Nanoparticle mediated cancer immunotherapy
Introduction
The current surge and significance of cancer immunotherapy can be realised by the 2018 Nobel Prize in Physiology or Medicine which was jointly awarded to James P. Allison and Tasuku Honjo for the discovery of inhibition of negative immune regulation. Cancer immunotherapy exclusively employs immune cells to target specific tumor cells sparing normal tissues. In comparison to conventional cancer treatment regimens, immunotherapy is more effective owing to need for activation of only a few thousand immune cells versus action against a million tumor cells in the former. It can systematically target both primary tumor cells as well as secondary metastatic tumors. Here both the host immune cells in lymphoid tissues and antitumor immune cells in tumor microenvironment (TME) are triggered to browse and destroy tumor cells. Besides, development of memory makes it even more promising against possible recurrence. The enhancement of the monitoring activity by the immune system can lead to an increase in the defense mechanisms of other parts of the body, which can cause inflammation [1]. Moreover, certain therapies may require multiple doses to achieve concentrations that are biologically relevant in the target tissues and this may lead to toxicities. Thus, the current efforts aim for further development to enhance specificity, effectiveness and reduce toxicity.
The advent of nanotechnology holds promising opportunities for safer, specific and more effective cancer immunotherapy. The flexibility to tune biodistribution, biocompatibility, specific targeting, immunogenicity, controlled loading, sustained release kinetics, minimal degradation of bioactive molecules, controlled spatiotemporal delivery profiles along with adjuvants has embraced the nanoparticle (NP) based therapy to emerge as an efficient tool [2,3].
Section snippets
Immune surveillance and tumor immune evasion
The immune system has a stringent control over ‘self’ and ‘non-self’ antigens. However, tumor cells arise due to mutations and altered pattern of differentiation. Hence, tumor cells can be better termed as ‘abnormal self’ cells. The two arms of immune system (nonspecific innate and specific adaptive) work in synergy to eliminate the ‘non-self’/ foreign or tumor cells. The ‘self’ cells are further protected in a process called negative selection in which the B and T lymphocyte clones that
NPs in cancer immunotherapy
The leaky vasculature in the TME results in enhanced permeation and retention effect for particles with small sizes ranging in few hundred nanometers. Smaller size and larger specific surface area provide NPs with efficient loading capacities. Several reports suggest that nanomaterials prevent degradation of payload from the acidic and proteolytic TME [35]. Antigens along with adjuvants can be co-delivered in NPs to optimize the effects, resulting in a sustained depot of antigen and therefore
NPs as delivery systems for antigens
NPs offer advantages of greater cellular uptake because of the EPR effect and enhanced immune response as compared to free peptide or protein-based cancer vaccines [52]. In conventional cancer vaccines, delivery of antigens and adjuvants separately in free forms may cause immune tolerance due to lack of danger signals to DCs at appropriate time [53,54]. NPs therefore promote activation of DCs by facilitating co-encapsulation of antigens and adjuvants [55]. Molino et al. [56] reported that E2
NPs assisted adoptive T cell therapy
Adoptive T cell therapy (ACT) involves isolation of immune cells from cancer or normal patients, followed by ex vivo genetic or chemical modulation of cells and reinjection back to the patient to activate the immune system and combat cancer. Two chimeric antigen receptor (CAR)-T therapies, Yescarta and Kymriah for lymphoma and leukemia respectively have been approved by FDA. However, the ACT suffers from major challenges which includes manufacturing difficulties, the immunosuppressive TME and
NPs mediated dissolution of ECM
The extracellular matrix (ECM) which comprises of hyaluronic acid, proteoglycan, fibronectin and collagen, acts as the main barrier for the diffusion of NPs. Use of inhibitors [116,117] or solubilising agents for these components enhances penetration of NPs [118]. Co-administration of hyaluronidase with NPs helpsincrease tumor penetration. A 4T1 breast tumor bearing mice when injected with hyaluronidase intratumorally, followed by PEG coated photosensitizer chlorine 6 (Ce6) containing
NPs mediated targeting of negative immune checkpoints
The checkpoint blockade with specific mAbs facilitates inhibition of pathways that keep the duration and strength of immune system in check. Inhibition of these checkpoint molecules work by re-educating the adaptive immune system and selectively eliminating primary and metastatic tumors. CTLA4, PD1, PDL-1, PDL-2 inhibitors are the major targets for immunotherapy. PD1 is considered a better target than CTLA4 owing to mitigated side effects and higher response rates demonstrated in tumor patient
NPs as artificial antigen presenting cells
Besides the targeting, modulation and reprogramming of innate immune cells present in TME, the immunosuppression can be relieved if the cytotoxic T cell population can be increased in the TME. One such approach involves delivering artificial antigen presenting cells (aAPCs) which can activate and promote expansion of antigen specific CD8+ T cells [208]. The NPs surface are coated with MHC-I with the peptide antigen (signal 1) and the costimulatory molecules B7.1, 4-1BBL (signal 2) [209]/
Challenges in commercialization
The major goal of the research and development in area of nanomedicines for cancer lies in its translation to clinics which is justified by FDA approval [215]. However, the path to clinical translation is sturdy and requires major hurdles to be passed at every level. This is one of the major reasons that despite much research and preliminary promising preclinical results, not many nanomedicines have reached the market [216]. It is imperative to assess the fate of nanomedicines and its
Concluding remarks
A plethora of literature is available on NP mediated cancer immunotherapy. Despite such an extensive documentation available, currently there are no NPs based prophylactic or therapeutic cancer vaccines translated to clinic. To translate the efficiency of NPs as clinical drug, advanced studies solving mechanism of NPs based strategies have to be worked upon at a faster pace. Also, in vivo studies involving stringent controls are to be performed to facilitate proper assessment about safety and
Funding source
None.
Declaration of Competing Interest
Authors declare that there exists no conflict of interest.
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2022, Journal of Controlled ReleaseCitation Excerpt :Quantitative analysis of metastatic lung nodules posts DHCRJ treatments were 14.3 and 4.8-fold lower than control and DOX@HA + JQ1 group, respectively, demonstrating the activation of the systemic antitumor immune response stimulated by DHCRJ for metastasis rejection (Fig. S12, Supporting Information). Immune exhaustion (“cold”) tumor microenvironment, that is, lack of infiltrated cytotoxic T lymphocytes (CTLs) but plenty of immunosuppressive regulatory T lymphocytes (Tregs), myeloid-derived suppressive cells (MDSCs), and tumor-associated macrophages (TAMs), which lead to limit immunotherapy effectiveness in TNBC [50–53]. To investigate the antitumor immune response activation and immune resistance reduction among immune contexts after different treatments, tumor-infiltrating immune cells and cytokine production were analyzed post three times treatments.