Immunotherapy has changed the paradigm for treating cancers, which are designed to increase anti-tumor immune responses to attack cancer cells through natural mechanisms, reducing off-target effects, unlike chemotherapy and other drugs that directly kill cancer cells. . It is therefore considered a promising strategy for treating and even curing certain types of cancer.
Recently, the University of Pennsylvania's CAR-T bull, Carl H. June, as one of the authors, explored the challenges of cancer immunotherapy and the new delivery strategies that may make it safer and more effective at Nature Reviews Drug Discovery.
Classification of cancer immunotherapy
The first commercial cancer immunotherapy was a recombinant form of the cytokine interferon-alpha (IFNa), which was approved by the US Food and Drug Administration (FDA) for hairy cell leukemia in 1986. Some patients who underwent treatment experienced partial remission in early clinical trials, but because of the short duration of treatment with IFNα, they were quickly replaced by guanidine analogues as first-line treatments for hairy cell leukemia.
Shortly thereafter, recombinant interleukin-2 (IL-2) was studied as a cancer immunotherapy and was approved by the FDA for metastatic renal cell carcinoma in 1992 and approved for metastatic melanoma in 1998. Initially, there was great enthusiasm for IL-2 treatment because its use prompted a sustained and complete response in some patients. However, due to the short half-life of IL-2, high doses are required, which leads to serious side effects, including cytokine release syndrome and vascular leakage syndrome.
Despite the promising early clinical studies of these therapies, progress in the field of cancer immunotherapy was stagnant at the beginning of the 21st century, largely due to the failure of many vaccine clinical trials.
The first successful therapeutic cancer vaccine, sipuleucel-T, an autologous dendritic cell therapy, was approved by the FDA for prostate cancer in 2010, but its clinical transformation is hampered by production complexity and other problems.
Shortly thereafter, the pioneer checkpoint inhibitor ipilimumab, a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte antigen 4 (CTLA4), was approved for advanced melanoma in 2011.
In the past few years, new immunotherapies - including other checkpoint inhibitor mAbs against programmed cell death protein 1 (PD-1) or its ligand PD-L1, and the first chimeric antigen receptor (CAR) T cell therapy - has been developed and approved for clinical use. The emergence of ipilimumab and CAR-T cell therapy is a turning point in cancer immunotherapy, and the authoritative journal Science emphasized that cancer immunotherapy is the top of the top ten scientific breakthroughs in 2013.
There are currently more than a dozen immunotherapies approved for cancer treatment, and more immunotherapy is undergoing clinical trials. These immunotherapies fall into several categories, including checkpoint inhibitors, lymphocyte-activated cytokines, CAR-T cells and other cell therapies, agonistic antibodies against costimulatory receptors, cancer vaccines, oncolytic viruses, and bispecific antibodies. .
Some FDA-approved cancer immunotherapy (Source: Nature Reviews Drug Discovery)
Efficacy and safety challenges
Despite these significant advances, the clinical application of immunotherapy still faces several challenges related to efficacy and safety. Applying cancer immunotherapy in a safer, more controlled manner can extend the therapeutic potential to a broader patient population and can also reduce toxicity. In particular, improved delivery techniques can increase the accumulation of immunotherapy within diseased tissue, enabling more efficient targeting of desired tumors and/or immune cells, and reducing off-target side effects.
In terms of efficacy, only some patients respond to immunotherapy and are difficult to predict.
Thus, there is a growing interest in developing patient-specific immunotherapy based on cancer cell biomarker expression and evaluating combination therapy strategies to increase response rates.
The microenvironment in many solid tumors poses a challenge to the widespread implementation of all immunotherapeutic categories. For example, the microenvironment of solid tumors can be divided into immunological "hot" (highly immunogenic) or "cold" (low immunogenic), which have high or low levels of cytotoxic lymphocytes in the tumor space, respectively. infiltration. This key difference in microenvironment composition suggests that tumors with high immunogenicity respond more strongly to checkpoint inhibitors than tumors with lower immunogenicity. Thus, delivery techniques can be utilized to modulate immunogenicity in cold tumors.
