Cell therapies in the clinic

Abstract

Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.

Keywords: T cell; blood cell; cell; cell therapy; clinical translation; clinical trials; microbes; stem cell.

FIGURE 1

Various types of cell therapies in clinical trials. T cells dominate the current clinical studies of cell therapies, followed by stem cells, dendritic cells, natural killer cells, microbes, red blood cells, mononuclear cells, and platelets

FIGURE 2

Current landscape of cell therapies in clinical trials. In this review, all clinical trials that include blood cells and stem cells delivered as a suspension were cataloged. Trials using microbes (delivered via various routes and dosage forms) were also included, as they represent an emerging class of therapies for similar applications. The relevant cell types include T cells, NK cells, mononuclear cells, DCs, RBCs, platelets, stem cells, and microbes. Tissue‐specific cells were excluded from the analysis. The total number of trials identified for each cell type is displayed in the figure, however the sum of these trials for all cell types (1760) exceeds the total number of analyzed trials (1705) because some trials use two or more cell therapies in combination. For phase classification, dual‐phase trials (e.g., Phase 1/2) were counted as both Phase 1 and 2. Eleven broad indications were identified for the purpose of trial classification (i.e., cancer, infectious diseases, autoimmune diseases, nonautoimmune inflammatory diseases, cardiovascular diseases, transplant‐related diseases, trauma, blood disorders, degenerative diseases, metabolic disorders, etc.), with relevant abbreviations listed in the box at the bottom of the figure. Because some trials are used to treat more than one of these conditions, the total number of indications used to generate each pie chart exceeds the total number of trials for each cell type

FIGURE 3

Current landscape of T‐cell clinical trials; 767 T cell clinical trials were analyzed and classified according to genetic modification status as: (a) genetically modified (GM) or (b) nongenetically modified (NGM) T cells. Trials in the GM category were further classified according to the type of genetically modified receptors: (i) CAR‐T cells, (ii) TCR‐T cells, or (iii) T cells with receptor that is not applicable (N/A). Similarly, trials in the NGM category were further classified according to the type of target: (i) virus‐specific T cells, (ii) TAA‐specific T cells, or (iii) T cells with receptor that is not applicable (N/A)

FIGURE 4

Current landscape of stem cell clinical trials; 620 stem cell clinical trials were analyzed and classified as one of the following types: (a) hematopoietic stem cells, (b) mesenchymal stem cells, (c) neural stem cells, (d) bone marrow‐derived stem cells and (e) others (cardiac stem cells, limbal stem cells, and endothelial progenitor cells)

FIGURE 5

Current landscape of dendritic cell and natural killer cell clinical trials. (a) About 136 clinical trials using DCs were further classified according to DC modifications, route of administration, and accompanying therapies; (b) 116 trials using NK‐cell therapies were further classified according to indication, NK cell subtype, and combination therapy regimen. mRNA: messenger RNA; GM‐CSF: granulocyte‐macrophage colony‐stimulating factor; AML/CML: acute/chronic myeloid leukemia; CAR: chimeric‐antigen receptor; CIK: cytokine‐induced killer cells; NKT: natural killer T cells