Introduction

Cancer immunotherapy describes a compelling pathway in the treatment of malignant tumors, leveraging a patient’s adaptive immune system in combating their own unique cancers. Such therapies often utilize complex nanotechnology, relying upon synthetic particles and engineered carriers to induce a desired immune response in the tumor microenvironment (TME). The widely accepted paradigm of nanomedicine assumes its ability to selectively deliver cytotoxic agents to tumor sites, minimizing the system-adverse effects typically associated with other standards of care. This approach confers a modest improvement in patient survival outcomes and is the focus of a broad spectrum of ongoing research. A second category of treatment relies upon the specific molecular targeting of immune checkpoints, called immune-checkpoint inhibition (ICI). Here, dramatic improvements in patient outcomes have been observed, demonstrating unprecedented efficacy in small subsets. As a consequence, there is a strong emerging interest in understanding and enhancing nanomedical cancer immunotherapies. This report will summarize the modern scope of immunoengineering, proceed to an analysis of its primary challenges, and conclude on a discussion of future development. 

Exploring Immunoengineering

Multiple forms of nanotherapeutics already see practical use and are readily available to cancer patients at the discretion of their medical caregivers. Further treatments are the focus of intense professional interest, with ongoing projects spanning early development to late-stage clinical trials. Immunoengineering refers to a fledgling field of interdisciplinary research combining expertise from materials science, bioengineering, nanotechnology, and immunology to influence the human immune system. In particular, it explores channels through which strong antitumor immune responses can be elicited through means unavailable to the conventional application of drugs in solution. The biological sciences work in conjunction with engineering methodologies in monitoring the diagnostics of biomarkers and enhancing the development of therapeutics. Biomaterials are employed in constructing targeted drug delivery solutions, focusing synthetic payloads on particular cell types in the TME and at specified anatomical locations. 

Recent work in immunoengineering can be subdivided into five primary categories: widening the risk-to-safety therapeutic index, augmenting adoptive cell therapy, enhancing endogenous immune responses, improving mRNA and peptide vaccines, increasing the uptake of nucleic-acid based therapies, and improving perioperative immunotherapy. The therapeutic index is substantially bolstered by the intratumoral injection of immunotherapeutic particles, as matrices are localized and systemic side effects are highly reduced. Nanotechnology allows for the effective production and delivery of cultured T cells, which are further improved by particles that stimulate lymphocyte function and modify the TME for easier infiltration. Endogenous immune responses can be reinforced by the direct stimulation of antitumor immune cells, as well as the reprogramming or elimination of immunosuppressive macrophages. Vaccinations are enhanced by the co-delivery of multiple components in nanotechnology formulations and the specific targeting of lymph nodes. Nucleic-acid based therapies benefit from the use of targeted polymeric nanoparticles to transfect T cells, resulting in the expression of therapeutically significant proteins. Finally, macroscale delivery devices can promote the dispersal of T cells at tumor resection sites and the intraoperative local release of various classes of cancer immunotherapy. As such, modern immunoengineering already confers formidable advantages in cancer treatment.

Analyzing Challenges

Although immunoengineering presents various advantages in the permeability and retention of therapeutic agents at tumor sites, the primary barrier to both nanomedicines and immunotherapeutic treatments still lies in the tumor microenvironment. Local changes induced by cancer cells inhibit effective delivery and compromise efficacy, even when therapeutic molecules are able to accumulate in the TME. These changes are pathophysiological and primarily manifest in the form of abnormalities in angiogenic and fibrotic signaling. The TME of primary tumors and any metastases derive their treatment resistance by directly and indirectly inducing immunosuppression through pathological angiogenesis and desmoplasia. Indirect immunosuppression occurs as oxygen delivery is inhibited, resulting in hypoxia and increased acidity. This dysfunctional growth in tumor vasculature varies substantially and explains high levels of spatial intratumor and intertumor variance in drug distribution, even between patients with tumors of the same type and between multiple tumors in the same patient. 

