CAR-T Cell Therapies for Hematological Malignancies

Study Notes

Kymriah (tisagenlecleucel) was authorized by the FDA in 2017, marking a crucial step forward in treating blood cancers.
Five more CAR-T therapies have been approved for the treatment of hematological malignancies since then.

CAR-T cell therapies are associated with severe side-effects such as Graft-versus-Host Disease (GvHD), cytokine release syndrome (CRS), and neurotoxicity.

NK cells are innate, cytotoxic lymphocytes that contribute to immunosurveillance by identifying and killing virally infected cells and tumor cells.
NK cells can be genetically modified to improve their therapeutic efficacy in various ways.
Viral transduction of NK cells remains inefficient and induces cytotoxic effects.

Non-viral transfection technologies are being developed to address the shortcomings of viral vectors.
These technologies aim to engineer NK cells for cancer immunotherapies.

NK cells do not rely on antigen-specific receptors for their activation.
Their activation depends on the integration of signals derived from inhibitory and activating receptors expressed on their surface.
Inhibitory receptors such as Killing Inhibitory Receptor (KIR) and NKG2A can interact with MHC-associated molecules and inhibit NK cell activation.
Activating receptors such as NKG2D, Natural Cytotoxicity Receptors (NCRs), and DNAM-1 can result in NK cell activation upon interaction with tumor ligands.

NK cells can mediate cytotoxicity immediately upon interaction with the target cell.
Upon activation, they release cytolytic granules and cytotoxic cytokines such as interferon γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
These chemokines and cytokines influence an array of immune cells, including B and T cells, macrophages, neutrophils, and dendritic cells.