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Review
. 2019 Sep 10:459:192-203.
doi: 10.1016/j.canlet.2019.114427. Epub 2019 Jun 8.

Induction of anti-cancer T cell immunity by in situ vaccination using systemically administered nanomedicines

Geoffrey M Lynn  1 , Richard Laga  2 , Christopher M Jewell  3
Affiliations
Review

Induction of anti-cancer T cell immunity by in situ vaccination using systemically administered nanomedicines

Geoffrey M Lynn et al. Cancer Lett. .

Abstract

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

Keywords: Chemotherapeutic and immunostimulant; Immunogenic cell death; Nanomedicine and biomaterials; Nanoparticle and microparticle; Pattern recognition receptor.

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Figures

Figure 1:
Figure 1:. Conventional and in situ vaccination can be used to induce anti-cancer T cell immunity.
Conventional vaccines often use tumor antigens identified from biopsies, which are manufactured in one of several common formats (e.g., peptide/protein, nucleic acid, viral vector or dendritic cell-based) and then administered in the skin or muscle to prime anti-cancer T cells in lymph nodes. In contrast, in situ vaccination involves (1) delivery of immunostimulants or cytotoxic chemotherapeutics into tumors to (2) kill cancer cells, as well as deplete suppressor cells (MDSCs, Tregs) and/or promote immunogenic cancer cell death. Immunogenic cancer cell death is characterized by both the translocation of calreticulin (CRT) to cancer cell surfaces, which promotes their uptake by dendritic cells (DCs), as well as cancer cell release of danger associated molecular patterns (DAMPs) that recruit and activate immune cells. Activated DCs loaded with tumor antigens migrate to draining lymph nodes and prime anti-cancer T cells (3) that hone to tumors and kill cancer cells. The accompanying table summarizes different types of conventional and in situ vaccines that have been used for inducing T cell immunity.
Figure 2:
Figure 2:. In situ vaccination with immunostimulants and chemotherapeutics can promote durable tumor regression through immunological mechanisms.
(A) Mice with established CT26 tumors received either intratumoral (i.t.) injections with a CpG oligodeoxynucleotide (ODN)-based TLR-9 agonist, SD-101, i.t. SD-101 + systemic anti-PD1, i.t. control (inactive) ODN + systemic anti-PD1 or i.t. control ODN alone. Tumor growth kinetics are shown and indicate that i.t. treatment with the TLR-9 agonist (SD-101) combined with anti-PD1 leads to optimal tumor regression. (B) CT images taken from a patient with metastatic melanoma that was treated with SD-101 and anti-PD1 show regression of a non-injected tumor, suggesting that the treatment induced systemic anti-cancer T cell immunity. (C, D) Intratumoral injection of a CDN-based STING agonist leads to acute rejection of B16F10 melanoma tumors. Mice were implanted with 5×105 B16F10 cells on day 0 and then treated with either CDN or PBS for a total of three treatments (red arrows). Tumor growth kinetic (C) and representative images (D) of mice treated with PBS (i) or CDN (ii) are shown. (E) CT26 tumor cells were cultured with the indicated chemotherapeutic agents (x-axis) for 24-48 hours and then injected into the left flank of mice. Live tumor cells were injected into the right flank of the same mice 8 days later and the percentage of tumor-free mice was assessed 120 days later (note: n is the total number of mice used across multiple studies). Tumor rejection indicates that anti-cancer T cell immunity was primed by the treated cells, which suggests that the treatment promoted immunogenic cell death. (F) Mice with established MCA205 fibrosarcoma cells were treated with intratumoral doxorubicin or PBS and a subset of these mice were treated with either anti-IFN-γ or anti-CD8 antibodies to evaluate the impact of IFN-γ and CD8 T cell depletion on tumor regression by doxorubicin. Panel (A) adapted from ref. [34]; (B) adapted from ref. [37]; (C,D) adapted from ref. [41]; (E) adapted from ref. ; and, (F) adapted from ref. .
Figure 3:
Figure 3:. Nanomedicines based on polymer-drug conjugates, micelles and liposomes.
The polymer-drug conjugate represented in the cartoon schematic is a linear copolymer wherein multiple drug molecules are attached to the backbone of the polymer. The micelle particle represented in the schematic is comprised of multiple amphiphilic di-block polymers; the hydrophobic portion of the di-block polymer drives particle assembly and solubilizes hydrophobic drugs in the core of the particles, while the hydrophilic portion of the di-block polymer stabilizes the micelle. The liposome schematic shows a cross-section of a lipid bilayer vesicle coated with hydrophilic PEG chains; hydrophilic drugs can be encapsulated inside the liposomal particle, whereas hydrophobic drugs can insert into the bilayer membrane.
Figure 4:
Figure 4:. Nanomedicine properties that impact tumor accumulation.
Nanomedicines administered by the intravenous route must evade clearance by the kidneys and avoid capture by cells of the reticuloendothelial system (RES), principally located within the liver, spleen and lungs, to allow for prolonged circulation needed for tumor accumulation. Nanomedicines between 10-30 nm diameter with near neutral charge most efficiently extravasate and penetrate tumors.
Figure 5:
Figure 5:. Nanomedicines based on star polymers mediate durable tumor regression.
(A) Star polymers can be prepared by the attachment of multiple hydrophilic polymer arms to dendrimer cores. Drug molecules are attached to the core and/or arms of the star polymer to produce star polymer-based nanomedicines. (B) Mice with established S-180 tumors were treated with 5 mg/kg equivalent dose of either the free anthracycline drug, THP (also referred to as Pirarubicin), THP conjugated to linear HPMA-based polymers (HPMA-THP) or THP conjugated to the arms of star polymers (star polymer-THP). Tumor volume was assessed at various timepoints thereafter. Panel (B) adapted from ref. [139].
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