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Abstract
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed spectacular efficacy in the treatment of leukemia in recent early phase trials. Patient’s T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG1+ CD57+ CD7− CCR7− phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134) stimulation. We discuss the strategy with respect to prolong the anti-tumor response and to improve the over-all efficacy of adoptive cell therapy.
Highlights
ADOPTIVE THERAPY WITH chimeric antigen receptor (CAR) ENGINEERED T CELLS SHOWED SPECTACULAR EFFICACY IN EARLY PHASE TRIALS Recent success in the immune therapy of malignant diseases has sustained the promise that the immune system can control cancer in the long-term
To overcome the situation strategies were developed to engraft T cells with defined specificity by genetic engineering; the so-called “T-body” strategy equips patient’s T cells with a recombinant trans-membrane receptor molecule which is composed in the extracellular part of an antibody-type recognition domain for MHC-independent binding and in the intracellular part of T cell activating domains, mostly the TCR CD3ζ endodomain linked to a costimulatory domain like CD28, OX40, or 4-1BB (Gross and Eshhar, 1992; Eshhar, 2008)
The process is observed in a mouse tumor model in which after adoptive transfer of young CCR7+ CAR T cells the majority of tumor infiltrating CAR T cells are of CCR7low phenotype (Hombach et al, 2013)
Summary
ADOPTIVE THERAPY WITH CAR ENGINEERED T CELLS SHOWED SPECTACULAR EFFICACY IN EARLY PHASE TRIALS Recent success in the immune therapy of malignant diseases has sustained the promise that the immune system can control cancer in the long-term. This is basically due to the CD28 mediated improvement of T cell effector functions and the protection from activation-induced cell death resulting in prolonged persistence in vivo (Savoldo et al, 2011).
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