Scientists have developed a tumor enzymatic microenvironment-activatable antibody nanoparticle for robust cancer immunotherapy


Immune checkpoint blockade (ICB) therapy using the antibody that combats the programmed cell death ligand 1 (PD-L1) shows great potential and is causing a revolution in clinical cancer management.

Unfortunately, only a subset of treated patients responds to current ICB therapies, likely due to the immunological tolerance of tumors.

Therefore, developing a practical strategy to combat this immunological tolerance and amplify ICB therapies has become a priority.

To meet this challenge, scientists from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences have developed a tumor enzymatic microenvironment-activatable antibody nanoparticle for robust cancer immunotherapy.

This research was published online in Science Immunology.

In this study, Prof. Yu Haijun, Prof. Li Yaping and their colleagues engineered the antibody nanoparticles by integrating anti-PD-L1 antibody (αPDL1) and indocyanine green (ICG) into a single nanoplatform. ICG is a clinically approved fluorophore for fluorescence imaging in live surgery, and a photosensitizer for photodynamic therapy (PDT).

The antibody nanoparticles remain inert in blood circulation and protect αPDL1 from binding with normal tissues.

Once accumulated at the tumor site through the enhanced permeability and retention (EPR) effect, the antibody nanoparticles become activated to release αPDL1 for tumor-specific PD-L1 blockading.

Moreover, the scientists revealed that the antibody nanoparticles triggered the release of tumor antigens and promoted intratumoral infiltration of cytotoxic T lymphocytes (CTLs) through the ICG-based PDT effect.

“This is crucial for cancer immunotherapy since CTLs have been well-identified as the killer of tumor cells,” explained Prof. Yu, co-corresponding author of the study.

Elegant antibody nanoparticles override immunological tolerance of tumors
Illustration of activated nanoparticles carrying PD-L1 antibody (blue) and photosensitizer (green). Credit: Wang et al., Sci. Immunol. 4, eaau6584 (2019)

Finally, they showed that the antibody nanoparticles not only boost antitumor immunity with great efficiency, but also elicit long-term immune memory effects in BALB/c mice, thus leading to remarkable tumor regression.

In particular, the antibody nanoparticle-mediated combination of ICB and PDT therapy effectively suppressed tumor growth and metastasis to the lung and lymph nodes when using a 4T1 tumor-bearing BALB/C mouse model, which resulted in survival for >70% of the mice for more than 65 days, compared to complete mouse death in 42 days for the free αPDL1 group.

Distribution of nanoparticles carrying PD-L1 antibody (blue) and photosensitizer (red) in a mouse’s lymph nodes four hours post injection. The nanoparticles were highly efficient in accumulating at all the draining lymph nodes and distributed throughout the sections of tumoral metastatic regions. Credit: Wang et al., Sci. Immunol. 4, eaau6584 (2019)

“We provided a robust antibody nanoplatform for priming the antitumor immunity and inhibiting the immune checkpoint, which could be readily adapted to other immune checkpoint inhibitors for enhanced ICB therapies.

Given the simplicity of the nanostructures, our study has the potential of being translated into future generations of cancer immunotherapy,” Prof. Yu said.

Antibodies that block the immune checkpoint receptors PD1 and CTLA4 have revolutionized the treatment of melanoma and several other cancers, but in the process, a new class of drug side effect has emerged – immune related adverse events.

The observation that therapeutic blockade of these inhibitory receptors is sufficient to break self-tolerance, highlights their crucial role in the physiological modulation of immune responses.

Here, we discuss the rationale for targeting immune checkpoint receptors with agonistic agents in autoimmunity, to restore tolerance when it is lost.

We review progress that has been made to date, using Fc-fusion proteins, monoclonal antibodies or other novel constructs to induce immunosuppressive signaling through these pathways.

Finally, we explore potential mechanisms by which these receptors trigger and modulate immune cell function, and how understanding these processes might shape the design of more effective therapeutic agents in future.

Immune checkpoint receptors

The immune system comprises a powerful arsenal of effector mechanisms capable of inflicting devastating damage on invading pathogens, but also with the capacity to do great harm to the body itself.

In order to prevent such destruction of host tissues and to restore quiescence after an inflammatory response, careful immune regulation is required.

