Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors

Abstract

Adoptive T-cell therapy of cancer is a treatment strategy where T cells are isolated, activated, in some cases engineered, and expanded ex vivo before being reinfused to the patient. The most commonly used T-cell expansion methods are either anti-CD3/CD28 antibody beads or the “rapid expansion protocol” (REP), which utilizes OKT-3, interleukin (IL)-2, and irradiated allogeneic feeder cells. However, REP-expanded or bead-expanded T cells are sensitive to the harsh tumor microenvironment and often short-lived after reinfusion. Here, we demonstrate that when irradiated and preactivated allosensitized allogeneic lymphocytes (ASALs) are used as helper cells to license OKT3-armed allogeneic mature dendritic cells (DCs), together they expand target T cells of high quality. The ASAL/DC combination yields an enriched Th1-polarizing cytokine environment (interferon (IFN)-γ, IL-12, IL-2) and optimal costimulatory signals for T-cell stimulation. When genetically engineered antitumor T cells were expanded by this coculture system, they showed better survival and cytotoxic efficacy under oxidative stress and immunosuppressive environment, as well as superior proliferative response during tumor cell killing compared to the REP protocol. Our result suggests a robust ex vivo method to expand T cells with improved quality for adoptive cancer immunotherapy.

Activated dendritic cells delivered in tissue compatible biomatrices induce in-situ anti-tumor CTL responses leading to tumor regression

“…However, beDCs were not directly exposed to the suppressive tumor environments. Moreover, the soluble factors secreted by the DCs in scaffolds were sufficient to attract and activate infiltrated host lymphocytes inside the biomatrix [33]. However, a lack of organized cellular clusters inside biomatrix may be due to the absence of specific soluble mediators that are required for a coordinate cellular organization [30].…”

Engineered materials for cancer immunotherapy

“…The isolation of cancer-reactive TILs from tumor samples represents a particularly promising approach for the treatment of various cancers [9, 121], and has shown exceptional efficacy in the clinic for the treatment of advanced melanoma [122]. However, the ex vivo culture of TILs still represents a bottleneck in TIL-based ACT, wherein, using standard methods, it is challenging to expand the cells in a rapid and cost-efficient manner while maintaining them in an undifferentiated and functional state, and in which a consistent product is obtained following the ex vivo culture protocol [18, 19]. In addition, challenges also remain with respect to maintaining cell persistence and sustained effector functionality following bolus cell administration, wherein lymphodepletion regimens and systemic co-administration of survival factors, which are associated with significant morbidity and inflammatory toxicities, respectively, are necessary for effective TIL-based ACT [20, 21].…”

“…An alternative approach that is currently used in the clinical setting is the “rapid expansion protocol” (REP) which employs inactivated allogeneic feeder cells in the presence of a CD3 antibody and the mitogenic cytokine IL-2 [122]. However, the use of allogeneic cells can also lead to suboptimal and inconsistent T cell products [18]. Genetically engineered “artificial APCs” (aAPCs) have also been developed to facilitate more efficient ex vivo T cell expansion, and this is described elsewhere [132].…”

“…The coordinated provision of both signals is important because signal 1 in the absence of signal 2 has been shown to induce T cell anergy [133]. Mitogenic cytokines such as IL-2, IL-15, or IL-21 can also be added, and have been shown to fulfill the role of a “signal 3” important for optimal T cell expansion [18, 134]. The benefits of using synthetic aAPCs for T cell expansion are the design versatility, reproducibility, cost-efficiency, and scalability of synthetic systems.…”

“…Soluble bolus-based vaccine formulations typically elicit weak cellular immune responses [16, 17], limiting their effective use for cancer. Current methods for ex vivo cell expansion for ACT are suboptimal and do not always facilitate the generation of high quality T cells [18, 19], and achieving high T cell persistence and sustained functionality with limited systemic toxicity following transfer remains challenging [20, 21]. The use of biomaterials as platforms for cancer immunotherapy could allow for some of these limitations to be overcome.…”