Using nanoparticles for in situ vaccination against cancer: mechanisms and immunotherapy benefits

Abstract

Immunotherapy to treat cancer is now an established clinical approach. Immunotherapy can be applied systemically, as done with checkpoint blockade antibodies, but it can also be injected directly into identified tumors, in a strategy of in situ vaccination (ISV). ISV is designed to stimulate a strong local antitumor immune response involving both innate and adaptive immune cells, and through this generate a systemic antitumor immune response against metastatic tumors. A variety of ISVs have been utilized to generate an immunostimulatory tumor microenvironment (TME). These include attenuated microorganisms, recombinant proteins, small molecules, physical disruptors of TME (alternating magnetic and focused ultrasound heating, photothermal therapy, and radiotherapy), and more recently nanoparticles (NPs). NPs are attractive and unique since they can load multiple drugs or other reagents to influence immune and cancer cell functions in the TME, affording a unique opportunity to stimulate antitumor immunity. Here, we describe the NP-ISV therapeutic mechanisms, review chemically synthesized NPs (i.e., liposomes, polymeric, chitosan-based, inorganic NPs, etc.), biologically derived NPs (virus and bacteria-based NPs), and energy-activated NP-ISVs in the context of their use as local ISV. Data suggests that NP-ISVs can enhance outcomes of immunotherapeutic regimens including those utilizing tumor hyperthermia and checkpoint blockade therapies.

Keywords: in situ vaccination; Nanoparticles; anti-tumor immunity; combinatorial immunotherapy; therapeutic devices.

Fig.1.

NP-ISV classes and therapeutic approaches. NP-ISVs are chemically synthesized or derived from biological agents. NP-ISVs can be utilized for multiple functions such as antigen capture, immune adjuvants, gene and drug delivery, immune cell targeting, or amplified via external devices to induce local and systemic anti-tumor immunity.

Fig. 2.

Proposed mechanisms and targets of NP-ISVs in the tumor microenvironment. Typically, the antigen presenting cells (APC) can be targeted with NP-ISVs to deliver antigens, or activate pattern recognition and toll-like receptors, and CD40s. Tumor cells can also be induced to generate DAMPs and release tumor antigents with energy depositing devices for NP-ISV antigen capture. The resultant APC activation and production of tumor recognizing T-cells that leave the draining lymph nodes can attack tumor cells anywhere in the patient. The activated T-cells can also synergize with CBTs to improve therapeutic outcomes.