Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

Abstract

The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune‐oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune‐oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi‐omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient‐specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune‐oncology.

Immuno-oncology therapies: a looming mid-life crisis?

“…The introduction of immune-oncology therapies for the treatment of cancer marked a shift away from targeting cells to utilising the immune system to fight cancer. These therapies have become standard of care for many different tumour types [1] as they offer the possibility of long-term survival and improved toxicity profile for cancer patients when compared to chemotherapies. The first immune-oncology therapy approved by the Australian Therapeutics and Goods Administration (TGA) was ipilimumab for treatment of melanoma in 2012 (Table 1).…”

“…Another area that has drawn a lot of attention recently are combination treatment with IO therapies. There are more than 180 phase trials examining IO therapies in combination with other IO therapies, chemotherapies, radiation therapy as well as biological therapies according to a recent review [1]. One of the first IO combination therapies to receive market authorisation was ipilimumab in combination with nivolumab for the treatment of advanced melanoma.…”

Chemo-Immunotherapy Regimes for Recurrent or Metastatic Nasopharyngeal Carcinoma: A Network Meta-Analysis and Cost-Effectiveness Analysis

“…Since the 21st century, immune checkpoint inhibitor (ICI) has gradually attracted the attention of tumor community ( Glisch et al, 2020 ; Singh et al, 2020 ; Watson et al, 2020 ; Luo et al, 2021 ). And studies have increasingly confirmed the effectiveness of these immunotherapies for malignant tumors ( Ferris et al, 2016 ; Burtness et al, 2019 ; Paz-Ares et al, 2019 ; Schmid et al, 2020 ; Colombo et al, 2021 ; Hua et al, 2021 ; Jiang et al, 2021 ; Paz-Ares et al, 2021 ; Zhou et al, 2021 ).…”

Molecular imaging of tumor-specific markers and their expression in other organs

“…Understanding the mechanisms employed by the cancer cells for immune evasion and surveillance and its targeting by monoclonal antibodies has resulted in the development of highly powerful and effective therapies for the treatment of cancers. 16 Similarly, a better understanding of the mechanism(s) employed by the tumors to induce a phenotypic change in normal fibroblasts and vascular endothelial cells to partner with tumors, may provide very effective targets for interruption of tumor growth. Imaging agents like 68 Ga-FAPI can play an important role in this direction.…”