Golden age of immunoengineering

IF 7.5 2区 医学 Q1 IMMUNOLOGY Immunological Reviews Pub Date : 2023-10-23 DOI:10.1111/imr.13283
Wilson W. Wong, Wendell A. Lim
{"title":"Golden age of immunoengineering","authors":"Wilson W. Wong,&nbsp;Wendell A. Lim","doi":"10.1111/imr.13283","DOIUrl":null,"url":null,"abstract":"<p>Immunology has long been the source of many significant medical breakthroughs, from vaccines for infections to therapeutics for cancer, autoimmunity, and transplant rejection. Indeed, the only diseases we have successfully eradicated, for example, smallpox and polio, were achieved through our understanding of the immune system. Furthermore, the immune system often plays an unexpected role in the outcome of a treatment not designed to engage the immune system. For instance, many chemotherapy or radiation therapies were initially designed to target cancer cells directly. However, subsequent investigations have uncovered the critical role these therapies have in stimulating the immune system.</p><p>As our understanding of the immune system deepens, its involvement in homeostasis and surveillance in almost every human organ becomes more apparent. For instance, the bidirectional response between the immune and central nervous systems has now been recognized as a major determinant for some neurodegenerative (e.g., Parkinson's disease) and psychiatric disorders. Other major chronic diseases, such as heart disease and diabetes, are influenced by the immune system. As such, the study of disease mechanisms would be deemed incomplete without considering the dynamic interaction of the aliment with the immune system. This recognition poses a significant challenge in understanding diseases, especially in humans, because studying the organ of interest is no longer sufficient to get the whole picture.</p><p>Due to its importance, many therapeutics have been developed to modulate the immune response for various diseases. A balance between activation and suppression is critical to maintaining a healthy, functional immune system. For instance, uncontrolled and overactive immune responses can lead to autoimmunity and tissue damage. Yet a hyporesponsive immune system can render the patient vulnerable to infection and cancer development. Many current therapies have been designed to either enhance or restrain the immune system. However, systemic immune system modulation tends to generate severe side effects. Therefore, precise spatiotemporal control of the immune response has become a major focus for the next generation of immunotherapy.</p><p>In this issue, 13 reviews have been prepared by some of the most innovative research groups describing the development of tools and strategies to harness the immune system for therapeutic applications. This issue will not be a comprehensive overview of immunoengineering. Instead, it will focus on applying protein and genetic engineering to improve the safety, specificity, and efficacy of immunotherapies. Furthermore, the immune system's direct interaction with almost all organs provides an intriguing opportunity for innovative and precise medical intervention. The immune system, while highly complex, is also very accessible. One can collect and genetically modify primary human immune cells, essentially converting them into smart drug delivery devices and cell-killing machines with active homing capability that can be remotely controlled by small molecules, light, or ultrasound. These attributes are being explored to treat various immune-mediated diseases (PMID: 37495877).</p><p>Cytokines are small soluble proteins that regulate the immune system and have been exploited as a treatment for many cancer types. The most prominent examples are interleukin- (IL) 2 and interferon-gamma, which are clinically approved. However, due to their ability to widespread inflammation, their toxicity has limited their utility in the clinics. Much effort has been devoted to improving the performance of cytokine therapy, yet success in the clinics has been marginal. Santonelli and Wittrup<span><sup>1</sup></span> elegantly summarize the field and discuss challenges in developing cytokine therapy. They also provide rationales based on engineering principles and clinical data that challenge current conventions and highlight the most promising developments.</p><p>Heller and Spangler's team<span><sup>2</sup></span> dive deeply into the biology of IL-4/IL-13, a specific class of cytokine critical to type 2 inflammatory response. This class is well-known for protecting against multicellular pathogens and is involved in responding to allergens. In addition to providing an overview of the biology, they thoroughly discussed therapeutic and diagnostic opportunities on the IL-4/IL-13 pathway through protein engineering and synthetic gene circuits for allergy, cancer, and other diseases.</p><p>Besides cytokines, other molecules derived from the immune system have enormous biotechnological and therapeutic potential. Antibodies derived from B cells are an example, and we encourage readers to peruse other excellent reviews for the latest developments. Recently, a new class of molecule derived from T-cell receptors (TCR) has emerged as a compelling modality for cancer therapeutics. While less versatile than antibodies, TCR can bind to intracellular-derived peptides, thus accessing mutated intracellular proteins and undruggable targets. Dao, Scheinberg, and their team<span><sup>3</sup></span> discussed the potential and challenge of developing TCR as therapeutics. They also compare TCR to other modalities, such as antibodies and chimeric antigen receptors (CAR). Interestingly, cytokines, antibodies, and TCR can be combined together to create novel therapies (Figure 1).