The microenvironment surrounding various tumors can be broadly attributed to three main, cycling immune phenotypes, which significantly influence sensitivity to immunotherapies and nanomedicines. First, the immune-desert phenotype is characterized by a lack of antitumor immune cells, reduced response to antigen presentation, and limited T cell priming. Local hypoxia induces angiogenic growth factors that promote immunological ignorance to antigens and increase the expression of chemokines that promote tumor-supporting immune regulatory cells. Second, the immune-excluded phenotype localizes immune cells to the periphery of the tumor microenvironment, inhibiting their further penetration through immature blood vessels and extravascular stroma. This dysfunctional growth stems from the expression of a transforming growth factor, resulting in an excessive extracellular matrix and a high density of cancer-associated fibroblasts. Although more susceptible to immunotherapies through reactivation of surrounding T cells, desmoplasia and angiogenesis prevent cytotoxic lymphocytes from migrating to cancer cells through a variety of motility inhibiting factors. Lastly, the inflamed phenotype contains immune cells within the parenchyma, indicative of a failed immune response. With T cells already within the TME, this phenotype is most vulnerable to immunotherapy but often contains numerous hypoxia-suppressed immune cells. The activation of certain growth factors recruits more immunosuppressive cells, as well as upregulating the expression of immune checkpoint molecules. Although preliminary strategies exist to “normalize” the TME, they represent the greatest current barrier to effective immunotherapeutic treatment. 

Examining Opportunities

As a burgeoning field, research opportunities in immunoengineering are extensive. In particular, the avenues through which further progress can be made are multiform. While novel therapies are a constant focus, improvements in bioengineering and materials science constitute the body of advancement in nanomedical cancer immunotherapy. Uniquely, quantitative and materials-based approaches are critical in the design of therapeutic agents, aiming to enhance their delivery, specificity, and efficacy in the TME. Another primary point of emphasis, however, is the potential for the synthetic manufacturing of immune cells and tissue. Technological advancements that support the large-scale production of primary, secondary, and tertiary lymphoid organs naturally enable the concomitant growth of immune-cell based therapeutics. Although many aspects of the immune system remain the subject of ongoing research, certain elements can be constructed under the constraints of modern bioengineering systems. 

Examining primary lymphoid organs, the bone marrow and the thymus constitute the most compelling targets for artificial production. As the primary site of development for all hematopoietic cells and the main location for B cell maturation, the construction of bone marrow is critical to facilitating further growth in cancer immunotherapy. The thymus follows closely after, as it allows for the generation of self-tolerant T cells essential for adaptive immunity. In engineering secondary lymphoid organs, the synthesis of activated T and B cells represent attractive challenges for future development. Artificially cultured T cells are a necessary component of adoptive T cell therapy, promising revolutionary applications in immunotherapy once fundamental roadblocks in inactivation and dysfunction are resolved. Activated B cells are inherently important to immune health, differentiating into antibody-secreting cells such as plasma cells and memory B cells. Challenges here lie in reconstructing the germinal center, as well as several less-understood components of B cell activation. Finally, ectopic tertiary structures present inherent difficulties in synthetic manufacture due to their complexity, variance, and unclear nature. Although suspected to be immune inductive sites for protective immunity in infectious diseases, current literature continues to investigate the exact function of tertiary lymphoid structures. Under the existing body of research, engineered models will have to carefully delineate their immunological purpose. Further investigation on all levels of lymphoid organization is necessary to facilitate the scalable ex vivo generation of immune cells and tissue. 

Conclusion

Immuno-engineering represents an attractive avenue for cancer treatment with incredible potential for future advancement. As a field in its infancy, the breadth of current research is naturally limited, yet the advantages of immuno-therapeutic treatment are increasingly clear as larger aggregates of clinical data are collected. Future development may result in highly effective remediation for a wide array of cancer forms, especially if key challenges in the tumor microenvironment are surpassed and innovative engineering strategies allow for the large-scale production of immune organs. 

References

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Kim, S., Shah, S. B., Graney, P. L., & Singh, A. (2019). Multiscale engineering of immune cells and lymphoid organs. Nature Reviews Materials, 4(6), 355–378. https://doi.org/10.1038/s41578-019-0100-9

Martin, J. D., Cabral, H., Stylianopoulos, T., & Jain, R. K. (2020). Improving cancer immunotherapy using nanomedicines: Progress, opportunities and challenges. Nature Reviews Clinical Oncology, 17(4), 251–266. https://doi.org/10.1038/s41571-019-0308-zWang, D., Wang, T., Yu, H., Feng, B., Zhou, L., Zhou, F., Hou, B., Zhang, H., Luo, M., & Li, Y. (2019). Engineering nanoparticles to locally activate T cells in the tumor microenvironment. Science Immunology, 4(37). https://doi.org/10.1126/sciimmunol.aau6584

Zhengyang Wang, Youth Medical Journal 2020