Recent advances in T‐cell immunotherapy for haematological malignancies

Abstract

In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.

Engineering Natural Killer Cells for Cancer Immunotherapy

“…66,67 CARs are composed of an extracellular antigen-binding domain, typically the single-chain variable fragment (scFv) derived from a monoclonal antibody, and an intracellular signaling domain, usually the CD3z chain of the TCR. 68 While CARs have been used extensively to redirect the specificity of T cells for clinical use, studies of CAR-modified NK cells have been largely preclinical to date.…”

“…67 Another attractive strategy is the development of CAR-NK cells that target ligands for activating NK receptors such as NKG2D. NKG2D ligands, including major histocompatibility complex (MHC) class I chain-related A (MICA), MICB, and several UL-16-binding proteins (ULBPs), are upregulated on the surface of many tumor cells and virally infected cells.…”

“…79 Lastly, given the recent safety concerns associated with infusion of CAR-modified T cells, careful consideration of whether a suicide system (e.g., based on caspase-9 or thymidine kinase) deserves incorporation into the construct must be taken into account. 67,104,138 Further unanswered questions include whether repeated infusions could trigger immunogenicity, especially since the majority of scFvs are murine-based, and may elicit human anti-mouse antibodies (HAMAs) or cellular-mediated rejection/sensitization. While the development of HAMA immunogenicity has been studied extensively following CAR-T cell infusions, it has not been a significant problem in CAR-T cell studies, likely because most patients to date have received a single infusion of autologous cells.…”

Are we there yet? The never-ending quest for an Epstein-Barr virus vaccine

“…Epstein-Barr virus (EBV) is a primary cause of infectious mononucleosis (IM) and is globally associated with various malignancies, most notably post-transplantation lymphoproliferative disease (PTLD), de novo Hodgkin/non-Hodgkin lymphoma (HL/NHL), and nasopharyngeal carcinoma (NPC) (1). Despite the development of preventive vaccines against other malignant viruses (2)(3)(4)(5), and notwithstanding substantial efforts undertaken by a number of groups (6)(7)(8), an effective vaccine against EBV infection and malignancy prevention has yet to be developed.…”

Nanotechnology Promotes Genetic and Functional Modifications of Therapeutic T Cells Against Cancer

“…[ 1–3 ] Besides positive clinical results obtained in the treatment of B‐cell malignancy, several spectacular endeavors are in progress to expand the use of CARs in the treatment of solid tumors and other clinical conditions such as autoimmune and infectious diseases. [ 4–6 ] Despite these advances, summarized in Table 1 , CAR‐T cell therapy still faces several major issues to be addressed with respect to the preparation of CAR‐T cells, safety concerns, and therapeutic efficacy, especially against solid tumors.…”