 249ec139
DOI: 10.1126/scitranslmed.3010119

The resurgence of immunotherapy strategies for treating cancer can be mostly attributable to the ability to manipulate T cells, whether through checkpoint blockade or redirection with chimeric antigen receptors (CARs). The majority of human T cells express αβ T cell receptors, which are exquisitely restricted to the set of major histocompatibility complex (MHC) molecules that define tissues as “self.” It is this specificity that drives the need for tissue matching in allogeneic bone marrow transplantation. However, there are smaller subsets of T cells, such as invariant natural killer T cells (NKT cells), that are a sort of hybrid between T cells and NK lymphocytes. NKT cells have a conserved T cell receptor that is CD1d-restricted instead of MHC-restricted. Importantly, these invariant NKT cells can kill tumor-associated macrophages that express CD1d.

Now, Heczey et al. have designed a new platform for cancer immunotherapy by transducing invariant NKT cells with chimeric antigen receptors specific for the ganglioside GD2. This GD2 antigen has been targeted with antibodies and with CAR (αβT) cells in neuroblastoma, with encouraging results. The authors tested CARs transduced into NKT cells in vitro and in mice carrying human neuroblastoma xenografts. The researchers found that the endodomains of the CARs polarized cytokine production, driving NKT cell survival just like they do in αβ T cells. They also found that NKT cells retained their ability to kill tumor-associated macrophages and did not cause graft-versus-host disease the way that αβ T cells do.

Invariant NKT cells may expand the platform of CAR immunotherapy and may be naturally synergistic with approaches that, for example, target the tumor microenvironment. Invariant NKT cells also have the potential for “universal donor” use. On the other hand, invariant NKT cells may still be susceptible to rejection by the host, and the methods used for isolating and growing them may be more difficult than for αβ T cells because they are so rare. However, these issues potentially can be solved, and clinical trials using CAR-NKT cells are worth exploring.

A. Heczey et al., Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 10.1182/blood-2013-11-541235 (2014). [Abstract]

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