TY - JOUR
T1 - Biomaterials to enhance antigen-specific T cell expansion for cancer immunotherapy
AU - Isser, Ariel
AU - Livingston, Natalie K.
AU - Schneck, Jonathan P.
N1 - Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Under a licensing agreement between NexImmune and the Johns Hopkins University, JPS is entitled to shares of royalty received by the University on sales of aAPC products described in this article. He also owns NexImmune stock, which is subject to certain restrictions under University policy. Dr. Schneck is a member of the company’s Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. JPS also acknowledges grant funding from AstraZenca.
Funding Information:
The findings above have been invaluable to the understanding of T cell biology and how to better create substrates for the activation of tumor-specific T cells for adoptive immunotherapy. One study synthesized a hydrogel from hyaluronic acid, a common component of the extracellular matrix (ECM), and conjugated it with pMHC and ?CD28 to form an artificial T cell stimulating matrix (aTM) for antigen-specific T cell stimulation [150]. The study investigated the effects of stiffness, ligand density, and a variety of ECM proteins on T cell proliferation, function, and phenotype. Interestingly, in contrast to some of the studies previously mentioned, this study found that softer 0.5 kPa gels led to significantly greater proliferation, function, and CD3 cluster formation than stiffer 3 kPa gels. Moreover, culturing T cells on the aTM led to an increase in expansion and polyfunctionality of endogenous antigen-specific CD8+ T cells, compared to culturing T cells on a tissue culture plate or a blank hydrogel in the presence of magnetic nano-aAPCs. Similarly, endogenous T cells expanded on the aTM and adoptively transferred into tumor-bearing mice significantly slowed tumor growth and increased mouse survival, compared to T cells stimulated with nano-aAPCs on a tissue culture plate. Another study produced a composite APC mimetic scaffold (APC-ms) by forming a supported lipid bilayer with T cell signaling cues on high-aspect ratio mesoporous silica micro-rods (MSRs) [81]. The MSRs were pre-loaded with IL-2, coated with liposomes, and then conjugated with signal 1 and 2 for T cell stimulation. In vitro, the MSRs self-assembled into a three-dimensional scaffold with high enough porosity to allow for cell infiltration. T cells cultured with the APC-ms formed denser clusters with the MSRs than with traditional aAPC microbeads, due in part to both the larger size (70 ?m vs 4.5 ?m) and higher aspect ratio of the MSRs. Moreover, paracrine release of IL-2 from the MSRs was shown to be more potent at T cell stimulation than adding the same amount of bulk IL-2, as in previous studies [112,119]. This platform was shown to be more effective than aAPC microbeads for polyclonal expansion of primary T cells or tumor-specific CAR T cells. Similarly, the platform outperformed moDCs for expansion of rare antigen-specific CD8+ T cells. CAR T cells expanded with APC-ms showed similar antitumor efficacy compared to CAR T cells expanded with aAPC microbeads. Together, the results from these two studies show promise for future clinical studies using artificial scaffolds to expand patient-specific CD8+ T cells for ACT.This project is supported by National Science Foundation Graduate Research Fellowships 2016218370 (A.I.) and 2018268995 (N.K.L.) and National Institutes of Health Grants R01 EB029341 (J.P.S.), R33 CA229042 (J.P.S.), and P41 EB028239 (J.P.S.).
Funding Information:
This project is supported by National Science Foundation Graduate Research Fellowships 2016218370 (A.I.) and 2018268995 (N.K.L.) and National Institutes of Health Grants R01 EB029341 (J.P.S.), R33 CA229042 (J.P.S.), and P41 EB028239 (J.P.S.).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - T cells are often referred to as the ‘guided missiles’ of our immune system because of their capacity to traffic to and accumulate at sites of infection or disease, destroy infected or mutated cells with high specificity and sensitivity, initiate systemic immune responses, sterilize infections, and produce long-lasting memory. As a result, they are a common target for a range of cancer immunotherapies. However, the myriad of challenges of expanding large numbers of T cells specific to each patient's unique tumor antigens has led researchers to develop alternative, more scalable approaches. Biomaterial platforms for expansion of antigen-specific T cells offer a path forward towards broadscale translation of personalized immunotherapies by providing “off-the-shelf”, yet modular approaches to customize the phenotype, function, and specificity of T cell responses. In this review, we discuss design considerations and progress made in the development of ex vivo and in vivo technologies for activating antigen-specific T cells, including artificial antigen presenting cells, T cell stimulating scaffolds, biomaterials-based vaccines, and artificial lymphoid organs. Ultimate translation of these platforms as a part of cancer immunotherapy regimens hinges on an in-depth understanding of T cell biology and cell-material interactions.
AB - T cells are often referred to as the ‘guided missiles’ of our immune system because of their capacity to traffic to and accumulate at sites of infection or disease, destroy infected or mutated cells with high specificity and sensitivity, initiate systemic immune responses, sterilize infections, and produce long-lasting memory. As a result, they are a common target for a range of cancer immunotherapies. However, the myriad of challenges of expanding large numbers of T cells specific to each patient's unique tumor antigens has led researchers to develop alternative, more scalable approaches. Biomaterial platforms for expansion of antigen-specific T cells offer a path forward towards broadscale translation of personalized immunotherapies by providing “off-the-shelf”, yet modular approaches to customize the phenotype, function, and specificity of T cell responses. In this review, we discuss design considerations and progress made in the development of ex vivo and in vivo technologies for activating antigen-specific T cells, including artificial antigen presenting cells, T cell stimulating scaffolds, biomaterials-based vaccines, and artificial lymphoid organs. Ultimate translation of these platforms as a part of cancer immunotherapy regimens hinges on an in-depth understanding of T cell biology and cell-material interactions.
KW - Artificial antigen-presenting cells
KW - Cancer immunotherapy
KW - Immunoengineering
KW - Particles
KW - Scaffolds
KW - T cell
UR - http://www.scopus.com/inward/record.url?scp=85097782400&partnerID=8YFLogxK
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U2 - 10.1016/j.biomaterials.2020.120584
DO - 10.1016/j.biomaterials.2020.120584
M3 - Article
C2 - 33338931
AN - SCOPUS:85097782400
VL - 268
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
M1 - 120584
ER -