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95Polymeric scaffolds for antitumor immune cell priming

CHAPTER FOUR

Biomaterials and devices for immunotherapy

Emily M. Jordana, Mario Milazzo

University of Texas Rio Grande Valley, Brownsville, TX, United States

Scuola Superiore Sant’Anna, Pisa, Italy

Massachusetts Institute of Technology, Cambridge, MA, United States

University of Pisa, Pisa, Italy

b,c

, Sue Anne Chewa, and Serena Danti

b,c,d

Contents

1. Introduction 98

2. Immunotherapy and chemotherapy combinations 99

2.1 PD-1 and PD-L1 inhibition 99

2.2 Selenium 103

2.3 Heme oxygenase 1 (HO-1) inhibitors 103

2.4 Interleukin-2 104

2.5 P5 peptide 105

2.6 Indoximod 105

2.7 Cytosine-guanosine oligodeoxynucleotides 106

2.8 Tyrosinase-related protein-2 106

2.9 Anti-CD326 antibody 107

2.10. Stimulator of interferon genes pathway 107

3. Nanoscale biomaterial-based strategies applied 108

3.1 Polymeric and lipid nanoparticles 108

3.2 Lipid-based nanoparticles or liposomes 109

3.3 Other types of nanobiomaterials delivery systems 111

4. Introduction to micro/nanorobots 113

5. Propulsion engines for MNRs 115

6. Applications of MNRs 118

6.1 Magnetic-driven MNRs 118

6.2 Electric and piezoelectric MNRs 121

6.3 Light-driven MNRs 122

6.4 Ultrasound-propelled MNRs 122

6.5 Endogenous engines for MNRs 123

7. Conclusion and future outlook 123

References 125

98 Emily M. Jordan et al.

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1. Introduction

The incidence of malignant cancers continues to rise each year and thus, the development of new treatment methods is still much needed to combat this disease. Besides the application of surgery, chemotherapy, and radiation, cancer cell death can also be induced by immunotherapy, which is a relatively newer and promising concept to combat cancer. The body’s natural immune responses are often suppressed in the tumor microenvironment. Immunotherapy can be applied to activate or enhance the host immune system response to attack and destroy tumor cells [1]. Although it offers an emerging and novel way to treat cancer, the efficiency of immunotherapy alone is underwhelming with little to no response rates in many cases [2,3]. As such, strategies to enhance or supplement immunotherapy are much needed. Chemotherapy, which is often the frontline treatment method for different cancers, is usually associated with having immunosuppressive effects, therefore, it was originally not considered as a combination therapy with cancer immunotherapy [4]. However, in recent years, chemotherapy and immunotherapy combinations have shown promising results and offer a promising avenue to increase response rates and possible outcomes in synergized anticancer effect [1]. The synergistic or combined effects of these agents may allow for the decreased dosage of each agent and thus, minimizing their unwanted side effects.

Biotechnology approaches, including nanoscale biomaterials and microrobots/ nanorobots (MNRs), have special characteristics that are useful to increase the efficacy and reduce the nontarget side effects of traditional treatment methods. In this chapter, nanoscale biomaterial-based strategies that have been utilized to deliver both an immunotherapy and a chemotherapy agent via biomaterials (i.e., dual delivery of both agents with the same biomaterial or separate biomaterials, for example, using two different liposomes) or only the immunotherapy agent with biomaterials (i.e., the chemotherapy agent is delivered systemically or locally, without a biomaterial) are discussed, as summarized in Fig. 1.

Fig. 1 Summary of the immunotherapy and chemotherapy combination that have been investigated using different nanoscale biomaterial-based strategies.

Nanosized biomaterials have turned out to be very effective as drug carriers since they can provide a better-controlled delivery, thus reduce toxicity, and improve efficacy by several ways, such as by increasing drug uptake. Due to their ultrasmall size, NPs can pass across tissue barriers and reach tumor cells, being up-taken by tumor cell through the enhanced permeability and retention (EPR) effect. In contrast to macro-scaled biomaterials [5], which can result in local delivery at the implanted site, nanosized objects even if delivered locally, can easily escape to other tissues, posing the need for a targeted delivery using different strategies, usually based on chemical recognition, such as cell type affinity via specific ligand overexpression.