</p><p>Small molecules and biologics are the dominant form of therapeutics. However, advances in cell engineering and synthetic biology have enabled the development of a new modality—immune cell therapy. The most prominent is the chimeric antigen receptor (CAR) T-cell therapy, with six FDA approvals for various hematological malignancies since 2017. Several reviews in this issue cover the foundation of CAR T-cell therapy. Roybal and his team outline some clinical considerations needed to create more effective CAR T-cell therapies.<span><sup>4</sup></span> Maus and colleagues specifically summarize preclinical and clinical results using CAR T cells against various digestive tract cancers and discuss opportunities and hurdles in applying CAR technology to this class of cancer.<span><sup>5</sup></span> Even with this impressive number of approvals in such a short time, these currently approved treatments only represent the foundation for various possibilities.</p><p>The most challenging part of successfully treating cancer has always been killing enough cancer cells while sparing healthy tissues. This typically requires precise delivery or recruitment of cytotoxic agents to the tumor, a challenge that is fundamentally difficult to address with small molecules or antibodies alone. Immune cell therapies are well suited to tackle this challenge, integrating complex genetic circuits into immune cells to enhance their precision. Hernandez-Lopez and his team<span><sup>6</sup></span> have summarized some of the latest developments in genetic circuit design that would improve specificity and provide safety controls to CAR T cells (Figure 2A).</p><p>Designing the optimal receptor is a crucial consideration for ensuring the appropriate function of cellular therapies. An example of where this is of critical importance is the treatment of solid tumors, which have many means of suppressing or evading the immune response. Furthermore, CAR T cells can also suffer from exhaustion through chronic stimulation by the cancer cells. Multiple strategies are available to address these issues related to CAR T potency, with one way being to engineer the CAR to promote survival. Wang, Xu, and their team recently discovered the importance of the electrostatic interaction of the intracellular signaling domain on CARs. Their review<span><sup>7</sup></span> in this issue discusses recent findings and strategies to harness the knowledge of charge-based interaction for designing better CARs (Figure 2A).</p><p>A CAR is comprised of several signaling domains that can impact T-cell physiology in different ways. Comprehensively exploring all the possible combinations of signaling domains in a CAR would be too time-consuming. While incorporating literature data can reduce the CAR design space, a more efficient receptor design approach is needed. Daniels and Capponi<span><sup>8</sup></span> discuss the potential of using artificial intelligence (AI) and machine learning (ML) to improve adoptive immune cell therapy. Specifically, they provide an overview of their recent work constructing a library of CARs and using AI to facilitate and understand the CAR designs that would improve persistence and survival. AI and large-scale cell engineering technology will undoubtedly be one of the primary sources of innovative CAR immune cell therapy design (Figure 2A).</p><p>Besides the receptor, engineering the cell host can improve its performance against cancer cells. Irving and colleagues summarize the concept of “coengineering”,<span><sup>9</sup></span> highlighting the benefit of introducing multiple features besides the tumor-targeting receptor into immune cells to enhance their safety, specificity, and efficacy (Figure 2B). For instance, therapeutic antibodies (e.g., checkpoint inhibitors) or cytokines can be inducibly overexpressed in CAR T cells to enhance their proliferation and survival within the tumor microenvironment. In addition to gene overexpression, directly modifying the genome is an important coengineering approach. CRISPR/Cas has become the most essential tool in genome engineering. Chen and colleagues<span><sup>10</sup></span> summarize the latest developments and experimental considerations in using CRISPR/Cas for unbiased functional screens in immune cells. They also discussed critical advances in creating more potent therapeutic immune cell therapies using CRISPR (Figure 2B). The ever-expanding capability of CRISPR technology will profoundly impact the understanding and development of immunotherapy.</p><p>T cells are the primary cell type for creating CAR immune cell therapy. While T cells have proven to be a potent vehicle for CAR therapy, they also have shortcomings. One of the main challenges in using T cells is that they have a TCR, which leads to graft vs. host disease if the T cells are allogeneically sourced. As such, all clinically approved CAR T-cell therapies use T cells from the patient as the cell source. This drastically increases the complexity and cost of the manufacturing process. It is widely recognized that the next generation of immune cell therapy should be allogeneic or in situ engineered to ensure comprehensive patient access and commercial viability.</p><p>Deleting the TCR from the T-cell genome is one of the most prominent approaches to creating allogeneic CAR T cells. While intriguing, this approach also increases the manufacturing complexity. Therefore, other immune cell types with cell-killing capability that do not express a TCR are also being explored as potential vehicles for CAR. Natural killer (NK) cells are an intriguing alternative to T cells as the cell host because they have proven to be an essential player against cancer. Interestingly, the foundational CAR design also works in NK cells. In the review by Rezvani and colleagues,<span><sup>11</sup></span> they highlight advances and understanding in CAR T and NK cells. Recent clinical trials with CAR NK cells have demonstrated exciting clinical efficacy with fewer side effects than CAR T cells. However, NK cells inherently have a shorter lifespan than T cells. Further advances in improving NK cell activity could pave the way for an off-the-shelf, allogeneic CAR immune cell therapy with activity comparable to T cells but with fewer side effects (Figure 3A).