Immunoengineering: How Nanotechnology Can Enhance Cancer Immunotherapy

This Article is excerpted from [CELL] written by Michael S. Goldberg

Although cancer immunotherapy can lead to durable outcomes, the percentage of patients who respond to this disruptive approach remains modest to date. Encouragingly, nanotechnology can enhance the efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics.

Awakening the Immune System
Although the research community has made great inroads into understanding the underlying etiology of cancer, our ability to confer durable responses to patients remains rather limited. The complexity of cancer aside, a major obstacle impeding our progress has been the widespread emphasis on cancer as a cell-autonomous disease. Few biologists would study gill physiology by removing a fish from water, yet we routinely interrogate cancer cells outside of their natural habitat, discounting the importance of the tumor microenvironment. In addition to stromal cells and extracellular matrix, immune cells greatly impact disease initiation, progression, and invasion.
Indeed, the type, density, and location of immune cells within tumors predict patient survival as well as, if not better than, traditional histopathological methods. This so-called 섃쁦mmune contexture쇺쇺봫ost notably the presence of CD8+CD45RO+ T cells and TH1 cells봧s associated with a good prognosis across at least 20 different cancer types (Fridman et al., 2012).
Accordingly, oncologists are eager to arouse exhausted immune cells, and clinical data confirm that stimulating a patient셲 natural antitumor immune response can cure relapsed, refractory patients with difficult-to-treat cancers who have exhausted other treatment options (Topalian et al., 2011).
Challengingly, tumors can evade immune surveillance. Consequently, most immunotherapies, particularly those directed against solid tumors, have thus far benefited only a minority of patients. For this reason, facilitating antitumor immune cells to overcome the activation energy barrier presented by the immunosuppressive tumor microenvironment is an area of active investigation.
Emerging preclinical and clinical data suggest that delivery of immunostimulatorymolecules fromnanoparticles and scaffolds can rouse the immune system with greater rigor than delivery of these same molecules in solution, leading to improved antitumor immunity and survival outcomes. Accordingly, biologists and engineers are working to improve our understanding ofwhich cells and pathways should be perturbed to maximize efficacy and what tools are most appropriate to perturb them as desired.

The Killer App for Nanomedicine?

Nanoparticles are synthetic particles (generally derived from polymers, lipids, or metals) with sizes on the nanometer scale, which confers properties that bridge bulk and molecular structures.
Such nanoparticles can be loaded with therapeutic compounds to achieve concentrated local drug delivery with potential for sustained release when biodegradable carriers are used.
Their high surface-area-to-volume ratio enables them to be coated with various ligands (e.g., antibodies or aptamers) that can facilitate interaction with cognate molecules, including receptors present on the surface of target cells. Although nanoparticles can improve the pharmacokinetic properties of their drug payloads (Chow and Ho, 2013), their ability to target cancer cells specifically and efficiently has proven somewhat elusive. Targeting nanoparticles to specific receptors on cancer cells augments cellular uptake but not tumor localization, which is governed by passive accumulation through leaky vasculature. In contrast, leukocytes can actively traffic to tumors along chemokine gradients, rendering these cells the ultimate 섃쁳argeted쇺 therapy.
Delivery of immunostimulatory drugs to antitumor immune cells may be a more efficient tactic to eradicate tumors than delivery of cytotoxic drugs to cancer cells (Figure 1). While the ability to concentrate nanoparticles within tumors upon systemic administration remains a challenge, immune cells proliferate extensively upon activation. As a consequence, unlike for cancer cells, successful payload delivery to even a small fraction of immune cells can achieve robust antitumor efficacy. Moreover, tumors are heterogeneous and ever evolving, so drugs that are designed to kill cancer cells directly by targeting cellintrinsic pathways inherently select for resistant clones that lead to relapse. In contrast, immune cells can generate a coordinated and adaptive antitumor response with capacity for memory that is not achievable using any other therapeutic modality. Improving the Efficacy of Cancer Vaccines Dendritic cells (DCs) are critical initiators of adaptive immune responses and are thus extremely relevant targets for anticancer nanomedicines. Co-administration of antigen and adjuvant as free drugs can result in delivery of antigen to some DCs and adjuvant to others.

Delivery of antigen in the absence of adjuvant induces immunologic tolerance, thereby inhibiting robust antitumor responses. Co-encapsulation of antigen and adjuvant in
a common particle enables co-delivery of both components to
the same DC, leading to improved induction of antigen-specific CD8+ T cells, which are critical mediators of antitumor immunity.
Sustained antigen release from a particle within DCs can further
enhance cytolytic T lymphocyte (CTL) priming in vitro by extending
antigen presentation (Audran et al., 2003). Such particles
serve as antigen reservoirs, thereby mimicking both prime and
boost injections following a single administration.

Figure 1. Applications of Nanotechnology Clockwise from bottom left: nanocarriers can be used to (1) deliver cancer vaccine antigens and adjuvants to dendritic cells, (2) stimulate T cells
directly as artificial antigen presenting cells, (3)concentrate immunostimulatory compounds in the immunosuppressive tumor microenvironment, and (4) deliver supportive drugs to T cells in the
circulation. (Image credit to Mohammad H. Saleh.)


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