In recent years, several immunotherapies, including activated cytokines and monoclonal antibodies for checkpoint blockade, have been approved by the FDA for solid tumor treatment. It is worth noting that CAR-T cell therapy has not been approved by the FDA for solid tumors, but researchers are developing CAR-T cells that are highly specific for solid tumor cells.
In terms of safety, immunotherapy can induce autoimmune side effects that lead to attacks on healthy tissues.
Checkpoint inhibitors, cytokines, and agonistic antibodies have similar delivery challenges. The success of these therapies depends on their interaction with the target protein. One of the main obstacles to its use is the production of large amounts of autoimmunity, limiting the amount of drug that is allowed to be administered. Many immunotherapies cause cytokine release syndrome and vascular leak syndrome, leading to severe hypotension, fever, renal insufficiency and other potentially fatal adverse reactions.
For this reason, delivery techniques for these therapies should achieve targeted and controlled release, limit exposure of the drug to specific tissues to reduce systemic toxicity of immunotherapy, and minimize off-target effects.
New delivery platform
Currently, new delivery platforms for immunotherapy are being developed, including nanoparticles, implants, scaffolds, biomaterials, and cell-based platforms. Some materials, including lipids, polymers, and metals, have been utilized to develop delivery technologies. The delivery platform offers many benefits over separate therapeutic drugs:
First, they can be designed to protect therapeutic cargo until delivered to target cells;
Second, if the delivery system is responsive to a stimulus such as pH, light or ultrasound, the delivery system can achieve spatiotemporal control of the treatment, thereby keeping the cargo inactive until it accumulates within the target cells;
Finally, delivery platforms such as implants have been developed for localized, controlled delivery of drugs, and cell therapies have been developed to minimize toxicity associated with systemic administration.
Characteristics of cancer immunotherapy delivery strategies (Source: Nature Reviews Drug Discovery)
For decades, it has been thought that selective nano-drugs can utilize highly permeability and retention (EPR) effects - characterized by tumor blood vessels that are more permeable to macromolecules than normal blood vessels, and because Lymphatic clearance leads to retention of macromolecules. Although the EPR effect is significant in the preclinical model of solid tumors, which exhibits a leaky vasculature and is also observed in humans, its therapeutic potential in cancer patients remains unclear and is studied in clinical trials. Most nanotherapeutics do not show substantial benefits over conventional chemotherapy.
A meta-analysis of 117 nanomedical delivery studies showed that some of these studies relied on EPR effects or active targeting of cancer cells, indicating that only 0.7% (median) of nanoparticles reached the tumor. Magnetic resonance imaging (MRI) or positron emission tomography (PET) studies assess the role of the EPR effect in tumors, revealing a high degree of variability in solid tumor permeability between patients, tumors of individual patients. These findings demonstrate the importance of understanding the physical microenvironment of tumors and their permeability, helping to optimally design delivery systems for tumor penetration and uptake.
Examples of cancer nanomedicine (Source: Nature Reviews Drug Discovery)
Different routes of administration can affect the therapeutic efficacy of the delivery technique. For example, local delivery using intratumoral injection or implantable stents can result in higher accumulation of drugs in the tumor, but may not be feasible for inaccessible tumors. Therefore, the route of administration is an important consideration when evaluating the delivery techniques of immunotherapy for a particular type of cancer.
Currently, local delivery techniques such as injectable hydrogels, implantable biomaterials, and microneedles are also being explored.
Nanoparticle
Nanoparticle-based immunotherapy delivered to tumor infiltrating immune cells in the blood, rather than directly targeting tumor cells, is a potentially attractive means of improving immunotherapy localization and stimulating anti-tumor responses in tumors.
The immunotherapeutic agent is delivered to the endogenous immune cells using receptor-ligand interactions that occur within the vasculature, and then the endogenous immune cells can migrate into the tumor to deliver the therapeutic agent.
mRNA vaccines are promising platforms for cancer immunotherapy, however, their use is limited by unstable and inefficient mRNA delivery in vivo; cationic lipid nanoparticle candidates have shown promising immunity in melanoma patients reaction.