</p><p>In addition to T and NK cells, macrophages are also under investigation as a medium for immune cell therapy. Macrophages can naturally migrate into and accumulate in solid tumors, and many macrophages are routinely observed for various tumors. A modified CAR expressed in macrophages can induce antigen-dependent phagocytosis (Figure 3A). These properties make macrophages an attractive cell host for CAR. Our understanding of macrophage biology in the context of CAR is less than T cells. Gill and colleagues<span><sup>12</sup></span> have prepared a review summarizing the opportunities and challenges of developing CAR macrophages as cancer immunotherapy. Due to their natural abundance and tumor-homing capability over other immune cell types, unlocking the potential of macrophages could have a significant manufacturing advantage.</p><p>Most applications of immune cell therapy are designed for treating cancer. However, engineered immune cells can also be leveraged to tackle autoimmunity and transplant rejection. Autoimmunity and transplant rejection are typically caused by immune cells, such as B and T cells, attacking the patient's healthy tissues or allografts. Only a small subset of B and T cells are auto- or alloreactive. Systemic immunosuppression is the current standard of care, but it is also accompanied by many complications and reduced capacity for the patient to fight infections. Using a CAR approach, CAR T cells have been designed to specifically eradicate only the autoreactive or alloreactive immune cells while sparing other healthy immune cells, thus providing a highly precise approach to address these unwanted immune responses without systemic immunosuppression. However, identifying the autoreactive and alloreactive B and T cells in autoimmune or transplant cases remains challenging. An alternative approach is to leverage regulatory T (Treg) cells, a subset of CD4 T cells that can suppress the immune response when the TCR signaling pathway is activated (Figure 3B). Unsurprisingly, CAR-expressing Treg can lead to antigen-dependent immune suppression. Levings and colleagues<span><sup>13</sup></span> provide a detailed review of designer Treg's past achievements and current status. They also highlight the clinical potential of engineered Treg and discuss the ongoing preclinical studies and clinical trials on using designer Treg for various immune-mediated diseases.</p><p>We are now in the golden age of immunoengineering. The exciting and innovative immunoengineering developments summarized in this special issue of Immunological Reviews illustrate the immense potential that precise control over the immune system could have on developing disease-modifying, maybe even curative, therapies against some of the most untreatable diseases. These developments are, in part, accelerated by the convergence of multiple fields with immunology. For instance, the RNA technology that powers the unprecedented development of COVID vaccines is now being explored to create CAR T cells in situ, thus completely circumventing the need for cumbersome ex vivo cell processing. The main approach being investigated is to encapsulate messenger RNA (mRNA) encoding the gene of interest (e.g., CAR) into lipid nanoparticles and deliver the mRNA to immune cells inside the patient. The mRNA/LNP-based approach was recently leveraged to create CAR T cells against cardiac fibrotic tissues in mice to treat heart disease (PMID: 34990237).</p><p>Most conventional therapies aim to regulate one pathway or one cell type. However, that is different from how the therapy works in the complex, multicellular environment of a patient. For example, we learned from CAR T-cell therapy that we need both CD4 and CD8 T cells to be effective against cancer. Various combination therapies utilizing checkpoint inhibitors engage different parts of the immune response to elicit an efficacious response. Therefore, we anticipate that a purposeful modulation of multiple aspects of the immune system would further unlock the potential of immunotherapy. In addition, the immune response is a dynamic and carefully orchestrated process. We have seen that treating patients with chemotherapy to eliminate specific immune cells before administering CAR T cells could enhance their persistence and anti-cancer efficacy. Thus, considering the temporal order of multi-pronged regulation of the immune system could be the new dimension that can further accelerate the progress of immunotherapy.</p><p>W.W.W. holds equity in Senti Biosciences and 4Immune Therapeutics. W.A.L. holds equity in Gilead Sciences and Intellia Therapeutics and is an adviser for Allogene Therapeutics.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"320 1","pages":"4-9"},"PeriodicalIF":7.5000,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13283","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunological Reviews","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/imr.13283","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Immunology has long been the source of many significant medical breakthroughs, from vaccines for infections to therapeutics for cancer, autoimmunity, and transplant rejection. Indeed, the only diseases we have successfully eradicated, for example, smallpox and polio, were achieved through our understanding of the immune system. Furthermore, the immune system often plays an unexpected role in the outcome of a treatment not designed to engage the immune system. For instance, many chemotherapy or radiation therapies were initially designed to target cancer cells directly. However, subsequent investigations have uncovered the critical role these therapies have in stimulating the immune system.

