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 June 1, 2017
Citation Information: J Clin Invest. 2017;127(6):2176-2191. doi:10.1172/JCI87624.
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Categories: Research Article Therapeutics

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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cdGMP/CAR T cell–functionalized implants can efficiently treat heterogen...

Figure 10

cdGMP/CAR T cell–functionalized implants can efficiently treat heterogeneous melanoma.

(A) Series of images illustrating the codelivery of anticancer T cells and STING agonists via biomaterial carriers to prevent melanoma recurrence after surgery: (i) mouse B16F10 melanoma; (ii) surgical resection; (iii) resection cavity with residual tumor; (iv and v) implantation of biopolymer device; (vi) wound closure. (B) Heatmap depiction of flow cytometric data quantifying the cell-to-cell variability in the expression of GP75 by 10-day-old B16F10 tumors. Colors indicate the relative levels compared with an isotype control, and the results are from 1,800 randomly chosen cells pooled from 5 tumors. (C) Schematic of the anti-GP75 CAR. (D) 51Cr release assay. Each point represents the mean ± SEM. Data are representative of 4 independent experiments. (E) Progression of B16F10 tumor growth following therapy. Every line represents 1 animal, and each dot reflects the tumor size, as determined by caliper measurements. Data represent 10 animals pooled from 4 independent experiments. (F) Kaplan-Meier survival curves for treated versus control mice. Statistical analysis was performed using the log-rank test, and a P value of less than 0.05 was considered significant. (G) Kaplan-Meier survival curves of the 6 long-term survivors in panels E and F and age-matched naive control mice following tail vein injection of 25 × 104 B16F10 tumor cells. Asterisks indicate statistical significance.