Photothermal therapies to improve immune checkpoint blockade for cancer

Abstract

Immune checkpoint blockade (ICB) comprising monoclonal antibodies (mAbs) against immune 'checkpoints', such as CTLA-4 and the PD1/PDL1 axis have dramatically improved clinical outcomes for patients with cancer. However, ICB by itself has failed to provide benefit in a wide range of solid tumors, where recurrence still occurs with high incidence. These poor response rates may be due to the therapeutic shortcomings of ICB; namely, a lack of cancer-specific cytotoxicity and ability to debulk tumors. To overcome these limitations, effective ICB therapy may require the combination with other complementary therapeutic platforms. Here, we propose that photothermal therapy (PTT) is an ideal therapeutic modality for combination with ICB because it can generate both tumor-specific cytotoxicity and immunogenicity. PTT elicits these specific effects because it is a localized thermal ablation technique that utilizes light-responsive nanoparticles activated by a wavelength-matched laser. While ICB immunotherapy alone improves cancer immunogenicity but does not generate robust antitumor cytotoxicity, nanoparticle-based PTT elicits targeted and controlled cytotoxicity but sub-optimal long-term immunogenicity. Thus, the two platforms offer complementary and potentially synergistic antitumor effects, which will be detailed in this review. We highlight three classes of nanoparticles used as agents of PTT (i.e., metallic inorganic nanoparticles, carbon-based nanoparticles and organic dyes), and illustrate the potential for nanoparticle-based PTT to potentiate the effects of ICB in preclinical models. Through this discussion, we aim to present PTT combined with ICB as a potent synergistic combination treatment for diverse cancer types currently refractory to ICB as well as PTT monotherapies.

Keywords: Photothermal therapy; cancer; immune checkpoint blockade; immunotherapy; nanoparticle; thermal ablation.

Fig 1.

Representative mechanisms of action of monoclonal antibodies used in immune checkpoint blockade. (A) The binding of CTLA-4 to CD80/86 results in inhibition of T cell activity. An antibody to CTLA-4 (aCTLA-4) prevents this inhibitory interaction resulting in T cell activation. (B) The binding of PD-L1 to PD-1 on T cells results in inhibition of T cells. Monoclonal antibodies to PD-1 (aPD-1) and PD-L1 (aPD-L1) prevent this inhibitory interaction resulting in T cell activation.

Fig 2.

Schematic representation of the advantages of combination of nanoparticle-based photothermal therapy (PTT; panel A) with immune checkpoint blockade (ICB; panel B). (A) PTT can cause 1. Total tumor ablation; 2. Release of tumor-specific antigens and adjuvants by cancer cells in the tumor microenvironment (TME) that can help recruit immune cells and 3. The nanoparticles used as PTT agents can capture the released antigens and adjuvants at the TME leading to a long-lasting and improved localized immune response. (B) Addition of immune checkpoint blockade (ICB) such as aPD-1, aPD-L1 and aCTLA-4 can increase systemic immune response and produce long-term memory. Together PTT and ICB can work synergistically as an effective combination therapy for rapid tumor debulking and improved long-term tumor protection respectively.