CTLA4 antagonists in phase I and phase II clinical trials, current status  and  future perspectives for cancer therapy

ABSTRACT

Introduction: In cancer, the immune response to tumor antigens is often suppressed by inhibitors and ligands. Checkpoint blockade, considered one of the most promising frontiers for anti-cancer therapy, aims to stimulate the immune anti-cancer response. Agents such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) inhibitors offer prolonged survival with manageable side effects.

Areas covered: We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.

Expert opinion: Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance.

KEYWORDS:

• CTLA4
• antagonists
• cancer
• therapy
• checkpoint blockade
• CTLA-4 inhibitors

Article Highlights

• A better understanding of the immune system has allowed us to implement checkpoint inhibitors, such as CTLA-4 inhibitors in cancer therapy.

• Ipilimumab (CTLA-4 inhibitor) plus nivolumab (anti-PD-1 drug) joint-therapy yields positive results in clinical trials with relatively scarce side effects.

• Pembrolizumab (another anti-PD-1 drug) and ipilimumab seem to improve the outcome of patients with melanoma, but at the cost of relatively high toxicity.

• Neoadjuvant immunotherapy aims to reduce toxicity while preserving clinical efficacy; however, it requires further studies.

• Combined therapy of dabrafenib and trametinib is highly successful in the treatment of metastatic melanoma. Trials are under way to evaluate its potential synergistic value in combination with ipilimumab. Primary studies had to be discontinued due to severe side-effects.

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Acknowledgments

The authors would like to thank Mr. Mikołaj Kozłowski for his assistance in composing the figures.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was funded by the statutory budget of the Department of Physiology, Pomeranian Medical University, Szczecin, Poland.