As our understanding of the immune system deepens, its involvement in homeostasis and surveillance in almost every human organ becomes more apparent. For instance, the bidirectional response between the immune and central nervous systems has now been recognized as a major determinant for some neurodegenerative (e.g., Parkinson's disease) and psychiatric disorders. Other major chronic diseases, such as heart disease and diabetes, are influenced by the immune system. As such, the study of disease mechanisms would be deemed incomplete without considering the dynamic interaction of the aliment with the immune system. This recognition poses a significant challenge in understanding diseases, especially in humans, because studying the organ of interest is no longer sufficient to get the whole picture.

Due to its importance, many therapeutics have been developed to modulate the immune response for various diseases. A balance between activation and suppression is critical to maintaining a healthy, functional immune system. For instance, uncontrolled and overactive immune responses can lead to autoimmunity and tissue damage. Yet a hyporesponsive immune system can render the patient vulnerable to infection and cancer development. Many current therapies have been designed to either enhance or restrain the immune system. However, systemic immune system modulation tends to generate severe side effects. Therefore, precise spatiotemporal control of the immune response has become a major focus for the next generation of immunotherapy.

In this issue, 13 reviews have been prepared by some of the most innovative research groups describing the development of tools and strategies to harness the immune system for therapeutic applications. This issue will not be a comprehensive overview of immunoengineering. Instead, it will focus on applying protein and genetic engineering to improve the safety, specificity, and efficacy of immunotherapies. Furthermore, the immune system's direct interaction with almost all organs provides an intriguing opportunity for innovative and precise medical intervention. The immune system, while highly complex, is also very accessible. One can collect and genetically modify primary human immune cells, essentially converting them into smart drug delivery devices and cell-killing machines with active homing capability that can be remotely controlled by small molecules, light, or ultrasound. These attributes are being explored to treat various immune-mediated diseases (PMID: 37495877).

Cytokines are small soluble proteins that regulate the immune system and have been exploited as a treatment for many cancer types. The most prominent examples are interleukin- (IL) 2 and interferon-gamma, which are clinically approved. However, due to their ability to widespread inflammation, their toxicity has limited their utility in the clinics. Much effort has been devoted to improving the performance of cytokine therapy, yet success in the clinics has been marginal. Santonelli and Wittrup1 elegantly summarize the field and discuss challenges in developing cytokine therapy. They also provide rationales based on engineering principles and clinical data that challenge current conventions and highlight the most promising developments.

Heller and Spangler's team2 dive deeply into the biology of IL-4/IL-13, a specific class of cytokine critical to type 2 inflammatory response. This class is well-known for protecting against multicellular pathogens and is involved in responding to allergens. In addition to providing an overview of the biology, they thoroughly discussed therapeutic and diagnostic opportunities on the IL-4/IL-13 pathway through protein engineering and synthetic gene circuits for allergy, cancer, and other diseases.

Besides cytokines, other molecules derived from the immune system have enormous biotechnological and therapeutic potential. Antibodies derived from B cells are an example, and we encourage readers to peruse other excellent reviews for the latest developments. Recently, a new class of molecule derived from T-cell receptors (TCR) has emerged as a compelling modality for cancer therapeutics. While less versatile than antibodies, TCR can bind to intracellular-derived peptides, thus accessing mutated intracellular proteins and undruggable targets. Dao, Scheinberg, and their team3 discussed the potential and challenge of developing TCR as therapeutics. They also compare TCR to other modalities, such as antibodies and chimeric antigen receptors (CAR). Interestingly, cytokines, antibodies, and TCR can be combined together to create novel therapies (Figure 1).

Small molecules and biologics are the dominant form of therapeutics. However, advances in cell engineering and synthetic biology have enabled the development of a new modality—immune cell therapy. The most prominent is the chimeric antigen receptor (CAR) T-cell therapy, with six FDA approvals for various hematological malignancies since 2017. Several reviews in this issue cover the foundation of CAR T-cell therapy. Roybal and his team outline some clinical considerations needed to create more effective CAR T-cell therapies.4 Maus and colleagues specifically summarize preclinical and clinical results using CAR T cells against various digestive tract cancers and discuss opportunities and hurdles in applying CAR technology to this class of cancer.5 Even with this impressive number of approvals in such a short time, these currently approved treatments only represent the foundation for various possibilities.

The most challenging part of successfully treating cancer has always been killing enough cancer cells while sparing healthy tissues. This typically requires precise delivery or recruitment of cytotoxic agents to the tumor, a challenge that is fundamentally difficult to address with small molecules or antibodies alone. Immune cell therapies are well suited to tackle this challenge, integrating complex genetic circuits into immune cells to enhance their precision. Hernandez-Lopez and his team6 have summarized some of the latest developments in genetic circuit design that would improve specificity and provide safety controls to CAR T cells (Figure 2A).

Designing the optimal receptor is a crucial consideration for ensuring the appropriate function of cellular therapies. An example of where this is of critical importance is the treatment of solid tumors, which have many means of suppressing or evading the immune response. Furthermore, CAR T cells can also suffer from exhaustion through chronic stimulation by the cancer cells. Multiple strategies are available to address these issues related to CAR T potency, with one way being to engineer the CAR to promote survival. Wang, Xu, and their team recently discovered the importance of the electrostatic interaction of the intracellular signaling domain on CARs. Their review7 in this issue discusses recent findings and strategies to harness the knowledge of charge-based interaction for designing better CARs (Figure 2A).