Table 1 shows the specific chemotherapy and immunotherapy agents that have been

investigated and delivered using nanoscale biomaterial-based strategies to increase their efficacy and the major outcomes from the combination therapies. Moreover, by using chemically or physically active biomaterials, for example, biomaterial-based microobjects/nanoobjects, provided with actuation systems, which can be driven from the outside, even more targeted delivery can be obtained. MNRs usually need multibiomaterials and a more complex architecture than NPs, thus are considered as small devices, and are becoming very attractive in cancerous pathology and other diseases. To this purpose, we bring attention to the MNRs as the next step of biomaterial-based devices that have the potential of delivering combined immune-chemo therapy.

99Biomaterials and devices for immunotherapy

2. Immunotherapy and chemotherapy combinations

In the following sections, the mechanisms of action of the immunotherapy and chemotherapy agents that have been used as a combination, availing themselves of nanoscale biomaterial-based strategies to increase their efficacy are discussed.

2.1 PD-1 and PD-L1 inhibition

Programmed cell death protein 1 (PD-1) plays a vital role in the inhibition of both the adaptive and innate immune responses by modulating the activity of T-cells, activating apoptosis of antigen-specific T cells, and inhibiting apoptosis of regulatory T cells [16]. PD-1 is expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs), and monocytes and is highly expressed on tumor-specific T cells

[17]. The two known ligands of the PD-1 receptor are PD-L1 and PD-L2, which are

regulated by cytokines such as interferon (IFN) and tumor necrosis factor alpha (TNF-α) expressed in T, B, endothelial, and epithelial cells [18]. The PD-1/PD-L1 pathway plays particular important roles in suppressing antitumor immunity by inhibiting the activation of T-cell, lysing of tumor cell or the induction of tumor-specific T cell apoptosis [18]. The tumor microenvironment has been found to upregulate levels of PD-L1 and studies have shown that anti-PD-1 or anti-PD-L1 can restore T-cell activity and improve immune response and thus, are great target for cancer immunotherapy [19].

Table 1 Nanoscale biomaterial-based strategies that have been utilized to deliver a combination of immunotherapy and chemotherapy agents.

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Chemotherapy

Immunotherapy (I)

PD-L1 inhibitor Dox Liposomes Sensitize tumor cells to cytotoxic

T lymphocytes (CTLs) and increases tumor cell apoptosis

Anti-PD-1 Cisplatin

(CDDP)

Lipid NPs Inhibit cell proliferatio n, enhance T-cell

infiltration resulting in tumor cell apoptosis

Selenium Dox Selenium-Containing NPs Decrease in HLA-E expression and

increase in NK cell related tumor death

Tin mesoporphyrin

(SnMP) (a HO-1 inhibitor)

Daunorubicin

(DNR)

Lipid-Polymer Hybrid NP

(hNPs)

Increase the immune response by

reprogramming bone marrow myeloid cells with synergistic effect with DNR

Interleukin-2 (IL-2) Dox Liposomes Result in less myeloid suppression leading

to enhancement of IL-2 and synergistic response for tumor eradication

P5 Peptide Dox Liposomes Induce T cell population, cytokine

secretion, and prime an environment where future doses of Dox/Doxil decreases the population of MDSC

Indoximod (IND), an

indoleamine 2,3-dioxygenase

Dox Liposomes Prime the immune response tumor site and

boosts immunotherapy with immune checkpoint inhibitors

(IDO-1) inhibitor

Cytosine-Guanosine

(CpG) Oligodeoxynucleotides

Dox Near Infrared Red

(NIR)-Responsive Gold Nanorods

Induce cytokines and greatly enhance

immunostimulatory activity

(ODNs)

[4]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

Tyrosinase-Related

Protein-2 (Trp-2)

Paclitaxel

(PTX)

Anti-CD326 antibody Sorafenib

(SFN)

DMXAA, a stimulator of

interferon genes pathway activating

SN38, an

irinotecan metabolite

agent/agonist

Dox, doxorubicin; NPs, nanoparticles.

