Cell delivery devices for cancer immunotherapy

Abstract

Adoptive cell therapy (ACT) that leverages allogeneic or autologous immune cells holds vast promise in targeted cancer therapy. Despite the tremendous success of ACT in treating hematopoietic malignancies, its efficacy is limited in eradicating solid tumors via intravenous infusion of immune cells. With the extending technology of cancer immunotherapy, novel delivery strategies have been explored to improve the therapeutic potency of adoptively transferred cells for solid tumor treatment by innovating the administration route, maintaining the cell viability, and normalizing the tumor microenvironment. In this review, a variety of devices for cell delivery are summarized. Perspectives and challenges of cell delivery devices for cancer immunotherapy are also discussed.

Introduction

Cancer immunotherapy educates, activates, and boosts the immune system to recognize, fight, and eliminate cancer cells [1]. To date, many treatment strategies have been developed, including immune checkpoint inhibitors [2], adoptively transferred immune cells [3], bispecific antibodies [4], oncolytic virus [5], bacteria [6], cancer vaccines [7], and immune system modulators [8]. Among these different approaches, the engineered immune cell-based ACT, especially the chimeric antigen receptor T cells (CAR-T) therapy, has emerged as a curative and powerful treatment. In addition, other promising types of ACT under investigation or in clinical application include T cell receptor engineered T cells (TCR-T), tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor engineered natural killer cells (CAR-NK), and chimeric antigen receptor engineered macrophages (CAR-macrophages) [9].

In ACT therapy, the patient or donor immune cells are often genetically engineered to target cancer cells except using patient TIL [10]. After ex vivo expansion, the cells are infused into patients to eliminate cancer cells. Multiple hematologic malignancies, including B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma, and multiple myeloma, have been treated by ACT with remarkable clinical efficacy [[11], [12], [13]]. Notably, CAR-T therapy targeting B-lymphocyte antigen CD19 has exhibited unprecedented potency with 50–90% complete response rates for refractory B-cell malignancies in several clinical trials [[14], [15], [16], [17]]. This impressive treatment efficacy has prompted a focus on developing strategies to extend the application of CAR-T cells to other non-hematologic cancers. However, it remains challenging for CAR-T therapy to treat solid tumors due to the immunosuppressive tumor microenvironment, insufficient tumor infiltration of T cells, and tumor antigen heterogeneity [13]. In details, the compact structure of solid tumor contains numerous cell types, such as fibroblasts and immune inhibitory cells [18]. The nitration of the chemokine CCL2 is induced by reactive nitrogen species, resulting in the trapping of T cells in the stroma. Cancer-associated fibroblasts can produce CXCL12 to coat around tumor cells. The protection layer excludes T cells from attacking cancer cells. The tumor vasculature also expresses Fas ligand that induces apoptosis of effector T cells express Fas death receptor [19]. In addition, various immunosuppressive molecules in solid tumors, such as anti-inflammatory cytokines and immune checkpoints, can promptly downregulate the tumoricidal efficacy of T cells and further induce their exhaustion [20]. Furthermore, targeted tumor antigens may only distribute in a portion of tumor cells due to antigen heterogeneity in solid tumors or because cancer cells can evolve to reduce the expression of these antigens. In this case, T cells cannot recognize and eliminate all tumor cells, which eventually leads to tumor recurrences [21]. Current administration of CAR-T cells mainly relies on intravenous injection, which may result in insufficient tumor infiltration. Furthermore, side effects, such as acute kidney injury, bleeding episode, heart arrhythmia, cytokine storm, and neurotoxicity, also compromise the therapeutic outcome and prognosis [22,23].

To this end, cell delivery devices, including thin films, microparticles, scaffolds and microneedles have been exploited to enhance the viability and therapeutic efficacy of immune cells, while minimize side effects. The device assists immune cells to reach tumors directly, provides a location for delivered cells to reside, proliferate, and/or perform anti-tumor activities. Immune cells can be released into tumor tissues through active migration in response to the chemokines derived from tumor tissues or simply be released via diffusion with or without the facilitation of device degradation. Such manners can deliver essential amounts of therapeutic cells into tumor tissues within a short period of time or over days, which, to some extent, can improve the infiltration of immune cells into tumor tissues and/or solve the problem of cytokine storm. In addition, cell delivery devices can be loaded with immunomodulating drugs to support immune cells for enhanced proliferation and tumor elimination as well as normalize tumor immunosuppressive microenvironment for long-term preservation of cell bioactivities [24].

In this review, we summarize the devices for delivering diverse cell-based therapeutics (Fig. 1). First, we briefly discuss the design criteria for cell delivery devices such as key device characteristics and main types of device materials. Then, the typical devices that have been applied to cell delivery and cancer immunotherapy, particularly the scaffold, are discussed. Finally, we highlight the perspectives and challenges of cell delivery devices in cancer treatment, including the development of new delivery devices, evaluation of device biocompatibility and immunogenicity, and their applications in combination with other cancer therapies.