In the periphery, immune cell responses are controlled by a balance between positive and negative signals, which attune effector cells to their environment.

For a T cell these signals are delivered by a myriad of co-stimulatory and co-inhibitory surface receptors, whose inputs are integrated alongside T cell receptor (TCR) signaling to determine the cell’s fate.

The co-inhibitory receptors such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4), also known as immune checkpoints, recognize surface-expressed ligands on self-tissues and act to dampen unwanted immune activation.

In theory, a T cell which has escaped central tolerance, with a potentially autoreactive TCR, will be prevented from causing harm as it encounters its antigen in the context of healthy self-tissue expressing co-inhibitory ligands and no danger signals. Similar mechanisms control the response of innate immune cells to other inflammatory signals.

Immune checkpoint receptors as targets in cancer

In recent years it has become clear that cancers can co-opt these immune checkpoint pathways to evade the immune system, and therapeutic antibodies that block these receptors can take the brakes off the anti-tumor immune response, with astonishing results.

An antibody blocking the receptor CTLA4 was the first to show efficacy in treating malignant melanoma (1), followed by antibodies blocking PD1 or its ligand PDL1 (2).

These new immunotherapies, known as checkpoint inhibitors, have revolutionized the treatment of metastatic melanoma.

They offer a subset of patients a durable remission from a disease that was previously invariably terminal.

Since these initial trials checkpoint inhibitors have gone on to show efficacy in a wide range of other cancers (3) and whilst the list of indications for CTLA4 and PD1 blockade is growing, other immune inhibitory receptors are being investigated as potential targets in cancer therapy (4).

One of the limitations of checkpoint inhibitors has been the new genre of side effect they have led to, referred to as immune related adverse events (IRAEs).

Treated patients can develop a wide range of autoimmune phenomena affecting almost any organ, including the gut, skin, pituitary, thyroid, lung, liver, joints, kidneys, pancreas, or haematopoietic system (5).

These adverse events highlight the importance of immune checkpoint receptors in maintaining self-tolerance and raise the question of to what extent defects in these pathways could be contributing to spontaneous autoimmune disease.

Immune checkpoint defects in autoimmunity

In both humans and mice immune checkpoint receptors have been shown to play a crucial role in preserving peripheral tolerance.

CTLA4 knock out mice develop massive lymphoproliferation and die of multiorgan tissue destruction early in life (6), whilst human patients with heterozygous loss of function mutations in CTLA4 also develop widespread immune dysregulation (7).

PD1 knockout mice on a BALB/c background develop autoimmune cardiomyopathy (8) whilst on a C57BL/6 background they develop a late onset lupus-like disease (9).

In humans regulatory polymorphisms in the PDCD1 gene are associated with susceptibility to a variety of autoimmune conditions including systemic lupus erythematosus (10), atopy and rheumatoid arthritis (1112), and progression in multiple sclerosis (MS) (13).

It is in fact possible that the therapeutic benefit of interferon-beta in MS may be due to it upregulating PDL1 expression on myeloid cells (14).

Furthermore, autoantibodies against PDL1 have been found in patients with rheumatoid arthritis and correlate with disease activity (15).

In addition to PD1 and CTLA4 there are numerous other immune checkpoint receptors that have been shown to have important immune regulatory function.

B- and T-lymphocyte attenuator (BTLA) knock-out mice gradually develop multi-organ inflammatory infiltrates and a hepatitis-like disease (16), whilst a gene polymorphism in humans is associated with rheumatoid arthritis (17).

Mice lacking T cell Immunoreceptor with Ig and ITIM domains (TIGIT) do not develop spontaneous autoimmunity but have increased susceptibility to experimental autoimmune encephalitis (EAE) (18).

Similarly, mice without Lymphocyte-activation gene 3 (LAG3) do not develop spontaneous disease but have accelerated diabetes onset when bred onto a NOD background. Polymorphisms of the T cell immunoglobulin and mucin domain 3 (TIM-3) receptor in humans have been associated with MS (19), rheumatoid arthritis (20) and ankylosing spondylitis (21).

More information: D. Wang el al., “Engineering nanoparticles to locally activate T cells in the tumor microenvironment,” Science Immunology(2019). … 6/sciimmunol.aau6584

Provided by Chinese Academy of Sciences


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