Immune Checkpoint Inhibitor‐Based Strategies for Synergistic Cancer Therapy

Abstract

Immune checkpoint blockade therapy (ICBT) targeting checkpoints, such as, cytotoxic T‐lymphocyte associated protein‐4 (CTLA‐4), programmed death‐1 (PD‐1), or programmed death‐ligand 1 (PD‐L1), can yield durable immune response in various types of cancers and has gained constantly increasing research interests in recent years. However, the efficacy of ICBT alone is limited by low response rate and immune‐related side effects. Emerging preclinical and clinical studies reveal that chemotherapy, radiotherapy, phototherapy, or other immunotherapies can reprogramm immunologically “cold” tumor microenvironment into a “hot” one, thus synergizing with ICBT. In this review, the working principle and current development of various immune checkpoint inhibitors are summarized, while the interactive mechanism and recent progress of ICBT‐based synergistic therapies with other immunotherapy, chemotherapy, phototherapy, and radiotherapy in fundamental and clinical studies in the past 5 years are depicted and highlighted. Moreover, the potential issues in current studies of ICBT‐based synergistic therapies and future perspectives are also discussed.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study

“…Since the efficacy of PD-1 inhibitor monotherapy in STSs is extremely low, the use of various methods to reprogram the tumor microenvironment from immune-"cold" to immune-"hot" to increase the sensitivity of PD-1 inhibitors in STS is a promising approach [18,20]. Potential mechanisms of the combination therapy of PD-1 inhibitors with cytotoxic chemotherapy agents include immunogenic tumor cell death, anti-angiogenesis, selective depletion of myeloid immunosuppressive cells, reduction of tumor-induced immune suppression, and the sensitization of tumor cells to the immune response [20,29]. One patient with angiosarcoma had a complete response (100% decrease in target lesion size), six patients had a partial response (30% and more decrease in target lesion size), seven patients had stable disease (< 20% increase and < 30% decrease in target lesion size), and 14 patients had progressive disease (20% and more increase in target lesion size).…”

“…Each line represents the change in the size of a patient's target lesion over the time of treatment. Patients with a complete or partial response are indicated in green, those with progressive disease in red, and those with stable disease in yellow Chemotherapy combined with a PD-1 inhibitor has been shown to have a beneficial effect against various other malignancies [20,25,29]. Recent clinical trials have demonstrated the efficacy and safety of the combination of the PD-1 inhibitor, pembrolizumab, and the chemotherapy drug, doxorubicin, for treating patients with advanced STS [22,30].…”

Antimicrobial Polypeptides Capable of Membrane Translocation for Treatment of MRSA Wound Infection In Vivo

“…A similar phenomenon was also reported in other polymer systems. [ 21,26 ] Interestingly, the functionalization of p(lys‐ r ‐leu) with guanidinium functional groups also led to an increase in its hemolytic activity. Considering the high hemolytic activity of random copolymers p(lys‐ r ‐leu) and p(lys(Gua)‐ r ‐leu), subsequent studies were focused on the hydrophilic and amphiphilic homopolymers instead.…”

“…This was also observed with guanidinium‐functional polycarbonates. [ 26 ] There might be other mechanisms of action involved, which would be further explored in the future. On the other hand, red fluorescence was observed in part of the bacterial cells after incubation with PLL 22 ‐Gua‐VitE for 1 h, indicating that the polymer caused membrane disruption to some extent.…”

Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy

“…The development of checkpoint inhibitors, monoclonal antibodies that bind to and block the interactions of PD-1 and CTLA-4 with their cognate ligands, inhibits this interaction stimulating tumour clearing in a subset of patients [52]. However, a significant number of cancer patients do not respond to checkpoint inhibitors, presumably because they have tumours with immunologically cold TMEs where CTLs are not activated or trafficked [53,54]. Activation of STING by CDNs has significant potential to enhance current cancer immunotherapy treatments by inducing inflammation in these immunologically cold tumours to synergize with checkpoint inhibitors.…”