A CAR is comprised of several signaling domains that can impact T-cell physiology in different ways. Comprehensively exploring all the possible combinations of signaling domains in a CAR would be too time-consuming. While incorporating literature data can reduce the CAR design space, a more efficient receptor design approach is needed. Daniels and Capponi8 discuss the potential of using artificial intelligence (AI) and machine learning (ML) to improve adoptive immune cell therapy. Specifically, they provide an overview of their recent work constructing a library of CARs and using AI to facilitate and understand the CAR designs that would improve persistence and survival. AI and large-scale cell engineering technology will undoubtedly be one of the primary sources of innovative CAR immune cell therapy design (Figure 2A).

Besides the receptor, engineering the cell host can improve its performance against cancer cells. Irving and colleagues summarize the concept of “coengineering”,9 highlighting the benefit of introducing multiple features besides the tumor-targeting receptor into immune cells to enhance their safety, specificity, and efficacy (Figure 2B). For instance, therapeutic antibodies (e.g., checkpoint inhibitors) or cytokines can be inducibly overexpressed in CAR T cells to enhance their proliferation and survival within the tumor microenvironment. In addition to gene overexpression, directly modifying the genome is an important coengineering approach. CRISPR/Cas has become the most essential tool in genome engineering. Chen and colleagues10 summarize the latest developments and experimental considerations in using CRISPR/Cas for unbiased functional screens in immune cells. They also discussed critical advances in creating more potent therapeutic immune cell therapies using CRISPR (Figure 2B). The ever-expanding capability of CRISPR technology will profoundly impact the understanding and development of immunotherapy.

T cells are the primary cell type for creating CAR immune cell therapy. While T cells have proven to be a potent vehicle for CAR therapy, they also have shortcomings. One of the main challenges in using T cells is that they have a TCR, which leads to graft vs. host disease if the T cells are allogeneically sourced. As such, all clinically approved CAR T-cell therapies use T cells from the patient as the cell source. This drastically increases the complexity and cost of the manufacturing process. It is widely recognized that the next generation of immune cell therapy should be allogeneic or in situ engineered to ensure comprehensive patient access and commercial viability.

Deleting the TCR from the T-cell genome is one of the most prominent approaches to creating allogeneic CAR T cells. While intriguing, this approach also increases the manufacturing complexity. Therefore, other immune cell types with cell-killing capability that do not express a TCR are also being explored as potential vehicles for CAR. Natural killer (NK) cells are an intriguing alternative to T cells as the cell host because they have proven to be an essential player against cancer. Interestingly, the foundational CAR design also works in NK cells. In the review by Rezvani and colleagues,11 they highlight advances and understanding in CAR T and NK cells. Recent clinical trials with CAR NK cells have demonstrated exciting clinical efficacy with fewer side effects than CAR T cells. However, NK cells inherently have a shorter lifespan than T cells. Further advances in improving NK cell activity could pave the way for an off-the-shelf, allogeneic CAR immune cell therapy with activity comparable to T cells but with fewer side effects (Figure 3A).

In addition to T and NK cells, macrophages are also under investigation as a medium for immune cell therapy. Macrophages can naturally migrate into and accumulate in solid tumors, and many macrophages are routinely observed for various tumors. A modified CAR expressed in macrophages can induce antigen-dependent phagocytosis (Figure 3A). These properties make macrophages an attractive cell host for CAR. Our understanding of macrophage biology in the context of CAR is less than T cells. Gill and colleagues12 have prepared a review summarizing the opportunities and challenges of developing CAR macrophages as cancer immunotherapy. Due to their natural abundance and tumor-homing capability over other immune cell types, unlocking the potential of macrophages could have a significant manufacturing advantage.

Most applications of immune cell therapy are designed for treating cancer. However, engineered immune cells can also be leveraged to tackle autoimmunity and transplant rejection. Autoimmunity and transplant rejection are typically caused by immune cells, such as B and T cells, attacking the patient's healthy tissues or allografts. Only a small subset of B and T cells are auto- or alloreactive. Systemic immunosuppression is the current standard of care, but it is also accompanied by many complications and reduced capacity for the patient to fight infections. Using a CAR approach, CAR T cells have been designed to specifically eradicate only the autoreactive or alloreactive immune cells while sparing other healthy immune cells, thus providing a highly precise approach to address these unwanted immune responses without systemic immunosuppression. However, identifying the autoreactive and alloreactive B and T cells in autoimmune or transplant cases remains challenging. An alternative approach is to leverage regulatory T (Treg) cells, a subset of CD4 T cells that can suppress the immune response when the TCR signaling pathway is activated (Figure 3B). Unsurprisingly, CAR-expressing Treg can lead to antigen-dependent immune suppression. Levings and colleagues13 provide a detailed review of designer Treg's past achievements and current status. They also highlight the clinical potential of engineered Treg and discuss the ongoing preclinical studies and clinical trials on using designer Treg for various immune-mediated diseases.

