Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors
Tyrel T. Smith, … , K. Dane Wittrup, Matthias T. Stephan
Tyrel T. Smith, … , K. Dane Wittrup, Matthias T. Stephan
Published April 24, 2017
Citation Information: J Clin Invest. 2017;127(6):2176-2191. https://doi.org/10.1172/JCI87624.
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Research Article

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

Abstract

Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants.

Authors

Tyrel T. Smith, Howell F. Moffett, Sirkka B. Stephan, Cary F. Opel, Amy G. Dumigan, Xiuyun Jiang, Venu G. Pillarisetty, Smitha P. S. Pillai, K. Dane Wittrup, Matthias T. Stephan

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Figure 4

Polymer-launched CAR T cells robustly expand at the tumor site and bring about tumor regression, but spare cells that do not express the target antigen.

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Polymer-launched CAR T cells robustly expand at the tumor site and bring...
(A) Bioluminescence imaging of KPC tumors and adoptively transferred CAR T cells. Mice were treated with 107 NKG2D-transduced lymphocytes injected locally into the tumor or contained in bioactive scaffolds implanted directly onto the tumor surface. Five representative mice from each cohort (n = 10) are shown. (B) T cell signal intensities from sequential bioluminescence images captured every 2 days after cell transfer. Each line represents 1 animal, and each dot denotes the whole-animal photon count. At the indicated time points, pairwise differences in photon counts between treatment groups were analyzed using the Wilcoxon rank-sum test. Shown are data for 10 mice per treatment condition pooled from 3 independent experiments. (C) Quantification of KPC bioluminescent tumor signal. Pairwise differences in the bioluminescent T cell signals were analyzed at selected time points using the Wilcoxon rank-sum test. A P value less than 0.05 was considered significant. (D) Kaplan-Meier survival curves for treated and control mice. Shown are 10 mice per treatment group pooled from 3 independent experiments. Statistical analysis between the experimental and control groups was performed using the log-rank test, and a P value of less than 0.05 was considered significant. Asterisks indicate statistical significance. (E) Flow cytometric quantification of RAE1 antigen expression on KPC tumor cells following NKG2D CAR T cell therapy. Shown are 1,800 randomly chosen cells pooled from 5 tumors.