Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?

Abstract

While the number of oncology-related nanotherapeutics and immunotherapies is constantly increasing, cancer patients still suffer from a lack of efficacy and treatment resistance. Among the investigated strategies, patient selection and combinations appear to be of great hope. This review will focus on combining nanotherapeutics and immunotherapies together, how they can dually optimize each other to face such limits, bringing us into a new field called nano-immunotherapy. While looking at current clinical trials, we will expose how passive immunotherapies, such as antibodies and ADCs, can boost nanoparticle tumor uptake and tumor cell internalization. Conversely, we will study how immunotherapies can benefit from nanotherapeutics which can optimize their lipophilicity, permeability, and distribution (e.g., greater tumor uptake, BBB crossing, etc.), tumor, tumor microenvironment, and immune system targeting properties.

Keywords: combination; immunotherapy; nanotherapeutics; oncology.

Figure 1

Timeline of the marketing authorization of the keystone cancer nanotherapeutics. In 1995, Doxil®/Caelyx® was the first FDA-approved (pegylated) liposome, followed by unpegylated liposomes; Daunoxome®, Myocet®, Mepact®, Marqibo®, and Vyxeos® and pegylated one: Onyvide®. Vyxeos is the first commercialized nanotherapeutics encapsulating two chemotherapies (i.e., cytarabine and daunorubicin). Other formulations have been approved in the clinic, such as nab-drugs in 2005 and 2021 (i.e., Abraxane® and Fyarro®, respectively), pegylated aparaginase (i.e., Oncaspar®) in 2006, polymeric micelles (i.e., Genexol®) in 2007, and inorganic nanoparticles in 2019 (i.e., Hensify®).

Figure 2

Anticancer immunotherapies classified into passive and active immunotherapies. Passive immunotherapies are the administration of immune molecules directly and active immunotherapies stimulate the patient immune response. ADCs = antibody drug conjugates, T-cell = T lymphocyte, ICIs = immune checkpoint inhibitors, BsAbs = bispecific antibodies.

Figure 3

Schematization of the most relevant benefits nanotherapeutics and immunotherapies can get from being combined. Passive immunotherapies (e.g., antibodies) can optimize nanoparticle intratumoral accumulation and internalization (A). Nanotherapeutics can optimize passive immunotherapy distributions and modify the tumor phenotype for a better treatment efficacy (B). Nanotherapeutics can also optimize active immunotherapy efficacy by targeting the tumor cells, the TME (i.e., T cells or immunosuppressive cells such as MDSCs, Treg, tumor-associated macrophages) or the peripheral/central immune system (B). Together, the combination of nanotherapeutics with immunotherapies can protect the patient from poor efficacy, drug toxicity, and associated premedication (C). DC = dendritic cell, ICD = immunogenic cell death, IL = interleukin, ImmunoT = immunotherapy, IS = immune system, PK = pharmacokinetics, NanoT = nanotherapeutics, T cell = lymphocyte T, TME = tumor microenvironment, Treg = regulatory T cell, MDSCs = myeloid-derived suppressor cell.

Figure 4

Schematization of the most relevant types of merged (yellow zone) and associated (blue zone) nano-immunotherapies currently under clinical trial in oncology. Merged nano-immunotherapies include nanoparticles (mostly liposomes or nanocells) engrafted with antibodies or fragments of antibodies and nanoparticles used as nanocarrier for immune system activators such as RNA, specific proteins, ligands, enzymes interleukins, or cells. Associated nano-immunotherapies include the combination of ICIs with nab-paclitaxel, nanovaccines, or commercialized nanoparticles (i.e., Onyvide®, Doxil®/Caelyx®, ADCs, Hensify®). ADCs = antibody drug conjugates, dAb = single domain antibody, fab = fragment antigen binding, ICI = immune checkpoint inhibitors, IL = interleukins, scFv = single chain variable fragment.