We are now in the golden age of immunoengineering. The exciting and innovative immunoengineering developments summarized in this special issue of Immunological Reviews illustrate the immense potential that precise control over the immune system could have on developing disease-modifying, maybe even curative, therapies against some of the most untreatable diseases. These developments are, in part, accelerated by the convergence of multiple fields with immunology. For instance, the RNA technology that powers the unprecedented development of COVID vaccines is now being explored to create CAR T cells in situ, thus completely circumventing the need for cumbersome ex vivo cell processing. The main approach being investigated is to encapsulate messenger RNA (mRNA) encoding the gene of interest (e.g., CAR) into lipid nanoparticles and deliver the mRNA to immune cells inside the patient. The mRNA/LNP-based approach was recently leveraged to create CAR T cells against cardiac fibrotic tissues in mice to treat heart disease (PMID: 34990237).

Most conventional therapies aim to regulate one pathway or one cell type. However, that is different from how the therapy works in the complex, multicellular environment of a patient. For example, we learned from CAR T-cell therapy that we need both CD4 and CD8 T cells to be effective against cancer. Various combination therapies utilizing checkpoint inhibitors engage different parts of the immune response to elicit an efficacious response. Therefore, we anticipate that a purposeful modulation of multiple aspects of the immune system would further unlock the potential of immunotherapy. In addition, the immune response is a dynamic and carefully orchestrated process. We have seen that treating patients with chemotherapy to eliminate specific immune cells before administering CAR T cells could enhance their persistence and anti-cancer efficacy. Thus, considering the temporal order of multi-pronged regulation of the immune system could be the new dimension that can further accelerate the progress of immunotherapy.

W.W.W. holds equity in Senti Biosciences and 4Immune Therapeutics. W.A.L. holds equity in Gilead Sciences and Intellia Therapeutics and is an adviser for Allogene Therapeutics.

