2.1 CART therapy and CRISPR Cas9
One
of the most successful innovations in the area of hematology is the
CRISPR/Cas9-edited chimeric antigen receptor (CAR) T cell (CAR-T cell),
which is additionally a primary leap forward in the area of
immunotherapy and was approved by the FDA for the treatment of leukemia
and lymphoma 21,22.
Eshhar 23 et al. first suggested structural and
functional similarities between endogenous αβT cell receptors (TCRs) and
antibodies. Target cells carrying 2,4,6-trinitrophenyl (TNP)
semi-antigenic motifs can be recognized by chimeric TCR chains, which
consist of immunoglobulin V region and TCR C region, and do not elicit
immune response from the receptor as well as rejection. B cells
specifically express CD19, while CART cells modified by the CRISPR Cas9
gene themselves in particular recognize CD19 in addition to their T
lymphocyte-borne killing function, thus specifically killing tumor cells
with long-lasting effects 24,25.
However, there are a couple of elements that have an effect on the
efficacy of CAR-T therapy, together with T cell status, individual
specificity, etc.
Patients treated with CAR-T cells may develop serious adverse effects,
such as tumor lysis syndrome and cytokine release syndrome (CRS), and
although these syndromes are manageable, they may become serious
complications if not managed properly.
Delivery of bound CAR and CRISPR
RNA through electroporation with lentivirus leads to injury of TCR and
β-2-microglobulin (B2M) genes,
ensuing in homozygous CAR T cells missing TCR, HLA type I molecules and
PD1; as Fas receptor / Fas ligand (FasL) induces T cell apoptosis,
CTLA-4, PD- 1, LAG-3 and TIM-3
are T cell suppressor receptors or signaling molecules whose expression
motives T cell failure 26-28, therefore, knockdown of
these elements through CRISPR Cas9 can decrease T cell apoptosis and
amplify CAR T cells and therefore decorate their function.