Although the methods using cationic lipids have good effects, they are both toxic and immunogenic. In order to overcome the challenges faced by cationic lipids for mRNA-based immunotherapy, ionizable lipid materials have been designed. Reduces toxic side effects while maintaining its transfection properties. Preclinical studies have shown that ionizable lipid nanoparticles can improve the delivery of mRNA vaccines and induce strong immune responses.
Biomaterials: Local immunotherapy controlled release technology
Although immunomodulatory antibodies can induce potent anti-tumor immune responses, systemic delivery of these drugs can induce cytokine release syndrome and liver dysfunction. In order to minimize the effects outside the tissue, delivery systems for local and sustained release in vivo have been devised.
Biomaterials for local delivery of cancer immunotherapy (Source: Nature Reviews Drug Discovery)
Implantable biomaterial
Dendritic cell-based vaccines improve immune responses to cancer by isolating and activating dendritic cells ex vivo and reintroducing them into patients so that they can enter lymph nodes and present antigen to naive T cells, which are subsequently amplified and primed Anti-tumor response. However, these vaccines require complex modifications of the cells in vitro, and most of the injected cells die after transplantation.
To overcome this problem, implantable biomaterials have been used in cancer therapy, providing a physical structure to attract dendritic cells for in situ immunotherapy. In these systems, polymeric scaffolds are used as drug delivery devices to control the delivery of bioactive molecules in space and time to recruit dendritic cells and induce their proliferation. Tumor antigens can also be immobilized on these matrices, enabling them to serve as antigen-presenting structures in which dendritic cells are recruited, activated, loaded with antigen and released.
Injectable stent
Implantable stents require invasive surgery, which presents a logistical challenge.
Therefore, scaffolds that can be administered by injection without surgery, such as alginate hydrogels, gelatin and mesoporous porous silica particles, are also designed to produce a local immunogenic environment for recruitment in vivo. Activate and release immune cells. These materials are highly deformable and self-organizing. Although this strategy avoids the risks associated with surgical implantation, the biodegradation and safety of the injected materials will be further studied.
Injectable hydrogel
As a biodegradable alternative to silica, injectable in situ formed hydrogels have been designed to deliver a combination of immunotherapy and chemotherapy locally.
In one study, injectable poly(vinyl alcohol) (PVA) hydrogel networks were designed to respond to reactive oxygen species, which are present at high levels in the tumor microenvironment. This strategy is expected to improve the treatment outcome of cancers with low immunogenicity. In addition, this technique can avoid toxic side effects associated with systemically administered checkpoint inhibitors or chemotherapy.
Microneedle-based transdermal drug delivery
Although checkpoint inhibitors for systemic administration of CTLA4 or PD-1 have been approved for the treatment of melanoma, a significant proportion of patients do not respond to treatment. For example, the objective response rate against PD-1 mAb nivolumab is about 40%.
The minimally invasive transdermal delivery system is capable of sustained release of the anti-PD-1 mAb directly at the disease site in a controlled manner, thereby minimizing the required dose. These delivery systems consist of a degradable microneedle patch that penetrates the skin painlessly to the epidermis rich in immune cells to provide immunotherapy.
Microneedles are typically composed of a biodegradable polymer such as hyaluronic acid and are loaded with pH sensitive nanoparticles containing anti-PD-1. In a mild acidic tumor microenvironment, pH-sensitive anti-PD-1 nanoparticles are released to locally activate the immune system to attack cancer cells.
The microneedle-based transdermal delivery system provides a highly modular approach to local immunotherapy, using biological and remotely triggered stimuli to control drug release. Next, the study also needs to assess the bioavailability of the therapeutic agent within the patch and the biocompatibility of the delivery system.
