Author(s): Elisabetta Petrozziello aff1 , Tabea Sturmheit aff1 aff2 , Anna Mondino [*] aff1
adoptive T-cell therapy; common [gamma]-chain cytokines; hematological malignancies; innate and adaptive immune responses; proinflammatory cytokines; solid tumor; T-cell differentiation; T-cell homing; tumor microenvironment
The purpose of adoptive T-cell therapy (ACT) is to overcome limitations imposed by central and peripheral mechanisms of tolerance and to increase the precursor frequency of tumor-reactive T cells within the natural repertoire of the patient. Among available strategies, the isolation and in vitro expansion of tumor-infiltrating lymphocytes (TILs) derived from tumor lesions, followed by their re-infusion into the patient, has produced encouraging results in the therapy of metastatic melanoma. More recently, genetic engineering approaches have been used to instruct T cells to recognize given tumor-associated antigens [1,2 ]. This is commonly done via transduction of T cells with retro- or lenti-viral vectors either encoding the tumor-reactive [alpha] and [beta] chains of classical T-cell receptors (TCR) or the extra- and intracellular moieties of recombinant chimeric antigen receptors (CAR), thus giving rise to TCR-redirected T cells or CAR-redirected T cells, respectively recognizing the nominal antigen via major histocompatibility complex (MHC) class I (or class II)-dependent or independent means.
Both preclinical and clinical observations indicate that the efficacy of ACT approaches based on tumor-reactive T cells isolated from tumors or peripheral blood, or generated by genetic manipulation, benefits from controlled in vitro culture conditions and in vivo supportive means. For instance, preserving cells at an intermediate stage of differentiation during in vitro expansion or manipulation, as well as creating a favorable milieu at the time of in vivo infusion and tumor-infiltration, can be critical for optimal acute tumor debulking and long-lasting immunosurveillance. Here, we review how the use of cytokines impacts on the efficacy of ACT for the treatment of tumors, with an emphasis on their use at the time of: cell expansion and genetic engineering; in vivo T-cell transfer; and tumor-infiltration (refer to Figure 1).
On the use of cytokines for tumor-reactive T lymphocyte expansion & genetic engineering
When compared with more conventional therapies (such as chemotherapy and radiotherapy), ACT has the ambition to induce both acute tumor debulking and long-term protective immunity. While more differentiated effector T cells typically promote the former, the latter depends on the persistence of cells with memory features. Preclinical and clinical evidence have shown that the state of differentiation of T cells contained in ACT products can be instructed in vitro by using cytokines, and that therapeutic efficacy of ACT depends on the ability of the adoptively transferred T cells to persist, self-renew and differentiate into antitumor effectors.
Initial experiments performed in mouse models showed that while naive and memory cells are able to differentiate into tumor-reactive effector cells and also retain high proliferative and self-renewing potentials, terminally differentiated effectors are mainly capable of immediate tumor reactivity, but lack long-term persistence. Upon adoptive transfer into tumor bearing mice, naive T cells (TN ) proved more potent than central memory T cells (TCM ), effector memory (TEM ) and finally...