Sulfobutylether-β-cyclodextrin

(SBE)/Mannosylated N,N,NTrimethylchitosan (mTMC) Polycationic Polymer

Undecylenic Acid Modified

Thermally Hydrocarbonized Porous Silicon NPs (UnTHCPSi NPs)

Self-Assembled Amphiphilic

Polymeric NPs

Induce upregulation of DCs, increase

cytokine production, reduces the generation of immunosuppressive cells, and induces a synergistic antitumor immune response

Inhibit the growth of CD326 positive

cancer cells, enhances ADCC activity and cytokine release

Work synergistically to convert the

immunologically cold tumors to hot tumors, resulting in enhanced antitumor immunity

[13]

[14]

[15]

102 Emily M. Jordan et al.

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PD-1and PD-L1inhibitionworks by blockingthe bindingof PD-1 to PD-L1, whichresults in “unmaskingtumor cells,” thus allowing the activation of T cells that are able to ultimately get rid of the tumor cells [4,6].

2.1.1 PD-L1 inhibitor and doxorubicin

Liu et al. investigated the combined delivery of the immunotherapy agent, PD-L1 inhibitor, and the chemotherapy drug, doxorubicin (Dox) with liposomes [4]. The PD-L1 inhibitor can disrupt the interaction of PD-1 and PD-L1, and thus, resulting in T-cell activation. As a chemotherapy drug, Dox functions by intercalating within DNA, resulting in the prevention of topoisomerases II ability of DNA repair [20]. A low dose of Dox can also help to enhance immunotherapy. It sensitizes tumor cells to cytotoxic T lymphocytes (CTLs) through the process of upregulation and presentation of mannose-6-phosphate (M6P) receptors on the tumor cells. This results in increased tumor cell apoptosis since the permeability of granzyme B (GranB or Grzb2), a critical mediator of apoptosis, is increased as depicted in Fig. 2.

Fig. 2 Schematic illustrations of the mechanism of the tumor microenvironment/pH dual responsive polymer-liposomes for synergistic treatment of cancer immuno-chemotherapy. (Reprinted (adapted)

with permission from Liu Y, Chen X-G, Yang P-P, Qiao Z-Y, Wang H. Tumor microenvironmental pH and enzyme dual responsive polymer-liposomes for synergistic treatment of cancer immunochemotherapy. Biomacromolecules 2019;20:882–92. Copyright (2019) American Chemical Society.)

2.1.2 Anti-PD-1 and cisplatin

Anti-PD-1 is known as an immune checkpoint inhibitor and is a type of immunotherapy that is widely investigated as it has been revealed to be effective in a range of cancers. However, it is associated with low response rates and the development of resistance to this inhibitor [6].To overcome this, Lan et al. studied the combination of the immunotherapy agent, anti-PD-1, and another chemotherapy agent, cisplatin (CDDP) using lipid NPs [6].Platinum-based drugs such as CDDP can result in resistance due to diminish nuclear accumulation of the drug in cancer cells by fibroblasts [21]. CDDP chemoresistance can be abolished with CD8 + Tcells[21]; moreover, it has been shown that clonal expansion of T-cells can result in enhanced responsiveness to chemotherapy [22]. Thus, combining CDDP with immunotherapy can make it more effective. Lan et al. demonstrated that the anti-PD-1 + CDDP group exhibited a greater effect in an in vivo tumor model than the anti-PD-1 or CDDP groups alone. They concluded that CDDP could inhibit cell proliferation, and anti-PD-1 could enhance T-cell infiltration. The enhanced T-cell activity exerted by anti-PD-1 resulted in tumor cell apoptosis, leading to synergistic anticancer effects with CDDP.