T cell therapy delivery technology
T cell therapy delivery technology (Source: Nature Reviews Drug Discovery)
Treatment of adjuvant delivery
The main limitation of adoptive T cell therapy is that the viability and function of transplanted cells decline rapidly after administration. Therefore, such cell-based therapies require the simultaneous administration of adjuvant drugs to maximize the efficacy and performance of the cells. However, these drugs require systemic administration at high doses, resulting in many toxic side effects.
To overcome these obstacles, delivery techniques consisting of nanoparticles, stents, or a combination of both are now being explored. For example, nanoparticles loaded with therapeutic adjuvants are chemically conjugated to the surface of donor T cells as a means of stimulating transplanted cells and minimizing systemic side effects. This method is highly modular and is suitable for providing a range of immunostimulating drugs and achieving long-term release.
In situ T cell engineering by DNA nanocarriers
In order to overcome the complex procedures and high costs required to produce large numbers of adoptive T cells in vitro, delivery techniques for in situ engineered T cells are being developed.
As an alternative to in vitro genetic engineering, nanoparticle platforms are designed to reprogram T cells in the circulation. The platform is designed to target and enter T cells in the bloodstream of mice and then deliver the CAR gene into the T cell nucleus. Poly(β-amino ester) (PBAE)-based nanoparticles are used to deliver DNA cargo into the nucleus of T cells and further functionalized with peptides containing microtubule-associated sequences and nuclear localization signals to facilitate CAR-encoding DNA Nuclear input.
In preclinical models, the efficacy of the platform was comparable to that of traditional adoptive T cell therapy, and no substantial differences in animal survival were observed. Alternatively, the use of nanoparticle in situ engineered T cells can provide a practical and low cost method for designing CAR-T cells directly in patients to treat cancer. Future research will need to address whether the cost benefits of in vivo programming of CAR-T cells outweigh the potential safety concerns of unintentional gene transfer.
Biomaterial based implant
In addition to systemic routes of administration, biomaterial-based strategies have been investigated to deliver topical T cells locally to solid tumors.
Although adoptive T cell therapy has produced promising results for several types of cancer, including melanoma and hematological malignancies, successful targeting of T cells to most solid cancers remains challenging. These therapies are partially affected by the inefficient migration of T cells to tumors and the loss of T cell expansion in the immunosuppressive tumor microenvironment.
Therefore, techniques for locally delivering T cells to the tumor microenvironment and increasing their proliferation would be expected to enhance the efficacy of immunotherapy in solid tumors. Recently, polymer scaffolds have been investigated for the local delivery of T cells to the tumor microenvironment. In addition to localizing T cells near tumor sites or tumor sites, polymeric scaffolds are also advantageous because they act as reservoirs, and T cells are released when the material degrades.
Synthetic artificial antigen presenting cells (aAPC)
Synthetic artificial antigen presenting cells (aAPC) are cell-like particles, and T cell stimulating molecules bind to their surface to mimic APC. The resulting signal transduction activates T cells and triggers an anti-tumor response.
Compared to cell-based methods, aAPCs are easy to produce and can be stably stored and functionalized with various antigens and surface ligands for use in modulating immunotherapy. aAPC is usually composed of spherical particles (2-10 μm) of spherical particles, mainly including lipids, magnetic molecules or polymers. Although such aAPCs can activate T cells in vitro, it is still challenging to activate T cells in vivo using this method due to poor bioavailability and large size.
In order to achieve in vivo separation, nanoscale aAPC has recently been designed.
In summary, the synthetic aAPC delivery system provides a potential alternative to traditional adoptive T cell therapy by simultaneously presenting multiple signals on the surface of the synthetic particles to activate T cells in vivo. Future iterations of these systems should evaluate the effects of other physicochemical properties, such as particle rigidity and lipid membrane fluidity, to further optimize aAPC-T cell interactions.
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To overcome the challenges of clinical transformation of immunotherapy, a new delivery platform has been developed that is necessary. How to design to better improve the efficacy and safety of immunotherapy, and ultimately improve patient outcomes, will be the core of these delivery technologies for cancer immunotherapy.
