Treatment with Living Drugs: Pharmaceutical Aspects of CAR T Cells

Abstract

<b><i>Background:</i></b> Adoptive therapy with genetically modified T cells achieves spectacular remissions in advanced hematologic malignancies. In contrast to conventional drugs, this kind of therapy applies viable autologous T cells that are ex vivo genetically engineered with a chimeric antigen receptor (CAR) and are classified as advanced therapy medicinal products. <b><i>Summary:</i></b> As “living drugs,” CAR T cells differ from classical pharmaceutical drugs as they provide a panel of cellular capacities upon CAR signaling, including the release of effector molecules and cytokines, redirected cytotoxicity, CAR T cell amplification, active migration, and long-term persistence and immunological memory. Here, we discuss pharmaceutical aspects, the regulatory requirements for CAR T cell manufacturing, and how CAR T cell pharmacokinetics are connected with the clinical outcome. <b><i>Key Messages:</i></b> From the pharmacological perspective, the development of CAR T cells with high translational potential needs to address pharmacodynamic markers to balance safety and efficacy of CAR T cells and to address pharmacokinetics with respect to trafficking, homing, infiltration, and persistence of CAR T cells.

CAR T cells: engineered immune cells to treat brain cancers and beyond

“…They even present with unique advantages of long residence time and proliferative abilities, making them comparable to ‘living drugs’ [ 16 ]. Certain chemokines and adhesion molecules crucial for T cell trafficking into the brain have been identified.…”

Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors

“…Chimeric antigen receptor (CAR) T cells have shown great success in the treatment of B cell lymphoma and recently also against multiple myeloma, with five approved products on the European market and several trials ongoing. 1 , 2 , 3 Most CAR T cell products are generated by genetic modification of T cells using lentiviral vectors (LVs) pseudotyped with the vesicular stomatitis virus (VSV) glycoprotein G. Still, many challenges remain in the manufacturing process, which in its current form is highly laborious, time intensive, and expensive. 4 T cells need to be isolated from the patient’s blood by leukapheresis, activated through the endogenous CD3:T cell receptor (TCR) using recombinant antibodies against CD3 and CD28, genetically modified by viral vectors, and expanded several days prior to reinfusion into the patient.…”

IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities

“…Chimeric antigen receptor (CAR) T cells evolved into a crucial pillar of cancer immunotherapy in recent years ( 1 ). Following long-lasting complete remissions in patients with advanced B-cell malignancies, regulatory authorities in the US and Europe issued approval for CAR T cell treatment in patients with refractory or relapsing acute lymphoblastic leukemia and specific lymphoma entities ( 2 ). While numerous clinical trials are successfully evaluating CAR T cell therapy in a wide variety of hematological malignancies, a sizable portion of patients does not benefit from CAR T cell therapy.…”