2.2 Selenium

Selenium has been shown to sensitize cancer cells to NK cells due to oxidative stress [7]. The natural killer group 2A (NKG2A) is an inhibitory checkpoint receptor present on cancer cells that protects them from being targeted by NK cells. NKG2A binds to human leukocyte antigen-E (HLA-E), thus it decreases the expression of HLA-E, rendering cancer cells susceptible to NK cells. Selenium blocks HLA-E expression in cancer cells at the posttranscriptional level through increased intracellular oxidative stress [23].

103Biomaterials and devices for immunotherapy

2.2.1 Selenium and doxorubicin

Gao et al. tested the possible synergistic effects of the immunotherapy agent, selenium, and the chemotherapy drug, Dox [7]. The selenium (Se)- containing NPs was the delivery vehicle for Dox and also served as the immunotherapy. Gamma-radiation can cleave the diselenide bonds in the NPs, leading to seleninic acid which has the same anticancer effect as selenide, therefore, can also induce a decrease in HLA-E expression and an increase in NK cell-related tumor death. In addition to its chemotherapeutic and immunologic effects detailed in previous combination therapies, Dox has also been shown to be able to enhance NK cell-mediated antitumor effects (i.e., NK mediated killing) through the TRAIL pathway [24]. This is done through the activation of caspase 8 by its cleavage which signals the apoptotic pathway of TRAIL.

2.3 Heme oxygenase 1 (HO-1) inhibitors

Heme oxygenase 1 (HO-1) is an antioxidative and cytoprotective enzyme, which protects against inflammatory processes found in certain chemoresistant cancers and is also

104 Emily M. Jordan et al.

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known as an immune checkpoint molecule [8]. Thus, HO-1 inhibitors can induce an antitumor immune response.

2.3.1 Tin mesoporphyrin (a HO-1 inhibitor) and daunorubicin

Yong et al. investigated the delivery of an HO-1 inhibitor, tin mesoporphyrin (SnMP) with lipid polymer nanoparticles and in combination with systemic daunorubicin (DNR), a chemotherapy drug. They found that HO-1 inhibition was able to promote the immune response by reprogramming bone marrow myeloid cells. Furthermore, HO-1 inhibition was able to enhance the chemotherapeutic effect of DNR, which confirms the synergistic effect of using a chemotherapy and immunotherapy agent in combating cancer (Fig. 3).

2.4 Interleukin-2

Interleukin-2 (IL-2) mediates its antitumor effect through the generation of lymphokineactivated killer (LAK) cells [25]. LAK cells are capable of lysing NK cell-resistant tumor cell targets. Studies to define the in vivo role of IL-2 have documented that the lymphokine can promote the expansion of transferred LAK cells [26], as well as immune T-cells

[27,28]. The administration of IL-2 alone also stimulates the proliferation of endogenous

lymphoid cells, which, when recovered from tissues, have lytic activity for fresh tumors in in vitro assays [29].

2.4.1 Interleukin-2 and doxorubicin

High and frequent doses of IL-2 are needed to achieve a significant response due to the rapid clearance of this cytokine which can lead to serious side effects due to its association with vascular leakage syndrome [29–32]. This can result in capillary leakage, cardiac

DNR

U937 AML cell Apoptotic AML cell

DNR DNR

Immune

hNP/SnMP T-hNP/SnMP

activation

Leukemia-associated myeloid cell HO1-inhibited myeloid cell Gr1-int, F4/80-int monocytic cell

Immune

activation

Fig. 3 Experimental summary of therapeutic mechanism for HO1-inhibiting T-hNP. (Reprinted (adapted) from Yong S-B, Kim J, Chung JY, Ra S, Kim SS, Kim Y-H. Heme oxygenase 1-targeted hybrid nanoparticle for chemo-and immuno-combination therapy in acute myelogenous leukemia. Adv Sci 7 2020:2000487. CC BY 4.0, © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Immune

activation

Chemo- & Immunocombination therapy

Immune

activation

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