Use of transposons PiggyBac to transduce T and CIK cells with FcgR-Chimeric Receptors (CAR-T and CAR-CIK) for adoptive cell therapy of AML

Anno
2018
Proponente Maurizio Alimandi - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Abstract

Together with the check point T cell inhibition, Adoptive Cell Therapy (ACT) with chimeric antigen receptor (CAR) redirected T cells is perhaps, the most attractive anti-cancer strategy. CARs need to absolve dual function: antigen recognition and triggering of the lytic machinery of reprogrammed T cells. However, the full realization of the therapeutic potential of these approaches still relies on the possibility to overcome some of the limitations that obstacle the successful and the diffusion of clinical application of CAR-T cell-based immunotherapies. They are: the off-target toxicity, the cancer immune evasion, the high manufacturing cost and the elevated GMP standard conditions necessary for the production of viral vectors for cell transduction, safety for patients and operators.
We engineered two types of FcgR-CRs (CD16A-CR and CD64-CR equipped with CD28/z-chain signaling domains), to redirect T cell functions against opsonized tumor cells (Italian patent - Brevetto Italiano N° 0001429214). Among the advantages, "Universal FcgR-CRs" combine the mAbs therapeutic activities with a T cell-dependent activation at the tumor site, targeting antigens sequentially or in combination, according to appropriate administration of mAbs.
Furthermore, to advance the chimeric receptor towards its clinical application, we propose the transposon system PiggyBac in alternative to the viral-based systems for gene transduction of T lymphocytes.
In our application, we aim to:
a) verify the potentiality of using FcgR-CRs to kill opsonized acute myeloid leukemia (AML) cells.
b) optimize the strategy of gene delivery in cytokine-induced killer (CIK) and primary T cells using the transposon/transposase system PiggyBac.

ERC
LS6_4, LS6_3, LS6_2
Keywords:
TERAPIA GENICA, IMMUNOLOGIA, ONCOLOGIA, EMATOLOGIA

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