CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity

Abstract

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.

Inducible Polarized Secretion of Exosomes in T and B Lymphocytes

“…Moreover, exosomes have the ability to cross biological barriers such as the blood-brain barrier and blood-tumor barrier as corroborated by the extensive presence of tumor cell-derived exosomes in bodily fluids [135]. Considering that it is not known whether CAR signaling or the exosomal proapoptotic molecules mediate the therapeutic effects observed, these findings require further validation, although they strongly suggest the use of exosomes as biomimetic nanovesicles in the therapy against tumors [133].…”

“…Exosomes released from CAR-T lymphocytes exhibit excellent potential for use as direct attackers in immunotherapy, and the authors demonstrate in their study that ex vivo-produced human exosomes carrying human EGFR and HER2-specific CAR have potent in vivo activity against human tumor in xenograft models [133]. The use of CAR exosomes as cell-free immunotherapy has advantages, such as their independence of CAR-T lymphocytes life span and replication, their stability, the low risk of side toxicity (i.e., cytokine release syndrome) when compared with CAR-T lymphocytes, and the fact that exosomes lacking PD-1 (in contrast to PD-1-expressing T lymphocytes) are refractory to PD-L1 immunosupression by the tumor [133]. In addition, exosomes could be delivered through the blood circulation and other biological fluids as evidenced by the abundance of exosomes found in most biological fluids.…”

“…CAR consist of an extracellular domain, which confers antigen-recognition specificity, a transmembrane domain, and an intracellular signaling domain, which provides activation signals to T lymphocytes [134]. Exosomes released from CAR-T lymphocytes exhibit excellent potential for use as direct attackers in immunotherapy, and the authors demonstrate in their study that ex vivo-produced human exosomes carrying human EGFR and HER2-specific CAR have potent in vivo activity against human tumor in xenograft models [133]. The use of CAR exosomes as cell-free immunotherapy has advantages, such as their independence of CAR-T lymphocytes life span and replication, their stability, the low risk of side toxicity (i.e., cytokine release syndrome) when compared with CAR-T lymphocytes, and the fact that exosomes lacking PD-1 (in contrast to PD-1-expressing T lymphocytes) are refractory to PD-L1 immunosupression by the tumor [133].…”

“…Although the role of these exosomal molecules in both physiologic and pathologic biological responses in vivo has not been fully established (subheading 5), several strategies have been developed considering the presence of TCR and pro-apoptotic molecules on exosomes would endow them with both antigenic specificity and cytotoxicity. This assumption has been recently validated in preclinical studies by using exosomes derived from Chimeric Antigen Receptors (CAR)-T lymphocytes [133]. CAR consist of an extracellular domain, which confers antigen-recognition specificity, a transmembrane domain, and an intracellular signaling domain, which provides activation signals to T lymphocytes [134].…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Notably, a very elegant work has recently translated CAR-T cell technology beyond oncology into the cardiovascular field, to specifically address and treat cardiac fibrosis via the engineering of CAR receptor against a cardiac endogenous protein activating resident fibroblasts [225]. Likewise, CAR-EVs, as derived from CAR-T cells, have also been reported as maintaining target specificity with a much lower risk of cytotoxic cytokine release syndrome commonly caused by adoptive CAR-T cell therapy [226]. This may shed new light on the development of novel strategies to enhance EV cardiac tropism as putative future advanced medicinal paracrine therapy products to counteract cardiovascular disease and heart failure.…”