Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective

Abstract

The past decade has seen the materialization of immune checkpoint blockade as an emerging approach to cancer treatment. However, the overall response and patient survival are still modest. Various efforts to study the “cancer immunogram” have highlighted complex biology that necessitates a multipronged approach. This includes increasing the antigenicity of the tumor, strengthening the immune infiltration in the tumor microenvironment, removing the immunosuppressive mechanisms, and reducing immune cell exhaustion. The coordination of these approaches, as well as the ability to enhance them through delivery, is evaluated. Due to their success in multiple preclinical models, external‐stimuli‐responsive nanoparticles have received tremendous attention. Several studies report success in distantly located tumor regression, metastases, and reoccurrence in preclinical mouse models. However, clinical translation in this space remains low. Herein, the recent advancement in external‐stimuli‐responsive nanoconstruct‐synergized immune checkpoint blockade is summarized, offering an industry perspective on the limitations of current academic innovations and discussing challenges in translation from a technical, manufacturing, and regulatory perspective. These limitations and challenges will need to be addressed to establish external‐stimuli‐based therapeutic strategies for patients.

Bacteria‐Based Cancer Immunotherapy

“…Immune checkpoint blockade as the most typical clinical immunotherapy method, has displayed a series of achievements. [ 44 ] However, the high probability of immune‐related side effects such as fatigue, skin rashes, endocrine disorders, and hepatic toxicities limits its wider application. [ 45 ] To solve this problem, the key is to efficiently deliver immune checkpoint inhibitors to the tumor site and ensure an enduringly constant release of them.…”

Electromagnetic Nanomedicines for Combinational Cancer Immunotherapy

“…To the best of our knowledge, there are still no clinical evaluations of the combination of PTT, PDT, MHT or SDT with immunotherapies (Table 1). [14c] Only RT in combination with immunotherapies is currently being investigated in clinical trials, highlighting its great potential for clinical translation [112] …”

Proteolysis targeting chimera (PROTAC) for epidermal growth factor receptor enhances anti‐tumor immunity in non‐small cell lung cancer

“…Although using two antibody drugs to respectively target PD‐L1 and IDO1 is a straightforward way to promote NSCLC immunotherapy, immune‐related adverse events can also be greatly amplified. Thus, searching novel agents that can replace antibody drugs are also under active investigation (Xu et al, 2020). Comparing with genetic agents, such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated proteins and small interfering RNAs (siRNAs), small molecules are advantageous due to their superior pharmacodynamic and pharmacokinetic properties.…”