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免疫工程的黄金时代。
免疫学长期以来一直是许多重大医学突破的来源,从感染疫苗到癌症治疗,自身免疫和移植排斥。事实上,我们成功根除的唯一疾病,例如天花和小儿麻痹症,都是通过我们对免疫系统的理解而实现的。此外,免疫系统经常在治疗结果中发挥意想不到的作用,而不是设计用于免疫系统。例如,许多化疗或放射疗法最初都是直接针对癌细胞设计的。然而,随后的研究揭示了这些疗法在刺激免疫系统方面的关键作用。随着我们对免疫系统理解的加深,它在几乎每个人体器官的体内平衡和监视中的作用变得更加明显。例如,免疫系统和中枢神经系统之间的双向反应现在已被认为是一些神经退行性疾病(如帕金森病)和精神疾病的主要决定因素。其他主要的慢性疾病,如心脏病和糖尿病,都受到免疫系统的影响。因此,如果不考虑食物与免疫系统的动态相互作用,对疾病机制的研究将被认为是不完整的。这种认识对理解疾病,特别是人类疾病构成了重大挑战,因为研究感兴趣的器官不再足以获得全貌。由于它的重要性,许多治疗方法已经发展到调节各种疾病的免疫反应。激活和抑制之间的平衡对于维持健康、功能性的免疫系统至关重要。例如,不受控制和过度活跃的免疫反应会导致自身免疫和组织损伤。然而,反应迟钝的免疫系统会使患者容易受到感染和癌症的发展。目前的许多疗法都是为了增强或抑制免疫系统而设计的。然而,全身免疫系统调节往往会产生严重的副作用。因此,对免疫反应进行精确的时空控制已成为下一代免疫治疗的主要焦点。在这一期中,一些最具创新性的研究小组准备了13篇综述,描述了利用免疫系统进行治疗应用的工具和策略的发展。这一期将不会是免疫工程的全面概述。相反,它将专注于应用蛋白质和基因工程来提高免疫疗法的安全性、特异性和有效性。此外,免疫系统与几乎所有器官的直接相互作用为创新和精确的医疗干预提供了一个有趣的机会。免疫系统虽然非常复杂,但也很容易接近。人们可以收集并对人类的初级免疫细胞进行基因改造,本质上是将它们转化为智能药物输送装置和具有主动定位能力的细胞杀伤机器,这些机器可以通过小分子、光或超声波进行远程控制。正在探索这些特性以治疗各种免疫介导的疾病(PMID: 37495877)。细胞因子是一种调节免疫系统的小的可溶性蛋白质,已经被用来治疗许多类型的癌症。最突出的例子是临床批准的白介素- (IL) 2和干扰素- γ。然而,由于它们能够引起广泛的炎症,它们的毒性限制了它们在临床中的应用。许多努力已经投入到提高细胞因子治疗的性能,但在诊所的成功已经边缘。Santonelli和Wittrup1优雅地总结了该领域,并讨论了发展细胞因子治疗的挑战。它们还提供了基于工程原理和临床数据的基本原理,这些原理和数据挑战了当前的惯例,并突出了最有希望的发展。Heller和Spangler的团队深入研究了IL-4/IL-13的生物学特性,IL-4/IL-13是一类对2型炎症反应至关重要的细胞因子。这类以防止多细胞病原体而闻名,并参与对过敏原的反应。除了提供生物学概述外,他们还深入讨论了通过蛋白质工程和合成基因回路对过敏、癌症和其他疾病的IL-4/IL-13途径的治疗和诊断机会。除了细胞因子外,来自免疫系统的其他分子具有巨大的生物技术和治疗潜力。来自B细胞的抗体就是一个例子,我们鼓励读者阅读其他优秀的评论,了解最新的发展。最近,一类来自t细胞受体(TCR)的新分子已经成为癌症治疗的一种引人注目的方式。 虽然不如抗体通用,但TCR可以结合细胞内衍生的肽,从而接近突变的细胞内蛋白质和不可药物的靶标。Dao、Scheinberg和他们的团队讨论了开发TCR作为治疗方法的潜力和挑战。他们还比较了TCR与其他方式,如抗体和嵌合抗原受体(CAR)。有趣的是,细胞因子、抗体和TCR可以结合在一起创造新的治疗方法(图1)。小分子和生物制剂是治疗方法的主要形式。然而,细胞工程和合成生物学的进步使一种新的模式-免疫细胞疗法的发展成为可能。最突出的是嵌合抗原受体(CAR) t细胞疗法,自2017年以来,FDA批准了6种用于各种血液恶性肿瘤的疗法。本期的几篇综述涵盖了CAR - t细胞治疗的基础。Roybal和他的团队概述了创造更有效的CAR - t细胞疗法所需的一些临床考虑Maus及其同事特别总结了CAR - T细胞治疗各种消化道癌症的临床前和临床结果,并讨论了将CAR - T技术应用于这类癌症的机会和障碍即使在如此短的时间内获得如此多的批准,这些目前批准的治疗方法也只是各种可能性的基础。成功治疗癌症最具挑战性的部分一直是杀死足够多的癌细胞,同时保留健康组织。这通常需要精确地向肿瘤输送或招募细胞毒性药物,这是一个从根本上难以仅用小分子或抗体解决的挑战。免疫细胞疗法非常适合解决这一挑战,将复杂的遗传回路整合到免疫细胞中以提高其精度。Hernandez-Lopez和他的团队总结了遗传电路设计的一些最新进展,这些设计将提高CAR - T细胞的特异性,并提供安全控制(图2A)。设计最佳受体是确保细胞治疗适当功能的关键考虑因素。这一点至关重要的一个例子是实体瘤的治疗,实体瘤有许多抑制或逃避免疫反应的方法。此外,CAR - T细胞也可能因癌细胞的慢性刺激而衰竭。有多种策略可用于解决与CAR - T效力相关的这些问题,其中一种方法是设计CAR以促进生存。Wang, Xu和他们的团队最近发现了car细胞内信号域的静电相互作用的重要性。他们在本期的评论中讨论了利用基于电荷的交互知识来设计更好的car的最新发现和策略(图2A)。CAR由几个信号域组成,这些信号域可以以不同的方式影响t细胞的生理机能。全面探索CAR中所有可能的信号域组合将过于耗时。虽然结合文献数据可以减少CAR的设计空间,但需要一种更有效的受体设计方法。Daniels和Capponi8讨论了使用人工智能(AI)和机器学习(ML)来改善过继免疫细胞治疗的潜力。具体来说,他们概述了他们最近的工作,构建了一个CAR库,并使用人工智能来促进和理解将提高持久性和存活率的CAR设计。人工智能和大规模细胞工程技术无疑将成为创新CAR免疫细胞疗法设计的主要来源之一(图2A)。除了受体,改造细胞宿主可以提高其对抗癌细胞的性能。Irving及其同事总结了“协同工程”的概念,9强调了将肿瘤靶向受体以外的多种特征引入免疫细胞以增强其安全性、特异性和有效性的好处(图2B)。例如,治疗性抗体(如检查点抑制剂)或细胞因子可以在CAR - T细胞中诱导过表达,以增强其在肿瘤微环境中的增殖和存活。除了基因过表达外,直接修饰基因组也是一种重要的协同工程方法。CRISPR/Cas已成为基因组工程中最重要的工具。