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Review
. 2018 Mar 28:274:24-34.
doi: 10.1016/j.jconrel.2018.01.028. Epub 2018 Jan 31.

Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment

Samaresh Sau  1 , Hashem O Alsaab  2 , Ketki Bhise  3 , Rami Alzhrani  2 , Ghazal Nabil  4 , Arun K Iyer  5
Affiliations
Review

Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment

Samaresh Sau et al. J Control Release. .

Abstract

Several cancer immunotherapy approaches have been recently introduced into the clinics and they have shown remarkable therapeutic potentials. The groundbreaking cancer immunotherapeutic agents function as a stimulant or modulator of the body immune system to fight against or kill cancers. Although targeted immunotherapies such as immune check point inhibitors (CTLA-4 or PD-1/PD-L1), DNA vaccination and CAR-T therapy are revolutionizing cancer treatment, the delivery efficacy can be further improved while their off-target toxicity can be mitigated through nanotechnology approaches. Recent research has demonstrated that nanotechnology has multifaceted role for (i) reeducating tumor associated macrophages (TAM) to function as tumor suppressor agent, (ii) serving as an efficient alternative for Chimeric Antigen Receptor (CAR)-T cell generation and transduction, and (iii) selective knockdown of Kras oncogene addiction by nano-Crisper-Cas9 delivery system. The function of host immune stimulatory signals and tumor immunotherapies can further be improved by repurposing of nanomedicine platform. This review summarizes the role of multifunctional polymeric, lipid, metallic and cell based nanoparticles for improving current immunotherapy.

Keywords: CAR-T; CRISPR-Cas9; CTLA-4 targeting; Cancer; Cytokine storm; Dendritic cell vaccine; Immunotherapy; Nanomedicine; PD-1/PDL-1 targeting; Tumor associated macrophages.

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Conflict of interest statement

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Dual tumoricidal and tumorigenic role of tumor-associated immune cells. Thus, selective up-modulation of tumoricidal macrophages is the prime goal of cancer immune resurrection and immunotherapy. This figure is adopted and modified from ref. [8] with permissions. TAM: tumor-associated macrophages, TC: T cells, NK: natural killer cells, MDSC: myeloid-derived suppressor cells.
Figure 2
Figure 2
Mechanism of PD-1 and PDL-1 pathway in tumor environment and the complex crosstalk between cancer, tumor, T-cell, APC and macrophage and tumor stroma. The image was modified and reproduced from [16]. ECM: extracellular matrix, HGF: Hepatocyte growth factor, Ag: antigen.
Figure 3
Figure 3
Outline of tumor vaccination with nanoparticle: A. Antigen encapsulated nanoparticle to activate peripheral dendritic cells. B. This immune-modulating nanoparticle triggers the adaptive immune responses through reactivation of CD8+ cytotoxic T cells to function against the specific tumorigenic proteins. The figure was obtained and reproduced from ref.[39] with permissions.
Figure 4
Figure 4
Off-the-shelf engineering of patient’s dendritic cell vaccine specific to the tumor antigen. This DC infused to patients so that it can express the tumor antigen and guide the T-cell to kill tumor cells. The figure is adopted form ref. [45] with permissions.
Figure 5
Figure 5
A. schemetic representation of F(ab′)2 antibody ligation to PLGA-PEG polymeric nanoparticles through thiol-maliamide chemistry. B Scheme of antibody fragment conjugation to the surface of pre-formulated maleimide-functionalized PEG-PLGA polymeric nanoparticles (NPs). B Scanning electron microscopy images showed the nanoparticulate nature of free and antibody conjugated nanoparticle. C. Tumor growth inhibiton of TLR7/8 agonist encapsulated anti-PD-1 PLGA-PEG nanoparticle than combination of individual components. D. Smilarlt, significant improvement survial rate in nanoformulation encapsulated with TGFβ inhibitor (SD-208). These data demonstrate the superiority of nanoformulation for improving current cancer immunothrapy with least side effect. Images were reproduced form ref. [85].
Figure 6
Figure 6
A. Development of ~20 nm nanodics and co-encapsulated with antigen and adjuvant and due to smaller size nanodisc has faster access to lyphatic vessel, thus generating stronger immue responses compared to conventional peptide antigen. B. Higher expression of antigen (right panel) in case of nanodisc treated dendritic cell as compared to free peptide form of antigen (left panel). C. Complete rejection of tumor in sHDL-Ag/CpG (nanodics) vaccinated mice injected with B16Ova cancer cells. D. The strong activation of T-cell in sHDL-Ag/CpG vaccinated mice is the main reason for anti-tumor immune responses. images were reproduced from ref. [86]
Figure 7
Figure 7
Outline of CAR T-cell design, advancement, nano-formulation and application. (A) structure of the CAR gene. The CAR gene contains (i) an intracellular signaling domain(CD3ζ), (ii) co-stimulatory domain (CD28 and/or 4-1BB), (iii) transmembrane domain, (iv) an scFv binding domain specific to tumor antigen (here methicillin, MSLN). This CAR gene is transduced to host cell along with viral packaging plasmid to form a pseudo-viral particle, and this particle is traduced to host cells. (B) Advancement of different generations of CAR vector. The main difference between first, second and third generation CAR is the introduction of more specific co-stimulatory domain to increase the activation strength of T cells. Combinational antigen recognition with balanced signaling has been described. (C) a non-viral nanoparticle for containing mRNA of interest to re-program therapeutic T-cells that can act like CAR-T cells. (D) Brief schematic explanation on how to isolate T-cells from patients, in vitro reprogrammed to express therapeutically relevant transgenes carried in CAR-gene, then further expanded to more number of T-cells and transfused back to the patient. Figures organized in such as for ease of understanding the CAR-T technology and application. Figure A, B was reproduced from [92], C obtained from [93] and D reproduced from[94] with permissions.
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