Chen及其同事总结了在免疫细胞中使用CRISPR/Cas进行无偏功能筛选的最新进展和实验考虑。他们还讨论了利用CRISPR创造更有效的治疗性免疫细胞疗法的关键进展(图2B)。CRISPR技术不断扩展的能力将深刻影响免疫治疗的理解和发展。T细胞是产生CAR免疫细胞疗法的主要细胞类型。虽然T细胞已被证明是一种有效的CAR治疗载体,但它们也有缺点。 使用T细胞的主要挑战之一是它们具有TCR,如果T细胞是同种异体来源的,则会导致移植物抗宿主病。因此,所有临床批准的CAR - T细胞疗法都使用患者的T细胞作为细胞来源。这大大增加了制造过程的复杂性和成本。人们普遍认为,下一代免疫细胞疗法应该是同种异体或原位工程,以确保全面的患者可及性和商业可行性。从T细胞基因组中删除TCR是制造同种异体CAR - T细胞的最重要方法之一。虽然很有趣,但这种方法也增加了制造的复杂性。因此,其他不表达TCR的具有细胞杀伤能力的免疫细胞类型也正在被探索作为CAR的潜在载体。自然杀伤细胞(NK)是T细胞作为细胞宿主的一个有趣的替代品,因为它们已被证明是对抗癌症的重要角色。有趣的是,基本的CAR设计也适用于NK细胞。在Rezvani及其同事的综述中,他们强调了CAR - T和NK细胞的进展和理解。最近CAR - NK细胞的临床试验显示出令人兴奋的临床疗效,副作用比CAR - T细胞少。然而,NK细胞固有的寿命比T细胞短。提高NK细胞活性的进一步进展可能为现成的同种异体CAR免疫细胞疗法铺平道路,这种疗法的活性与T细胞相当,但副作用更少(图3A)。除了T细胞和NK细胞外,巨噬细胞作为免疫细胞治疗的介质也在研究中。巨噬细胞可以自然迁移到实体肿瘤中并在实体肿瘤中积累,在各种肿瘤中常规观察到大量巨噬细胞。巨噬细胞中表达的修饰CAR可诱导抗原依赖性吞噬(图3A)。这些特性使巨噬细胞成为CAR的有吸引力的细胞宿主。我们对CAR背景下巨噬细胞生物学的了解比T细胞少。Gill和他的同事们准备了一篇综述,总结了发展CAR -巨噬细胞作为癌症免疫疗法的机遇和挑战。由于巨噬细胞的天然丰度和肿瘤归巢能力超过其他免疫细胞类型,释放巨噬细胞的潜力可能具有显著的制造优势。大多数免疫细胞疗法的应用是为治疗癌症而设计的。然而,工程免疫细胞也可以用来解决自身免疫和移植排斥。自身免疫和移植排斥反应通常是由免疫细胞(如B细胞和T细胞)攻击患者的健康组织或同种异体移植物引起的。只有一小部分B细胞和T细胞具有自体反应性或同种异体反应性。全身免疫抑制是目前的标准治疗方法,但它也伴随着许多并发症,降低了患者抵抗感染的能力。使用CAR方法,CAR - T细胞被设计为只特异性地根除自身反应性或同种异体反应性免疫细胞,同时保留其他健康的免疫细胞,从而提供了一种高度精确的方法来解决这些不需要的免疫反应,而不需要全身免疫抑制。然而,在自身免疫或移植病例中识别自身反应性和同种异体反应性B细胞和T细胞仍然具有挑战性。另一种方法是利用调节性T细胞(Treg),这是CD4 T细胞的一个子集,当TCR信号通路被激活时,它可以抑制免疫反应(图3B)。不出所料,表达car的Treg可导致抗原依赖性免疫抑制。Levings和他的同事详细回顾了设计师Treg过去的成就和现在的状态。他们还强调了工程Treg的临床潜力,并讨论了正在进行的使用设计Treg治疗各种免疫介导疾病的临床前研究和临床试验。我们现在正处于免疫工程的黄金时代。本期《免疫学评论》特刊总结了令人兴奋和创新的免疫工程发展,说明了对免疫系统的精确控制在开发针对一些最无法治愈的疾病的疾病改善,甚至治愈疗法方面的巨大潜力。这些发展在一定程度上是由于免疫学多领域的融合而加速的。例如,目前正在探索为前所未有的COVID疫苗开发提供动力的RNA技术,以在原位制造CAR - T细胞,从而完全避免了繁琐的离体细胞加工的需要。目前正在研究的主要方法是将编码感兴趣基因(如CAR)的信使RNA (mRNA)封装到脂质纳米颗粒中,并将mRNA递送到患者体内的免疫细胞。基于mRNA/ lnp的方法最近被用于在小鼠中创建针对心脏纤维化组织的CAR - T细胞来治疗心脏病(PMID: 34990237)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Immunological Reviews
Immunological Reviews 医学-免疫学
CiteScore
16.20
自引率
1.10%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Immunological Reviews is a specialized journal that focuses on various aspects of immunological research. It encompasses a wide range of topics, such as clinical immunology, experimental immunology, and investigations related to allergy and the immune system. The journal follows a unique approach where each volume is dedicated solely to a specific area of immunological research. However, collectively, these volumes aim to offer an extensive and up-to-date overview of the latest advancements in basic immunology and their practical implications in clinical settings.
期刊最新文献
Issue Information Introduction Lessons Learned From Clinical Trials of Immunotherapeutics for COVID-19. Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer. Role of inflammasomes and neuroinflammation in epilepsy.
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